Aminopenicillins General Statement (Monograph)

Drug class: Aminopenicillins
VA class: AM111

Introduction

Aminopenicillins are semisynthetic penicillin antibiotics that have enhanced activity against gram-negative bacteria compared with natural and penicillinase-resistant penicillins.^{61 62 68 74 76 88 575 869}

Uses for Aminopenicillins General Statement

Amoxicillin^{36 61 67 73 428 742} and ampicillin^{38 39 42 45 46 48 49 61 67 741 917 1098} are used orally for the treatment of upper and lower respiratory tract infections,^{61 67 73 428 726 732} GI tract infections,^{67 73} skin and skin structure infections,^{67 73 428 732} genitourinary tract infections,^{61 67 73 428 732} and otitis media^{61 67 428 449 728 732 742} caused by susceptible organisms. Ampicillin is used IM or IV for the treatment of meningitis, endocarditis, or severe respiratory tract, GI tract, bone and joint, or genitourinary tract infections caused by susceptible organisms.^{38 39 61 63 67 736 751 985} .

Aminopenicillins are used principally for the treatment of infections caused by susceptible and gram-negative aerobic bacilli (e.g., Haemophilus influenzae, Escherichia coli, Proteus mirabilis, Salmonella).^{36 38 39 42 45 46 48 49 61 67 72 864} Aminopenicillins also are used for the treatment of infections caused by susceptible gram-positive aerobic cocci (e.g., enterococci, Streptococcus pneumoniae, nonpenicillinase-producing Staphylococcus aureus and S. epidermidis) or gram-positive bacilli (e.g., Listeria monocytogenes).^{36 38 39 42 45 46 48 49 61 67 864} However, with the possible exception of enterococcal infections, natural penicillins generally are the penicillins of choice for the treatment of infections caused by susceptible gram-positive cocci and aminopenicillins should not be used when penicillin G or penicillin V would be effective.^{63 64 67 80 864 869 904 906}

Amoxicillin and ampicillin appear to be equally effective for the treatment of most infections when used in appropriate dosages and, except for infections caused by Salmonella or Shigella, therapeutic superiority of either agent over the other has not been definitely established.^{67 73 76 461 741 742 744 906} Some clinicians suggest that oral amoxicillin^{61 74 511 744 864 906} may be preferred to oral ampicillin, especially for the treatment of respiratory tract infections, because of more complete absorption from the GI tract, higher serum and body tissue and fluid anti-infective concentrations attained following oral administration,^{511 906 907} less frequent dosing requirements,^{74 864 906} and a lower incidence of diarrhea.^{864 906 907}

Prior to initiation of therapy with an aminopenicillin, appropriate specimens should be obtained for identification of the causative organism and in vitro susceptibility tests.^{36 38 39 42 45 46 48 49} Aminopenicillin therapy may be started pending results of susceptibility tests but should be discontinued if the causative organism is found to be resistant to the drugs.^{36 38 39 42 45 46 48 49}

Gram-positive Aerobic Bacterial Infections

Streptococcal and Staphylococcal Infections

Aminopenicillins generally are effective when used for the treatment of otitis media,⁶⁴ skin and skin structure infections,¹⁰⁸⁹ and upper and lower respiratory tract infections⁶⁴ such as tonsillitis, pharyngitis, epiglottitis, sinusitis, and acute exacerbations of chronic bronchitis caused by susceptible gram-positive aerobic cocci (e.g., S. pneumoniae, S. pyogenes [group A β-hemolytic streptococci], groups B, C, or G streptococci, nonpenicillinase-producing S. aureus and S. epidermidis).^{64 1055} However, natural penicillins generally are the drugs of choice for the treatment of infections caused by susceptible strains of S. pneumoniae,^{63 64 67 744 866 869 1071} groups A, B, C, or G streptococci,^{61 63 64 67 70 72 867 869 904 906 939 1055 1089} nonenterococcal group D streptococci,⁶³ viridans streptococci,^{63 64 869} and nonpenicillinase-producing staphylococci.^{61 64 67 70 71 867 1089}

Amoxicillin is considered by some clinicians to be a drug of choice for the empiric treatment of otitis media and many respiratory tract infections since it generally is active against both S. pneumoniae and H. influenzae, the principal etiologic agents of these infections, unless there is a high incidence of ampicillin-resistant H. influenzae in the community.^{61 72 866 917 971 1098 2343} (See Haemophilus Infections in Uses: Gram-negative Bacterial Infections.)

Amoxicillin is used for the treatment of pharyngitis or tonsillitis caused by S. pyogenes (group A β-hemolytic streptococci; GAS).^{292 375 580} The American Academy of Pediatrics (AAP),²⁹² Infectious Diseases Society of America (IDSA),⁵⁸⁰ and American Heart Association (AHA)³⁷⁵ recommend a penicillin regimen (i.e., 10 days of oral penicillin V or oral amoxicillin or a single dose of IM penicillin G benzathine) as the treatment of choice for S. pyogenes pharyngitis and tonsillitis and prevention of initial attacks (primary prevention) of rheumatic fever.^{292 375 580} Although anti-infective therapy is not indicated for most chronic carriers of S. pyogenes, the fixed combination of amoxicillin sodium and clavulanate potassium is one of several options when eradication of S. pyogenes carriage is desirable.^{292 580}

Because aminopenicillins are inactivated by staphylococcal penicillinases, the drugs are ineffective for the treatment of infections caused by penicillinase-producing S. aureus or S. epidermidis.^{36 38 39 42 45 46 48 49 61 67}

Enterococcal Infections

Ampicillin^{38 39 42 45 46 48 49 61 67 904 2254} and amoxicillin^{36 61 67 904 1070 2254} are used orally for the treatment of urinary tract infections (UTIs) caused by susceptible enterococci, including E. faecalis, E. faecium, and E. durans. Amoxicillin and ampicillin have been considered drugs of choice for the treatment of enterococcal UTIs and, because of high urinary concentrations, the drugs may be effective in these infections when used alone.^{61 67 904 2254} Aminopenicillins, usually used in conjunction with an aminoglycoside, also are used for the treatment of septicemia or endocarditis caused by enterococci.^{64 80 450 452 904 2254} In vitro studies indicate that penicillins, including aminopenicillins, are generally only bacteriostatic against enterococci when used alone;^{942 947} however, a synergistic bactericidal effect has been demonstrated against enterococci in vitro and in animal studies when an aminoglycoside is used in conjunction with a penicillin.^{80 116 942 947 1175} (See Drug Interactions: Aminoglycosides.) Therefore, a penicillin is generally used parenterally in conjunction with an aminoglycoside for the treatment of endocarditis or other severe infections caused by enterococci.^{64 80 450 452 904 947 1175}

For the treatment of enterococcal endocarditis involving native valves or prosthetic valves or other prosthetic material caused by E. faecalis, E. faecium, or other enterococcal species susceptible to both penicillin and gentamicin, AHA states that a regimen of IV ampicillin sodium or IV penicillin G sodium given in conjunction with gentamicin is a reasonable choice.^{450 452} Treatment with the penicillin and aminoglycoside generally should be continued for a minimum of 4 weeks, but patients who have had symptoms of infection for more than 3 months prior to initiation of treatment and patients with prosthetic heart valves require a minimum of 6 weeks of therapy with both drugs.⁴⁵⁰ Partly because aminopenicillins are reported to be more active in vitro than natural penicillins against enterococci, some clinicians prefer IV ampicillin instead of IV penicillin G for the treatment of infections caused by E. faecalis.^{61 63 64 67 282 864 947} However, there are no controlled studies indicating whether IV ampicillin used in conjunction with an aminoglycoside is more effective than IV penicillin G used in conjunction with an aminoglycoside for the treatment of enterococcal endocarditis.^{947 1175}

AHA recommends that treatment of endocarditis should be managed in consultation with an infectious disease expert, especially when endocarditis is caused by S. pneumoniae, β-hemolytic streptococci, enterococci, or staphylococci.^{450 452}

For additional information regarding the treatment of endocarditis, current guidelines from AHA should be consulted.^{450 452}

Listeria Infections

IV ampicillin^{61 63 67 869 904 1647 2343 2371} used alone or in conjunction with an aminoglycoside (e.g., gentamicin, kanamycin) generally is considered the treatment of choice for infections caused by Listeria monocytogenes (e.g., infections during pregnancy, granulomatosis infantiseptica, sepsis, endocarditis, meningitis, foodborne infections).^{61 63 67 298 869 904 905 1196 1197 1647 2254} IV penicillin G used alone or in conjunction with other anti-infectives may also be effective in these infections,^{64 869 1196 1197} but IV ampicillin generally is preferred.^{63 67 298 869 904 905 986 1196 1197 1198 2343 2371}

For the treatment of foodborne Listeria infections, CDC recommends use of IV ampicillin, penicillin G, or co-trimoxazole when there is invasive disease.²⁵²⁴ The incubation period following ingestion of food contaminated with Listeria (e.g., soft cheeses, unpasteurized or inadequately pasteurized milk, deli meats, hot dogs) usually is 9–48 hours for GI symptoms and 2–6 weeks for invasive disease.²⁵²⁴

Nocardiosis

Ampicillin has been used in conjunction with sulfonamides or co-trimoxazole for the treatment of infections caused by Nocardia^{† [off-label]}.^{904 1412} Co-trimoxazole or a sulfonamide alone generally is considered the treatment of choice for nocardiosis,^{869 904 1402 2254} and tetracyclines, imipenem or meropenem, cycloserine, or linezolid are alternatives.²²⁵⁴

Anthrax

Amoxicillin is used as an alternative for postexposure prophylaxis of anthrax^{† [off-label]} following exposure to Bacillus anthracis spores and amoxicillin and ampicillin are used as alternatives for the treatment of anthrax^{† [off-label]}.^{671 672 673 2502 2505 2506} Strains of B. anthracis with naturally occurring penicillin resistance have been reported rarely, and there are published reports of B. anthracis strains that have been engineered to have penicillin and tetracycline resistance as well as resistance to other anti-infectives (e.g., macrolides, chloramphenicol, rifampin).^{2499 2501 2502 2510} Therefore, it has been postulated that exposures to B. anthracis that occur in the context of biologic warfare or bioterrorism may involve bioengineered resistant strains and this concern should be considered when selecting initial therapy for the treatment of anthrax that occurs as the result of bioterrorism-related exposures or for postexposure prophylaxis following such exposures.^{2502 2506 2510}

Postexposure Prophylaxis of Anthrax

Ciprofloxacin or doxycycline generally are considered the initial drugs of choice for postexposure prophylaxis following suspected or confirmed exposure to aerosolized B. anthracis spores that occurs in the context of biologic warfare or bioterrorism.^{671 672 673 2499 2502 2505 2506 2508} If exposure is confirmed and results of in vitro testing indicate that the organism is susceptible to penicillin, then consideration can be given to changing the postexposure prophylaxis regimen to a penicillin (e.g., oral amoxicillin, oral penicillin V).^{671 672 673 2499 2502 2506 2507 2508 2509} Although monotherapy with a penicillin is not recommended for the treatment of clinically apparent inhalational anthrax when high concentrations of the organism are likely to be present, penicillins may be considered an option for anti-infective prophylaxis, including when ciprofloxacin and doxycycline are contraindicated, since the likelihood of β-lactamase induction resulting in an increase in penicillin MICs is lower when only a small number of vegetative cells are present.^{2506 2509}

The possible benefits of postexposure prophylaxis against anthrax should be weighed against the possible risks to the fetus when choosing an anti-infective for postexposure prophylaxis in pregnant women.²⁵⁰⁹ CDC and other experts state that ciprofloxacin should be considered the drug of choice for initial postexposure prophylaxis in pregnant women exposed to B. anthracis spores and that, if in vitro studies indicate that the organism is susceptible to penicillin, then consideration can be given to changing the postexposure regimen to amoxicillin.^{672 2502 2509}

Anti-infective postexposure prophylaxis should be continued until exposure to B. anthracis has been excluded.²⁴⁹⁹ Because of the possible persistence of anthrax spores in lung tissue following an aerosol exposure, CDC and other experts recommend that the total duration of anti-infective prophylaxis should be at least 60 days.^{671 672 673 2499 2502 2505 2508}

Cutaneous Anthrax

Although natural penicillins (e.g., oral penicillin V, penicillin G benzathine, IM penicillin G procaine) generally have been considered drugs of choice for the treatment of mild, uncomplicated cutaneous anthrax caused by susceptible strains of B. anthracis that occurs as the result of naturally occurring or endemic exposure to anthrax,^{2500 2501 2502} the initial drugs of choice for the treatment of cutaneous anthrax that occurs following exposure to B. anthracis spores in the context of biologic warfare or bioterrorism are ciprofloxacin or doxycycline.^{671 672 673 2506} If penicillin susceptibility is confirmed, consideration can be given to changing to a penicillin (oral amoxicillin or oral penicillin V) in infants and children, pregnant or lactating women, or when the drugs of choice are not tolerated or not available;^{671 672 673 2506} oral amoxicillin may be preferred, especially in infants and children.^{671 672 673} Use of a multiple-drug parenteral regimen is recommended for the initial treatment of cutaneous anthrax when there are signs of systemic involvement, extensive edema, or lesions on the head and neck.^{671 672 673 2500 2502 2506}

Although 5–10 days of anti-infective therapy may be adequate for the treatment of mild, uncomplicated cutaneous anthrax that occurs as the result of natural or endemic exposures to anthrax, CDC and other experts recommend that therapy be continued for 60 days if the cutaneous infection occurred as the result of exposure to aerosolized anthrax spores since the possibility of inhalational anthrax would also exist.^{671 672 673 2502 2506} Anti-infective therapy may limit the size of the cutaneous anthrax lesion and it usually becomes sterile within the first 24 hours of treatment, but the lesion will still progress through the black eschar stage despite effective treatment.^{2500 2501 2502}

Gram-negative Aerobic Bacterial Infections

Aminopenicillins are used for the treatment of a variety of infections caused by susceptible H. influenzae^{36 38 39 42 45 46 48 49 61 64 726 866 869 917 1275} and for the treatment of infections caused by susceptible Enterobacteriaceae, including susceptible strains of E. coli, P. mirabilis, Salmonella, and Shigella.^{36 38 39 42 45 46 48 49 61 64} Aminopenicillins generally are inactive against other Enterobacteriaceae (e.g., Citrobacter, Enterobacter, Klebsiella, Proteus species other than P. mirabilis, Serratia)^{61 63 116 226} and Pseudomonas,^{61 73 116 217 226 228 317} and should not be used alone in the empiric treatment of gram-negative bacterial infections that may be caused by these organisms.^{61 63 906}

Strains of E. coli resistant to aminopenicillins have been reported with increasing frequency.^{61 64 74 139} Although amoxicillin and ampicillin have been used for the treatment of uncomplicated urinary tract infections caused by susceptible E. coli or P. mirabilis,^{63 67 1007 1009 1017 1096 1127} other anti-infectives (e.g., fluoroquinolones, oral amoxicillin and clavulanate potassium, oral third generation cephalosporins) frequently are recommended for the treatment of uncomplicated urinary tract infections caused by susceptible Enterobacteriaceae in outpatients.²²⁵⁴ Some clinicians consider ampicillin, used alone or in conjunction with an aminoglycoside, the treatment of choice for infections caused by P. mirabilis.^{63 67 2254} (See Urinary Tract Infections in Uses: Gram-negative Aerobic Bacterial Infections.)

Haemophilus Infections

Aminopenicillins are used orally in infants, children, or adults for the treatment of otitis media^{61 511 728 731 741 742 744 869 906 917 1069 1098 1389 1656 1657 1661 1664 1672 2343 2361 2362} or upper and lower respiratory tract infections^{61 64 726 744 869} such as bronchopneumonia,⁷⁴⁴ sinusitis,^{744 866 867 869 979} and acute exacerbations of chronic bronchitis⁷⁴⁴ caused by susceptible H. influenzae or H. parainfluenzae. Ampicillin also is used IM or IV in conjunction with chloramphenicol for the initial treatment of meningitis caused by H. influenzae^{39 63 67 736 751 869 985 1275} (see Uses: Meningitis) or osteomyelitis, septic arthritis, cellulitis, epiglottitis, septicemia, or other serious infections caused by the organism.^{39 61 63 67 736 751 985 1275} Because of the increasing incidence of ampicillin-resistant H. influenzae and because strains of the organism resistant to chloramphenicol or co-trimoxazole or to both ampicillin and one of these drugs have been reported rarely, most clinicians state that empiric treatment of serious infections that may be caused by H. influenzae should be based on the local pattern of resistance of the organism.^{736 869 958 1275 1299 1402 1731} Co-trimoxazole is considered by many clinicians to be the drug of choice for empiric treatment of upper respiratory tract infections or bronchitis caused by H. influenzae.²²⁵⁴ For empiric treatment of serious infections caused by H. influenzae, many clinicians recommend that cefuroxime, cefotaxime, or ceftriaxone be used for empiric treatment of these infections.^{736 869 958 1275 1299 1402 2254} However, some clinicians still consider aminopenicillins the drugs of choice for the treatment of infections caused by susceptible strains of H. influenzae.^{72 866 869}

Although oral ampicillin has been used for chemoprophylaxis in day-care center contacts of children with H. influenzae type b meningitis^{† [off-label]},¹⁹⁶⁴ efficacy of anti-infective prophylaxis in preventing H. influenzae disease has not been determined to date and AAP states that, when prophylaxis is indicated, rifampin is the drug of choice.²³⁴³

Aminopenicillins are used orally for the prophylaxis^{† [off-label]} and treatment of acute exacerbations of chronic bronchitis caused by susceptible H. influenzae, H. parainfluenzae, or S. pneumoniae.^{67 431 725 726 744 793 905 975 980 1174 1192} Although some clinicians recommend the use of amoxicillin^{61 431 474} rather than ampicillin for the treatment of bronchitis because of higher serum, sputum, and tissue anti-infective concentrations attained with these aminopenicillins, controlled studies indicate that amoxicillin and ampicillin are equally effective for the treatment of acute exacerbations of chronic bronchitis.^{76 725 744 980} Studies using ampicillin, amoxicillin, tetracycline, and co-trimoxazole in the treatment of acute exacerbations of chronic bronchitis suggest that these anti-infectives are probably all equally effective.^{61 1143 1174} Therefore, most clinicians recommend basing the choice of anti-infective used for prophylaxis or treatment of acute exacerbations of chronic bronchitis on the current pattern of resistance of H. influenzae in the community and also recommend rotating the commonly used anti-infectives.^{1143 1174} Bacteriologic cures cannot be expected in all patients with chronic respiratory disease caused by H. influenzae following treatment with an aminopenicillin.^{73 866 1174} Although anti-infective therapy may decrease the severity and duration of acute episodes of bronchitis if initiated as soon as symptoms become apparent, there are no data from well-designed clinical studies to date that demonstrate whether prophylactic anti-infective therapy has any effect on the frequency of acute exacerbations or on the long-term prognosis of patients with chronic bronchitis.^{725 866 1174 1192}

Gonorrhea and Associated Infections

Amoxicillin^{36 481 844 845 850 851 852 854 1518 1519} and ampicillin^{42 45 46 48 49 481 844 854 1518 1519} were used in the past for the treatment of uncomplicated gonorrhea and disseminated gonococcal infections caused by nonpenicillinase-producing strains of N. gonorrhoeae; however, penicillins are no longer recommended for the treatment of uncomplicated or disseminated gonococcal infections and are not included in CDC guidelines for treatment of the disease.³⁴⁴

Urinary Tract Infections

Aminopenicillins are used orally for the treatment of urinary tract infections (UTIs) caused by susceptible organisms, including uncomplicated UTIs known to be caused by susceptible E. coli or P. mirabilis;^{61 64 67 73 727 866 905 1010} however, some experts consider co-trimoxazole the drug of choice for empiric treatment of uncomplicated UTIs pending results of in vitro susceptibility tests.²²⁵⁴ Aminopenicillins may be ineffective for the treatment of chronic bacteriuria or complicated UTIs because these infections generally relapse or become reinfected with bacteria resistant to the drugs (e.g., Klebsiella, Enterobacter).⁶¹ Parenteral anti-infective therapy (e.g., an aminoglycoside) is generally used for the treatment of pyelonephritis or complicated UTIs, although oral ampicillin may be used as follow-up after parenteral therapy.¹⁰⁹⁶ Although safe use of aminopenicillins during pregnancy has not been definitely established, ampicillin frequently is used for the treatment of UTIs during pregnancy.^{61 468 1145}

Oral amoxicillin has been shown to be effective for the treatment of acute, uncomplicated UTIs in some women when given as a single dose^†.^{866 905 1007 1009 1017 1071 1096 1127 1574} Although results of some controlled studies indicate that single-dose therapy with oral amoxicillin (3 g), oral sulfisoxazole (2 g), or oral co-trimoxazole (320 mg trimethoprim and 1600 mg sulfamethoxazole) is equally effective for the treatment of acute, uncomplicated UTIs in women,^{1096 1127 1145} results of other studies suggest that a single dose of amoxicillin is less effective than a single dose of co-trimoxazole in these infections.^{1411 1555} Some clinicians suggest that single-dose therapy with amoxicillin, co-trimoxazole, or sulfisoxazole may be as effective as conventional 5- to 14-day anti-infective therapy in women and is generally associated with fewer adverse effects, a reduced rate of emergence of resistant bacteria, and less of an effect on the normal GI, urinary, or perineal flora.^{1012 1017 1096 1127 1145} However, other clinicians suggest that further study is needed to establish the relative rate of relapse and recurrence of infection following use of single-dose or conventional therapy for the treatment of uncomplicated UTIs.^{1016 1411 1555 1574} If amoxicillin is administered as a single dose for the treatment of acute, uncomplicated UTIs in women, many clinicians recommend that follow-up cultures be done 3–7 days after administration of the dose.^{1017 1127} Women who have recurrence of their acute infection within 2 weeks after use of a single dose of amoxicillin may have renal infections and should receive the conventional 5–14 days of anti-infective therapy.¹¹²⁷ Single-dose anti-infective therapy is generally ineffective for the treatment of UTIs in patients with underlying urinary tract abnormalities or patients with acute pyelonephritis.^{1007 1096 1127 1411} Single-dose amoxicillin therapy should not be used for the treatment of asymptomatic bacteriuria or uncomplicated UTIs in men or in pregnant women since single-dose anti-infective regimens have not been adequately studied to date in these patients.^{1096 1127} Although results of one preliminary study in females 2–18 years of age with lower UTIs indicate that a single oral dose of amoxicillin (50 mg/kg) is as effective as 10 days of amoxicillin therapy (40 mg/kg daily given in 3 divided doses),¹⁰¹⁶ further study is needed to evaluate efficacy of single-dose anti-infective regimens for the treatment of these infections in children.^{1016 1096}

Typhoid Fever and Other Salmonella Infections

Typhoid Fever

Ampicillin^{61 64 292 867 869 879 888 890 892 911 1053 1282 2254} and amoxicillin^{†292 744 866 867 879 883 885 892 911 2254} are used in adults or children for the treatment of typhoid fever (enteric fever) caused by susceptible strains of Salmonella typhi. There is some evidence that IV ampicillin is more effective than oral ampicillin for the treatment of typhoid fever. In one controlled study in children, IV amoxicillin (100 mg/kg daily given in 3 equally divided doses) was as effective as IV ampicillin (100 mg/kg given in 4 equally divided doses) for the treatment of typhoid fever;⁸⁷⁹ however, there are no controlled studies to date comparing efficacy of oral ampicillin and oral amoxicillin in the treatment of the disease. Although the time to defervescence in typhoid fever is reportedly slower with ampicillin therapy than with chloramphenicol therapy,^{61 869 888 892 911 1282} results of a few controlled studies indicate that the response time is faster with amoxicillin than with chloramphenicol.^{883 885}

Various anti-infectives have been used for the treatment of typhoid fever, including chloramphenicol, ampicillin, amoxicillin, co-trimoxazole, cefotaxime, ceftriaxone, or fluoroquinolones.^{2304 2305 2306 2343} Multidrug-resistant strains of S. typhi (i.e., strains resistant to ampicillin, chloramphenicol, and/or co-trimoxazole) have been reported with increasing frequency, and a third generation cephalosporin (e.g., ceftriaxone, cefotaxime) or a fluoroquinolone (e.g., ciprofloxacin, ofloxacin) are considered the drugs of first choice for the treatment of typhoid fever or other severe infections known or suspected to be caused by these strains.^{2343 2354 2304 2305 2306}

The treatment of choice for chronic typhoid carriers is usually an oral fluoroquinolone (e.g., ciprofloxacin); amoxicillin or ampicillin have also been used.^{866 867 869 876 884 880 892 2254} Amoxicillin, ampicillin, or ciprofloxacin is used in conjunction with cholecystectomy for the treatment of chronic typhoid carriers with gallbladder disease.^{866 867 869 880 2343}

Salmonella Gastroenteritis

Ampicillin and amoxicillin have been used in the treatment of acute enterocolitis or uncomplicated gastroenteritis caused by Salmonella.^{867 878} The incubation period for Salmonella gastroenteritis usually is 1–3 days and this foodborne-illness usually is associated with ingestion of contaminated eggs, poultry, unpasteurized milk or juice, cheese, and raw fruits and vegetables (alfalfa sprouts, melons).²⁵²⁴ Anti-infectives generally are not indicated in the treatment of uncomplicated (noninvasive) gastroenteritis caused by Salmonella (e.g., S. enteritidis, S. typhimurium) since such therapy may prolong the period of fecal excretion of the organism and there is no evidence that is shortens the duration of the disease.^{64 866 867 869 878 892 1071 1094 2343 2524 2527} Most cases of uncomplicated gastroenteritis caused by Salmonella should be treated with fluid and electrolyte replacement as needed and generally subside spontaneously without anti-infective therapy.^{866 867 869 1071 1094 2254 2343} However, CDC, AAP, IDSA, and others recommend anti-infective therapy (in addition to fluid and electrolyte replacement) in individuals with severe Salmonella gastroenteritis and in those who are at increased risk of invasive disease.^{2343 2524 2527} These individuals include infants younger than 3–6 months of age; individuals older than 50 years of age; individuals with hemoglobinopathies, severe atherosclerosis or valvular heart disease, prostheses, uremia, chronic GI disease, or severe colitis; and individuals who are immunocompromised because of malignancy, immunosuppressive therapy, HIV infection, or other immunosuppressive illness.^{64 292 866 867 869 1094 1402 2343 2524 2527}

When an anti-infective agent is considered necessary in an individual with Salmonella gastroenteritis, CDC, AAP, IDSA, and others recommend use of ceftriaxone, cefotaxime, a fluoroquinolone (should be used in children only if the benefits outweigh the risks and no other alternative exists), ampicillin, amoxicillin, co-trimoxazole, or chloramphenicol, depending on the susceptibility of the causative organism.^{2337 2343 2524 2527} The fact that multidrug-resistant Salmonella serotype Newport have been reported with increasing frequency in the US should be considered.²⁵²⁸ During January–April 2002, 47 cases of gastritis caused by Salmonella Newport were reported to CDC; the vehicle of transmission appeared to be exposure to raw or undercooked ground beef.²⁵²⁸ These strains usually are resistant to ampicillin, amoxicillin and clavulanate potassium, cefoxitin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline and have either decreased susceptibility or resistance to ceftriaxone.²⁵²⁸

Shigella Infections

Ampicillin^{61 63 869 889 891 904 1274} has been effective when used in the treatment of GI tract infections caused by susceptible strains of Shigella. Anti-infective therapy generally is indicated in addition to fluid and electrolyte replacement for the treatment of severe cases of shigellosis^{61 869 889 911 1094 1274 2343} since anti-infectives appear to shorten the duration of diarrhea and the period of fecal excretion of Shigella.^{869 889 911 1094 2343} Although ampicillin previously was considered the anti-infective of choice for the treatment of shigellosis,^{61 63 889 904 911 1094} especially in children, strains of Sh. flexneri and Sh. sonnei resistant to ampicillin have been reported with increasing frequency.^{61 74 869 881 911} Therefore, fluoroquinolones, ceftriaxone, or co-trimoxazole are considered the anti-infectives of choice for the treatment of shigellosis when the susceptibility of the isolate is unknown,^{61 881 869 1094 2254 2343} especially in areas where ampicillin-resistant strains of Shigella have been reported.^{869 881 2343}

Amoxicillin should not be used in the treatment of shigellosis^{61 744 906} because it is less active in vitro on a weight basis than ampicillin against susceptible strains of Shigella^{229 744} and has been ineffective when used in the treatment of infections caused by this organism.^{64 73 461 869 877} The ineffectiveness of amoxicillin in the treatment of shigellosis may partly result from low intraluminal (GI) concentrations of amoxicillin attained following oral administration.^{744 877 906}

Helicobacter pylori Infection

Amoxicillin is used in combination with clarithromycin and lansoprazole or omeprazole (triple therapy) for the treatment of Helicobacter pylori infection in patients with duodenal ulcer disease (active or 1-year history of duodenal ulcer).^{36 2283 2284 2288 2289 2290 2291} Amoxicillin also is used in combination with lansoprazole (dual therapy) for the treatment of H. pylori infection and duodenal ulcer disease in patients who are either allergic to or intolerant of clarithromycin or in whom clarithromycin resistance is known or suspected.^{36 2283 2284} Amoxicillin also has been used in other multiple drug regimens^† for the treatment of H. pylori infection and peptic ulcer disease.^{1845 1848 1849 1850 1851 1852 1853 1854 1855 1856 1857 1858 1859 1860 1861 1862 1863 2114 2209 2210 2211 2212 2213 2214 2215 2216 2217 2218 2219 2221 2222 2255 2256 2257 2258 2259 2260 2261 2284 2291} Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of duodenal and gastric ulcers;^{1845 1848 1851 1854 1864 1865 1866 1867 1868 1869 2112 2114 2209 2214 2255 2256 2257 2258} long-term H. pylori infection also has been implicated as a risk factor for gastric cancer.^{1848 1867 1870 1871 1872 1873 1874 1875 1876 1877 1878 2114 2209 2258}

Conventional antiulcer therapy with H₂-receptor antagonists, proton-pump inhibitors, sucralfate, and/or antacids heals ulcers but generally is ineffective in eradicating H. pylori, and such therapy is associated with a high rate of ulcer recurrence (e.g., 60–100% per year).^{1845 1854 1869 2114 2255 2256 2258} The American College of Gastroenterology (ACG), the National Institutes of Health (NIH), and most clinicians recommend that all patients with initial or recurrent duodenal or gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection.^{2224 2255 2256 2257 2258} Although 3-drug regimens consisting of a bismuth salt (e.g., bismuth subsalicylate) and 2 anti-infective agents (e.g., tetracycline or amoxicillin plus metronidazole) administered for 10–14 days have been effective in eradicating the infection, resolving associated gastritis, healing peptic ulcer, and preventing ulcer recurrence in many patients with H. pylori-associated peptic ulcer disease,^{1845 1848 1849 1851 1852 1853 1863 1868 1879 1880 1881 1896 2112 2114 2209 2214 2215 2218 2255 2256 2257 2258 2259 2275 2291} current evidence principally from studies in Europe suggests that 1 week of such therapy provides H. pylori eradication rates comparable to those of longer treatment periods.^{2256 2257 2258} Other regimens that combine one or more anti-infective agents (e.g., clarithromycin, amoxicillin) with a bismuth salt and/or an antisecretory agent (e.g., lansoprazole, omeprazole, H₂-receptor antagonist) also have been used successfully for H. pylori eradication,^{36 1845 1848 1849 1857 1858 1859 1860 1861 1881 1882 2114 2209 2210 2218 2219 2221 2222 2223 2224 2225 2226 2255 2256 2257 2258 2260 2261 2283 2284 2288 2289 2290 2291} and the choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient’s prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.^{2114 2224 2256 2258 2262 2275}

Current evidence suggests that inclusion of a proton-pump inhibitor (e.g., omeprazole, lansoprazole) in anti-H. pylori regimens containing 2 anti-infectives enhances effectiveness, and limited data suggest that such regimens retain good efficacy despite imidazole (e.g., metronidazole) resistance.^{2256 2258 2291} Therefore, the ACG and many clinicians^{2258 2259 2260 2291} recommend 1 week of therapy with a proton-pump inhibitor and 2 anti-infective agents (usually clarithromycin and amoxicillin or metronidazole), or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor, for treatment of H. pylori infection.^{2256 2258 2260 2291}

Other Gram-negative Aerobic Bacterial Infections

Ampicillin is considered the drug of choice for the treatment of infections caused by Eikenella corrodens^†.²²⁵⁴ Although natural penicillins are considered the drugs of choice for the treatment of infections caused by Pasteurella multocida^†, amoxicillin and clavulanate potassium, and ampicillin sodium and sulbactam sodium are considered alternatives.²²⁵⁴

Anaerobic and Mixed Aerobic-Anaerobic Bacterial Infections

Amoxicillin and ¹⁴³⁰ ampicillin^{61 472 856 857 1430} have been used for the treatment of anaerobic and mixed aerobic-anaerobic bacterial infections including biliary tract infections^{61 472} or gynecologic and obstetric infection such as acute pelvic inflammatory disease (PID)^{856 857} and postpartum infections^†.^{856 857} However, aminopenicillins should not be used alone for the treatment of these infections, especially when Bacteroides fragilis may be present.^{61 856 1430}

Meningitis

IV ampicillin is used in adults, children, or neonates for the treatment of meningitis caused by susceptible H. influenzae,^{39 736 751 985 1181 1182} S. pneumoniae,^{736 751} or N. meningitidis.^{39 736 751} IV ampicillin also is used alone or in conjunction with an aminoglycoside (e.g., gentamicin) for the treatment of meningitis caused by L. monocytogenes^†.^{61 986 1196 1197 2254}

Empiric Treatment of Meningitis

Pending results of CSF culture and in vitro susceptibility testing, the most appropriate anti-infective regimen for empiric treatment of suspected bacterial meningitis should be selected based on results of CSF Gram stain and antigen tests, age of the patient, the most likely pathogen(s) and source of infection, and current patterns of bacterial resistance within the hospital and local community.^{2249 2298 2300 2301 2307 2343} When results of culture and susceptibility tests become available and the pathogen is identified, the empiric anti-infective regimen should be modified (if necessary) to ensure that the most effective regimen is being administered.^{2249 2298 2301 2307}

Bacterial meningitis in neonates usually is caused by S. agalactiae (group B streptococci), L. monocytogenes, or aerobic gram-negative bacilli (e.g., E. coli, K. pneumoniae).^{2249 2250 2254 2298 2299 2300 2301 2343} AAP recommends that neonates 4 weeks of age or younger with suspected bacterial meningitis receive an empiric regimen of IV ampicillin and an aminoglycoside pending results of CSF culture and susceptibility testing.²³⁴³ Alternatively, neonates can receive an empiric regimen of IV ampicillin and IV cefotaxime or IV ceftazidime with or without gentamicin.^{2249 2250 2254 2298 2299 2300 2301 2343} Because frequent use of cephalosporins in neonatal units may result in rapid emergence of resistant strains of some gram-negative bacilli (e.g., Enterobacter cloacae, Klebsiella, Serratia), AAP cautions that cephalosporins should be used for empiric treatment of meningitis in neonates only if gram-negative bacterial meningitis is strongly suspected.²³⁴³ While S. pneumoniae is relatively rare in neonates, consideration should be given to including IV vancomycin in the empiric regimen if S. pneumoniae is suspected.²³⁴³ Because premature, low-birthweight neonates are at increased risk for nosocomial infection caused by staphylococci or gram-negative bacilli, some clinicians suggest that these neonates receive an empiric regimen of IV ceftazidime and IV vancomycin.²³⁰¹

In infants beyond the neonatal stage who are younger than 3 months of age, bacterial meningitis may be caused by S. agalactiae, L. monocytogenes, H. influenzae, S. pneumoniae, N. meningitidis, or aerobic gram-negative bacilli (e.g., E. coli, K. pneumoniae).^{2249 2250 2298 2299 2300 2301 2343} The empiric regimen recommended for infants in this age group is IV ampicillin and either IV ceftriaxone or IV cefotaxime.^{2249 2250 2298 2299 2300 2301 2343} Consideration should be given to including IV vancomycin in the empiric regimen if S. pneumoniae is suspected.^{2307 2343}

In children 3 months through 17 years of age, bacterial meningitis usually is caused by N. meningitidis, S. pneumoniae, or H. influenzae, and the most common cause of bacterial meningitis in adults 18–50 years of age is N. meningitidis or S. pneumoniae.^{2249 2254 2298 2300 2301 2343} Some clinicians recommend that children 3 months through 17 years of age and adults 18–50 years of age receive IV ceftriaxone or IV cefotaxime for empiric therapy of suspected bacterial meningitis;^{2249 2254 2298 2299 2300 2301 2343} an alternative empiric regimen in children 3 months through 17 years of age is IV ampicillin and IV chloramphenicol.^{2249 2298} In addition, because of the increasing prevalence of penicillin-resistant S. pneumoniae that also are resistant to or have reduced susceptibility to cephalosporins, AAP and others recommend that the initial empiric cephalosporin regimen include IV vancomycin (with or without rifampin) pending results of in vitro susceptibility tests;^{2250 2254 2300 2307 2308 2309 2343} vancomycin and rifampin should be discontinued if the causative organism is found to be susceptible to the cephalosporin.^{2254 2307 2309} While L. monocytogenes meningitis is relatively rare in this age group, the empiric regimen should include ampicillin if L. monocytogenes is suspected.^{2298 2299}

In adults older than 50 years of age, bacterial meningitis usually is caused by S. pneumoniae, L. monocytogenes, N. meningitidis, or aerobic gram-negative bacilli, and the empiric regimen recommended for this age group is IV ampicillin given in conjunction with IV cefotaxime or IV ceftriaxone.^{2298 2299 2301} Because of the increasing prevalence of penicillin-resistant S. pneumoniae, some clinicians suggest that the empiric regimen also should include IV vancomycin.^{2301 2308}

Meningitis Caused by Haemophilus influenzae

AAP suggests that children with meningitis possibly caused by H. influenzae can receive an initial treatment regimen of ceftriaxone, cefotaxime, or a regimen of ampicillin given in conjunction with chloramphenicol;²³⁴³ some clinicians prefer ceftriaxone or cefotaxime for initial treatment of meningitis caused by susceptible H. influenzae since these cephalosporins are active against both penicillinase-producing and nonpenicillinase-producing strains.^{2249 2301 2254 2298} Because of the prevalence of ampicillin-resistant H. influenzae,^{1299 1731 2343} ampicillin should not be used alone for empiric treatment of meningitis when H. influenzae may be involved.²³⁴³ The incidence of H. influenzae meningitis in the US has decreased considerably since H. influenzae type b conjugate vaccines became available for immunization of infants.^{2299 2300 2343}

Meningitis Caused by Neisseria meningitidis

While both IV ampicillin and IV penicillin G may be used for the treatment of meningitis caused by N. meningitidis,^{2298 2300 2301} AAP and other clinicians suggest that penicillin G is the drug of choice for the treatment of these infections and ceftriaxone and cefotaxime are acceptable alternatives.^{2301 2343}

Meningitis Caused by Streptococcus agalactiae

For the initial treatment of meningitis or other severe infection caused by S. agalactiae (group B streptococci), a regimen of IV ampicillin or IV penicillin G given in conjunction with an aminoglycoside is recommended.^{2298 2301 2343} Some clinicians suggest that ampicillin is the drug of choice for the treatment of group B streptococcal meningitis and that an aminoglycoside (IV gentamicin) should be used concomitantly in the first 72 hours until in vitro susceptibility testing is completed and a clinical response if observed; thereafter, ampicillin can be given alone.²³⁰¹

Meningitis Caused by Listeria monocytogenes

The optimal regimen for the treatment of meningitis caused by Listeria monocytogenes has not been established.^{2343 2371} AAP and other clinicians generally recommend that meningitis or other severe infection caused by L. monocytogenes be treated with a regimen of IV ampicillin used in conjunction with an aminoglycoside (usually gentamicin);^{2254 2301 2343 2371} alternatively, co-trimoxazole or a regimen of penicillin G used in conjunction with gentamicin can be used.^{2254 2298 2301 2371}

Otitis Media

Acute Otitis Media

Amoxicillin and amoxicillin and clavulanate potassium are used in the treatment of acute otitis media (AOM) and are considered the drugs of choice for uncomplicated AOM.^{683 1437 1656 1659 2180 2310 2311 2361 2362 2389 2398 2418 2429 2430 2432 2434 2450}

AOM is the most frequently diagnosed bacterial infection in children, and 65–95% of children will have at least one episode of AOM by 3 years of age.^{2311 2394 2395 2362 2402 2413 2419 2432} Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the bacteria most frequently recovered from middle ear fluid of patients with AOM; S. pyogenes and S. aureus also are recovered rarely.^{683 2180 2361 2362 2398 2402 2404 2405 2426 2427 2432 2440 2441 2451 2478 2482} In addition, there is evidence that respiratory viruses (e.g., respiratory syncytial virus, rhinoviruses, influenza virus, parainfluenza virus, enteroviruses) may be present either alone or in combination with bacterial pathogens and may play a role in the etiology and pathogenesis of AOM in some patients.^{683 2310 2361 2362 2409 2410 2432 2458 2459 2482}

Diagnosis and Management Strategies for AOM

AAP and American Academy of Family Physicians (AAFP) first issued evidence-based clinical practice guidelines for the diagnosis and management of AOM in 2004.⁶⁸³ In 2013, AAP revised and updated those guidelines after comprehensive reviews of more recent published evidence.⁶⁸³ The 2013 AAP evidence-based clinical practice guidelines provide recommendations for the diagnosis and management of uncomplicated AOM, including recurrent AOM, in children 6 months through 12 years of age and apply only to otherwise healthy children who do not have underlying conditions that may alter the natural course of AOM (e.g., tympanostomy tubes, cleft palate, genetic conditions with craniofacial abnormalities such as Down syndrome, immunodeficiencies, cochlear implants).⁶⁸³ These AAP guidelines should be consulted for additional information on diagnosis and management of AOM.⁶⁸³

Accurate diagnosis of AOM is critical for clinical decision-making since it avoids unnecessary treatment.⁶⁸³ AOM involves the presence of fluid in the middle ear accompanied by a wide spectrum of signs or symptoms of acute local or systemic illness (e.g., otalgia, otorrhea, hearing loss, swelling around the ear, vertigo, nystagmus, tinnitus, fever, irritability, headache, diarrhea, lethargy, anorexia, vomiting).^{683 2362 2404 2408 2419 2432} Older children with AOM usually have a history of rapid onset of ear pain,⁶⁸³ but preverbal infants and young children may have mild or nonspecific symptoms that overlap with those of an upper respiratory tract illness.⁶⁸³

Current AAP evidence-based clinical practice guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that clinicians should diagnose AOM in children who present with moderate to severe bulging of the tympanic membrane or new onset of otorrhea not due to acute otitis externa.⁶⁸³ A diagnosis of AOM also should be made in children who present with mild bulging of the tympanic membrane and recent (less than 48 hours) onset of ear pain (holding, tugging, rubbing of the ear in a nonverbal child) or intense erythema of the tympanic membrane.⁶⁸³ These guidelines state that a diagnosis of AOM should not be made in children who do not have middle ear effusion (MEE) based on pneumatic otoscopy and/or tympanometry.⁶⁸³

Current AAP evidence-based clinical practice guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that management of AOM should include an assessment of pain and, if ear pain is present, the clinician should recommend treatment to reduce the pain.⁶⁸³ AOM-associated pain can be substantial during the first few days of illness and often persists longer in young children.⁶⁸³ AAP states that pain management, especially during the first 24 hours of an AOM episode, should be addressed regardless of the use of anti-infectives.⁶⁸³ Treatment for otalgia should be selected based on a consideration of the benefits and risks and, whenever possible, incorporate parent and/or caregiver and patient preference.⁶⁸³ Acetaminophen or ibuprofen are effective for mild to moderate pain, readily available, and usually the mainstay of pain management for AOM.⁶⁸³

Up to 60–80% of cases of AOM resolve spontaneously within 7–14 days,^{2310 2311 2361 2362 2399 2404 2419 2465} and routine administration of anti-infectives is not considered necessary for the treatment of all cases of AOM.^{683 2399 2404 2408 2417 2425 2460 2461 2463 2464 2465 2469} Some clinicians have recommended that all cases of AOM be treated with an appropriate anti-infective regimen to facilitate resolution of the primary infection and associated symptoms and prevent suppurative complications or other sequelae, and state that judicious use of anti-infectives in the management of otitis media involves accurately diagnosing AOM and distinguishing AOM (which should be treated with anti-infectives) from otitis media with effusion (which is not usually treated with anti-infectives),^{2180 2184 2408 2413 2415 2416 2417 2419 2422 2424 2433 2435 2462 2482} However, for the majority of patients with uncomplicated AOM, anti-infective therapy appears to provide only minimal benefits in terms of resolution of the acute symptoms of infection (e.g., pain) and the proposed benefits of such therapy in terms of time to bacteriologic or clinical resolution of AOM or in terms of long-term consequences of otitis media (e.g., persistence of MEE, recurrence of AOM, hearing loss, need for adenoidectomy or insertion of tympanostomy tubes, mastoiditis) have never been substantiated in well-designed, placebo-controlled studies.^{683 2425 2460 2463 2464 2465 2466} In addition, there is evidence that overuse of anti-infectives, including overuse in the treatment of AOM, contributes to emergence of resistant bacteria (e.g., multidrug-resistant S. pneumoniae).^{2460 2463 2465 2467 2476} Based on these considerations, many clinicians now recommend a management strategy for AOM that involves use of symptomatic care with analgesics and close observation via telephone contact or office visits for the majority of patients with uncomplicated AOM and use of anti-infectives only in those who do not have symptomatic improvement within 24–72 hours after diagnosis and in those who appear least likely to have spontaneous resolution and most likely to have poor outcomes (e.g., more acutely ill, those with 3 or more episodes of AOM in the past 18 months, history of serous otitis or tympanostomy tubes).^{683 2460 2466 2469}

Current AAP evidence-based clinical practice guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age include an initial management option of observation with close follow-up without initial use of anti-infectives in certain selected children with uncomplicated AOM based on age, illness severity, and assurance of follow-up.⁶⁸³ The recommendation for initial observation with close follow-up in select children provides an opportunity for the patient to improve without anti-infectives and is based on results of randomized, controlled studies with limitations and consideration of the benefits and risks of such a strategy.⁶⁸³

Current AAP guidelines state that anti-infective treatment should be initiated in children 6 months of age or older who have AOM (bilateral or unilateral) with severe signs or symptoms (i.e., moderate or severe otalgia, otalgia for at least 48 hours, or temperature 39°C or higher) and in children 6 through 23 months of age who have nonsevere bilateral AOM without signs or symptoms (i.e., mild otalgia for less than 48 hours and temperature less than 39°C).⁶⁸³ However, these guidelines state that a management strategy of either initiation of anti-infective treatment or observation with close follow-up can be used in children 6 through 23 months of age who have nonsevere unilateral AOM without severe signs or symptoms (i.e., mild otalgia for less than 48 hours, temperature less than 39°C) and in children 24 months of age or older with nonsevere AOM (bilateral or unilateral) without severe signs or symptoms (i.e., mild otalgia for less than 48 hours, temperature less than 39°C).⁶⁸³ The strategy of observation with close follow-up should be based on joint decision-making between the clinician and the parent and/or caregiver and must include a mechanism that ensures follow-up and initiation of anti-infective therapy if AOM worsens or fails to improve within 48–72 hours after symptom onset.⁶⁸³

If the initial management strategy was observation with close follow-up, anti-infective therapy should be initiated if symptoms worsen or there is no improvement within 48–72 hours after onset of symptoms.⁶⁸³ If the initial management strategy was anti-infective treatment, consideration should be given to changing the anti-infective regimen if symptoms worsen or fail to respond within 48–72 hours after initiation of treatment.⁶⁸³ (See Anti-infectives for AOM after Initial Treatment Failure under Uses: Otitis Media.)

After the patient has shown clinical improvement, follow-up is based on the usual clinical course of AOM.⁶⁸³ Persistent MEE is common after resolution of acute symptoms of AOM and should not be viewed as requiring active therapy.⁶⁸³ (See Otitis Media with Effusion under Uses: Otitis Media.)

Anti-infectives for Initial Treatment of AOM

When anti-infectives are indicated for treatment of AOM, the initial anti-infective agent usually is selected empirically based on efficacy against the most probable bacterial pathogens.^{2178 2402 2404 2413 2419 2433 2440 2479} Other considerations in the choice of an anti-infective for initial empiric treatment of AOM include pharmacokinetic data related to distribution of the drug into middle ear fluid, compliance issues related to patient acceptance of dosage formulation and dosage schedule, adverse effects profile, and cost considerations;^{2181 2361 2362 2398 2399 2404 2405 2407 2443 2446 2449 2479} drug susceptibility patterns in the local community can be considered, but local surveillance data are not necessarily representative of AOM isolates found in otherwise healthy patients.²³⁹⁸

Amoxicillin usually is considered the drug of first choice for initial empiric treatment of AOM, unless the infection is suspected of being caused by β-lactamase-producing bacteria resistant to the drug, in which case amoxicillin and clavulanate potassium is recommended for initial treatment.^{683 1656 1657 1661 1664 2180 2181 2250 2310 2311 2343 2361 2362 2398 2400 2433 2446 2479 2482} The fact that multidrug-resistant S. pneumoniae are being reported with increasing frequency should be considered when selecting an anti-infective agent for empiric treatment of AOM.^{2181 2398 2403 2414 2428 2436 2437 2441 2455 2456 2479 2482 2485} However, AAP, AAFP, CDC, and others state that, despite the increasing prevalence of multidrug-resistant S. pneumoniae and presence of β-lactamase-producing H. influenzae or M. catarrhalis in many communities, amoxicillin remains the anti-infective of first choice for treatment of uncomplicated AOM since amoxicillin is highly effective, has a narrow spectrum of activity, is well distributed into middle ear fluid, is well tolerated, has an acceptable taste, and is inexpensive.^{683 2178 2343 2398 2403 2404 2413 2414 2433 2434 2476 2479 2482} Amoxicillin (when given in dosages of 80–90 mg/kg daily in 2 divided doses) usually is effective in the treatment of AOM caused by S. pneumoniae, including infections involving strains with intermediate resistance to penicillins, and also usually is effective in the treatment of AOM caused by most strains of H. influenzae.^{683 2398 2403 2433 2475} Because S. pneumoniae is the most frequent cause of AOM (25–50% of cases) and because AOM caused by S. pneumoniae is more likely to be severe and less likely to resolve spontaneously than AOM caused by H. influenzae or M. catarrhalis, it has been suggested that it may be more important to choose an empiric anti-infective based on its activity against S. pneumoniae rather than its activity against other possible pathogens.^{2362 2398 2403 2414}

Various other anti-infectives, including oral cephalosporins (cefaclor, cefdinir, cefixime, cefpodoxime proxetil, cefprozil, ceftibuten, cefuroxime axetil, cephalexin), parenteral ceftriaxone, oral macrolides (azithromycin, clarithromycin), and oral co-trimoxazole, have been used in the treatment of AOM.^{683 1656 1659 1661 1664 2178 2180 2181 2250 2310 2311 2343 2361 2362 2403 2446 2452 2471 2477 2479 2482} However, these usually are considered alternatives and are used when amoxicillin or amoxicillin and clavulanate potassium cannot be used or are ineffective.⁶⁸³

Current AAP evidence-based guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that high-dose amoxicillin (80–90 mg/kg daily in 2 divided doses) should be used for initial treatment when a decision has been made to use anti-infective therapy and the child has not received amoxicillin within the past 30 days or does not have concurrent purulent conjunctivitis or is not allergic to penicillin.⁶⁸³ These guidelines state that high-dose amoxicillin and clavulanate (90 mg/kg of amoxicillin and 6.4 mg/kg of clavulanate daily in 2 divided doses) should be used if the child received amoxicillin within the past 30 days or has concurrent purulent conjunctivitis or has a history of recurrent AOM unresponsive to amoxicillin.⁶⁸³ These AAP guidelines state that the preferred alternatives for initial treatment of AOM in penicillin-allergic patients are oral cephalosporins (cefdinir, cefpodoxime proxetil, cefuroxime axetil) or parenteral ceftriaxone.⁶⁸³

Results of controlled clinical studies indicate that 10-day regimens of most oral anti-infectives used in the empiric treatment of AOM are equally effective, and there is no evidence that the overall response rate to anti-infectives with a broader spectrum of activity (e.g., second and third generation cephalosporins) is any better than that reported with amoxicillin or amoxicillin and clavulanate potassium.^{2178 2180 2184 2393 2362 2403 2429 2430 2438 2439 2445 2452 2470 2471 2479} However, there is evidence that some anti-infectives (e.g., cefaclor, cefprozil, azithromycin) may be less effective than some other available agents for the treatment of AOM when β-lactamase-producing bacteria are present^{1656 1657 1659 1661 1664 1673 2076 2310 2457 2479 2481 2482} and some (e.g., cefixime, ceftibuten) may be less effective than some other available agents for the treatment of when S. pneumoniae with reduced susceptibility to penicillin are present.^{2361 2414 2442 2454 2456 2457 2476 2482}

Duration of Initial Treatment of AOM

The optimal duration of therapy for AOM is uncertain.⁶⁸³ Anti-infectives traditionally have been administered for 7–10 days for the treatment of AOM,^{2178 2343 2419 2422 2450} but shorter durations of treatment also have been used.^{2416 2418 2419 2422} Current AAP evidence-based guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that a 10-day regimen of an appropriate oral anti-infective is recommended for the treatment of AOM in children younger than 2 years of age and in those with severe symptoms.⁶⁸³ These guidelines state that a 7-day regimen of an appropriate oral anti-infective may be as effective as a 10-day regimen in children 2–5 years of age with mild to moderate AOM, and a 5- to 7-day regimen of an appropriate oral anti-infective may be adequate in children 6 years of age or older with mild to moderate AOM.⁶⁸³

Some clinicians suggest that short durations of treatment (i.e., 5 days or less) can be effective and may increase compliance, decrease the risk of emergence of resistant bacteria, decrease the risk of adverse effects, and decrease costs.^{2416 2418 2419 2422} There is some evidence from controlled clinical studies in pediatric patients with AOM that the clinical response rate to 5-day regimens of certain oral cephalosporins (e.g., cefaclor,²³⁹⁶ cefdinir,²⁴⁹⁶ cefpodoxime proxetil,²³⁸⁹ cefprozil,^{2395 2397} cefuroxime axetil^{2453 2485} ) is similar to that of 10-day regimens of oral cephalosporins, amoxicillin, or amoxicillin and clavulanate potassium.^{2394 2396 2453 2485} Short-term regimens of amoxicillin or amoxicillin and clavulanate potassium^† also have been used in a limited number of patients for the treatment of AOM; however, efficacy of these shorter regimens compared with the usual 10-day regimens of amoxicillin or amoxicillin and clavulanate has not been fully determined to date.^{2311 2394 2418 2394 2495}

While some clinicians suggest that 5-day regimens can be considered for adults and children 2 years of age or older with mild, uncomplicated AOM,^{543 2076} further study is needed to more fully evaluate efficacy of short-term regimens in infants and young children since studies to date have included only a limited number of children younger than 2 years of age.^{683 2076 2311 2388 2394 2396 2397 2416 2417 2418 2419} These clinicians state that short-term anti-infective regimens (i.e., 5 days or less) may not be appropriate for the treatment of AOM in children younger than 2 years of age or for patients with underlying disease, craniofacial abnormalities, recurrent or persistent AOM, or perforated tympanic membranes and spontaneous purulent drainage.^{2311 2388 2394 2397 2416 2417 2418 2419 2422}

Anti-infectives for AOM after Initial Treatment Failure

Consideration can be given to changing the anti-infective regimen in children who do not have clinical improvement within 48–72 hours after the initial anti-infective regimen is started.⁶⁸³ Current AAP evidence-based clinical practice guidelines for diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that patients who fail to respond to an initial regimen of high-dose amoxicillin (80–90 mg/kg daily in 2 divided doses) should be retreated with high-dose amoxicillin and clavulanate potassium (90 mg/kg of amoxicillin and 6.4 mg of clavulanate daily in 2 divided doses).⁶⁸³ Those who fail to respond to an initial regimen of high-dose amoxicillin and clavulanate potassium or an initial regimen of an appropriate oral cephalosporin (cefdinir, cefpodoxime proxetil, cefuroxime axetil) should be treated with parenteral ceftriaxone (50 mg/kg daily for 3 days).⁶⁸³

Clindamycin (30–40 mg/kg daily in 3 divided doses) can be used (with or without a third generation cephalosporin) as an alternative for the treatment of AOM in patients who fail to respond to an initial anti-infective regimen.⁶⁸³ Although clindamycin may be effective for penicillin-resistant S. pneumoniae, it may not be effective against multidrug-resistant S. pneumoniae and lacks efficacy against H influenzae.⁶⁸³ If clindamycin is used for retreatment, concomitant use of an anti-infective active against H. influenzae and M. catarrhalis (e.g., cefdinir, cefixime, cefuroxime) should be considered.⁶⁸³

Because of reported resistance in S. pneumoniae, AAP states that co-trimoxazole should not be used as an alternative for the treatment of AOM in patients who fail to improve while receiving amoxicillin.⁶⁸³

Primary treatment failure of AOM occurs most frequently in children younger than 2 years of age.^{2401 2412 2420} While primary treatment failure and persistent AOM may be the result of infection with bacteria resistant to the anti-infective administered (e.g., penicillin-resistant S. pneumoniae, β-lactamase-producing H. influenzae),^{2181 2401 2405 2412 2413 2420 2427 2432} many cases appear to be related to other factors since results of tympanocentesis indicate that the causative organism(s) often is susceptible in vitro to the primary treatment regimen or, in some cases, no bacteria are isolated.^{2412 2420 2421 2432} Patients with AOM who fail to respond to an initial anti-infective regimen often also fail to respond to a subsequent regimen, regardless of the anti-infective used.^{2398 2421}

If AOM persists after a series of anti-infective regimens, tympanocentesis should be considered and culture of middle ear fluid performed to make a bacteriologic diagnosis and obtain in vitro susceptibility test results.⁶⁸³ If tympanocentesis is not available, a regimen of oral clindamycin with or without an anti-infective to provide coverage against H. influenzae and M. catarrhalis (e.g., cefdinir, cefixime, cefuroxime) may be considered.⁶⁸³ Consultation with a pediatric medical subspecialist (e.g., otolaryngologist) for possible tympanocentesis, drainage, and culture and consultation with an infectious disease expert before use of unconventional anti-infectives should be considered.⁶⁸³

Recurrent AOM

Current AAP evidence-based clinical practice guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that anti-infective prophylaxis should not be prescribed to reduce the frequency of episodes of AOM in children with recurrent AOM.⁶⁸³ Recurrent AOM is defined as 3 or more episodes of AOM within a 6-month period or 4 or more episodes of AOM within a 12-month period that includes at least 1 episode in the preceding 6 months.⁶⁸³ About 50% of children younger than 2 years of age who are treated for AOM will have a recurrence within 6 months.⁶⁸³ Winter season, male gender, and passive exposure to tobacco smoke have been associated with an increased likelihood of AOM recurrence.⁶⁸³ Other risk factors for recurrence include AOM symptoms lasting more than 10 days, a family history of the infection, group day-care outside the home during the first 2 years of life, and use of bottles or pacifiers.^{683 2362 2419 2478} There is some evidence that breast-feeding for at least 4–6 months reduces episodes of AOM and recurrent AOM.^{683 2362 2478}

Anti-infectives (e.g., amoxicillin, sulfisoxazole) have been administered as long-term prophylaxis or suppressive therapy in an attempt to prevent recurrence of AOM^{†2343 2419 2423 2473 2478 2482 2486 2489 2490 2491 2492 2493} or have been administered intermittently as prophylaxis^† at the first sign of an upper respiratory tract infection in children with a history of recurrent AOM.^{2417 2419 2473 2478 2492} Although it has been suggested and there is some evidence that anti-infective prophylaxis may decrease the incidence of new symptomatic episodes of AOM in some children with a history of recurrent AOM,^{683 2362 2403 2408 2419 2422 2423 2432 2490 2491 2492 2493} such prophylaxis is not routinely recommended.^{683 2408 2419 2422 2478 2486} Results of a pooled analysis indicate that use of anti-infective prophylaxis results in an average decrease of only 0.11 episodes of AOM per patient per month (slightly more than 1 episode per year).²⁴²³ In addition, anti-infective prophylaxis does not provide any long-lasting benefit since any decrease in AOM episodes occurs only while prophylaxis is being given.⁶⁸³ AAP states that anti-infective prophylaxis is not appropriate for children with long-term MEE or for children with infrequent episodes of AOM.⁶⁸³ The small reduction in frequency of AOM must be weighed against the cost and potential adverse effects of anti-infective prophylaxis (e.g., allergic reactions, GI effects such as diarrhea)⁶⁸³ and concerns that prophylaxis may promote emergence of resistant bacteria, including multidrug-resistant S. pneumoniae, or alter nasopharyngeal flora and foster colonization with resistant bacteria.^{683 2343 2403 2408 2417 2422 2473 2478}

In a retrospective study evaluating use of prophylactic anti-infectives in pediatric patients 1 month to 15 years of age with a history of recurrent AOM, patients received a 10-day regimen of oral amoxicillin or oral cefaclor for treatment of the acute episode and then a suppressive regimen of amoxicillin (20 mg/kg once daily) or cefaclor (20 mg/kg once daily) for a mean duration of 8.6 months (range: 3–20 months).²⁴⁷³ Results indicate that suppressive therapy failed in 47% of those receiving cefaclor and 70% of those receiving amoxicillin; most of these patients required other interventions (e.g., placement of tympanostomy tubes).²⁴⁷³ In addition, in a placebo-controlled study in children 3 months to 6 years of age with recurrent AOM, amoxicillin prophylaxis (20 mg/kg daily given in 1 or 2 divided doses) did not result in a lower incidence of new episodes of AOM.²⁴⁸⁶

Otitis Media with Effusion

Amoxicillin or amoxicillin and clavulanate potassium have been used in the treatment of otitis media with effusion (OME);^{2430 2445 2482 2488 2498} however, anti-infectives are not usually recommended for management of OME.^{2361 2417 2419 2422 2423 2431 2551}

OME (also referred to as noninfected or nonsuppurative otitis media, secretory otitis media, serous otitis media, MEE, fluid ear, glue ear) is defined as the presence of residual or persistent MEE without signs or symptoms of acute ear infection.^{2419 2431 2432 2551} OME may occur as an inflammatory response following an episode of AOM or may occur spontaneously because of poor eustachian tube function.^{2361 2419 2422 2551} Approximately 90% of children have OME at some time before school age, usually between 6 months and 4 years of age.²⁵⁵¹ Many episodes resolve spontaneously within 3 months, but about 30–40% of children have recurrent OME and 5–10% have episodes that last a year or longer.²⁵⁵¹ The pathogenesis of OME is multifactorial, and the role of bacteria in OME is not completely understood.^{2423 2460 2482 2487} While some studies report that cultures of MEE from patients with OME rarely indicate the presence of bacteria, results of other studies using other methods (e.g., polymerase chain reaction testing) suggest the presence of bacteria, including Alloiococcus otitis (a recently recognized gram-positive cocci), in MEE fluid of patients with OME.^{2482 2487}

In most patients with acute AOM who receive appropriate treatment with anti-infectives, MEEs usually are sterilized within 2–6 days but the effusions may persist for weeks or months before eventually resolving spontaneously without further treatment.^{2310 2362 2419 2422 2431 2468} Although asymptomatic OME usually resolves spontaneously, resolution rates decrease the longer the effusion is present and relapse is common.²⁵⁵¹ About 60–70% of children have MEE present 2 weeks after successful treatment of AOM and 10–25% still have MEE at 3 months.⁶⁸³ In a group of children 2–6 years of age in group child-care who had OME, 80% had clearance of effusion within 2 months.²⁴³¹ Chronic OME (MEE present continuously for over 3 months) may occur in some children and can be associated with conductive hearing loss, which may adversely affect language development and academic performance.^{2362 2472 2551} Risk factors for chronic OME include attendance in group day-care outside the home, age younger than 2 years of age, and exposure to tobacco smoke associated with parental smoking.^{2406 2468}

AAP, AAFP, and American Academy of Otolaryngology-Head and Neck Surgery have issued evidence-based clinical practice guidelines regarding diagnosis and management of OME in children 2 months to 12 years of age (with or without developmental disabilities or underlying conditions that predispose to OME and its sequelae).²⁵⁵¹ These experts state that accurate diagnosis of OME is fundamental to proper management and that OME must be differentiated from AOM to avoid unnecessary anti-infective treatment.²⁵⁵¹ The evidence-based guidelines recommend that children with OME who are not at risk for speech, language, or learning problems should be managed with watchful waiting for 3 months from the date of effusion onset (if known) or date of diagnosis (if onset is unknown).²⁵⁵¹ This recommendation is based on systematic review of cohort studies and the preponderance of benefit over harm and take into consideration the self-limited nature of OME in most patients and the inherent risk associated with other interventions (medical or surgical).²⁵⁵¹ These guidelines state that antihistamines and decongestants are ineffective for OME and are not recommended for treatment and that anti-infectives and corticosteroids do not have long-term efficacy and are not recommended for routine management of OME.²⁵⁵¹ Although anti-infectives (with or without corticosteroids) have not been shown to be effective in long-term resolution of OME, some experts state that a short course of anti-infectives (10–14 days) may be considered for possible short-term benefits when the parent and/or caregiver expresses a strong aversion to impending surgery.²⁵⁵¹ However, prolonged or repeated courses of anti-infectives or corticosteroids is strongly not recommended.²⁵⁵¹

If OME persists for 3 months of longer or if language delay, learning problems, or a significant hearing loss is suspected, the evidence-based guidelines for management of OME recommend that the child’s hearing be tested; language testing is recommended for those with hearing loss.²⁵⁵¹ These guidelines state that if OME is asymptomatic and is likely to resolve spontaneously, intervention is unnecessary (even if OME persists for longer than 3 months) as long as there are no risk factors that would predispose the child to undesirable sequelae or predict nonresolution of the effusion.²⁵⁵¹ Those with persistent OME without such risk factors should be reexamined at 3- to 6-month intervals until the effusion is no longer present, significant hearing loss is identified, or structural abnormalities of the eardrum or middle ear are suspected.²⁵⁵¹ Surgical intervention may be indicated if moderate hearing loss is documented.²⁵⁵¹ There is some evidence that surgical intervention may shorten the time to resolution of severe, chronic OME in children²⁴⁶⁸ and may provide some benefits in terms of language development.²⁴⁸⁰ The risks of continued observation of children with OME must be balanced against the risks of surgery.²⁵⁵¹ Prolonged watchful waiting is not appropriate when regular surveillance is impossible or when the child is at risk for developmental sequelae of OME because of comorbidities.²⁵⁵¹ For these children, the risks of anesthesia and surgery may be less than those of continued observation.²⁵⁵¹

Although anti-infective are not usually recommended for patients with OME, amoxicillin or amoxicillin and clavulanate potassium has been suggested if an anti-infective is used.^{2482 2488 2498} In a study in children 7 months to 12 years of age with OME, a 14-day regimen of oral ceftibuten or oral amoxicillin resulted in resolution of MEE (based on otoscopy) in 27–30% of children, but there was recurrence of effusion at 16-week follow-up in 60–67% of children who were effusion free at completion of therapy.²⁴⁴⁵ In a placebo-controlled study evaluating 14-day regimens of amoxicillin, cefaclor, or erythromycin-sulfisoxazole in children with OME, MEE had resolved by the end of the treatment period in 22% of those who received cefaclor, 21% of those who received erythromycin-sulfisoxazole, and 31.6% of those who received amoxicillin; of those who were effusion-free at 4 weeks, there was recurrence of effusion during the next 12 weeks in 52% of those who received cefaclor, 47% of those who received erythromycin-sulfisoxazole, and 60.9% of those who received amoxicillin.²⁴⁹⁸

The evidence-based guidelines from AAP, AAFP, and American Academy of Otolaryngology-Head and Neck Surgery should be consulted for further information on the diagnosis and management of OME in children 2 months through 12 years of age (with or without developmental disabilities or underlying conditions that predispose to OME and its sequelae), including the role of surgical intervention.²⁵⁵¹

Spirochetal Infections

Lyme Disease

Amoxicillin is considered a drug of choice for the treatment of erythema migrans and certain other manifestations of Lyme disease.^{329 331 2254 2320 2321 2322 2323 2325 2326 2327 2328 2337 2338 2343 2503} Lyme disease is a spirochetal disease caused by tick-borne Borrelia burgdorferi.^{329 331 1739 1740 1742 1744 1746 2320 2321 2326} Anti-infective therapy shortens the duration of erythema migrans and usually prevents the development of late sequelae of Lyme disease.^{329 331 875 1066 1146 1148 1212 1215 1216 1751 2320 2321 2322 2328 2329 2320 2321 2322 2328 2329 2501 2503 2512}

IDSA, AAP, American Academy of Neurology (AAN), American College of Rheumatology (ACR), and others recommend that erythema migrans be treated with a 10-day regimen of oral doxycycline or a 14-day regimen of oral amoxicillin or oral cefuroxime axetil.^{292 329 331} For the treatment of meningitis, cranial neuropathy, radiculoneuropathy, or other peripheral nervous system manifestations in patients with Lyme disease, IDSA, AAN, and ACR recommend treatment with IV ceftriaxone, IV cefotaxime, IV potassium G, or oral doxycycline.³²⁹ For the treatment of Lyme arthritis, IDSA, AAN, and ACR recommend use of oral anti-infectives (doxycycline, amoxicillin, cefuroxime axetil) based on comparative efficacy of oral and IV regimens;³²⁹ if an IV regimen is used in patients with Lyme arthritis (e.g., arthritis symptoms persist after an oral anti-infective regimen), these experts recommend IV ceftriaxone.³²⁹ IV ceftriaxone is preferred for initial treatment of Lyme carditis in hospitalized patients;³²⁹ oral anti-infectives (doxycycline, amoxicillin, cefuroxime axetil) are used as follow-up to the initial IV regimen and can be used in patients with Lyme carditis who do not require hospitalization.³²⁹

In a randomized, controlled study, doxycycline 100 mg twice daily or amoxicillin 500 mg 3 times daily (plus probenecid 500 mg 3 times daily) for 21 days showed similar efficacy in preventing late complications (e.g., meningitis, myocarditis, arthritis) in patients with early Lyme disease (erythema migrans); mild fatigue or arthralgia occurred infrequently following antibiotic therapy but resolved in all cases within the 6-month follow-up period.¹⁷⁸⁴ Amoxicillin has been recommended for use in patients with relatively mild neurologic (e.g., isolated facial nerve palsy) or cardiac (e.g., first-degree AV block with a PR interval less than 0.3 seconds) manifestations, or for arthritic manifestations of early or late Lyme disease.^{1739 1740 1771 2320 2326} In addition, amoxicillin may be preferred to doxycycline for the treatment of early Lyme disease^† in pregnant or lactating women and in children younger than 8 years of age.^{1551 1580 1795 2254 2320 2321 2322 2323 2330 2337 2338 2343 2501 2503}

For additional information on the treatment of Lyme disease, current treatment guidelines from IDSA, AAN, and ACR available at the IDSA website [Web] should be consulted.³²⁹

Chlamydial Infections

Oral amoxicillin is recommended by CDC for the treatment of uncomplicated urethral, endocervical, or rectal infections caused by Chlamydia trachomatis ^† in pregnant women.³⁴⁴ In a controlled study in pregnant women with genital chlamydia infections, a 7-day regimen of amoxicillin (500 mg 3 times daily) was as effective as a 7-day regimen of erythromycin (500 mg 4 times daily) and was associated with a lower incidence of adverse GI effects.²²⁵¹

Prophylaxis

Perioperative Prophylaxis

Some experts state that the fixed combination of ampicillin sodium and sulbactam sodium is one of several options recommended for perioperative prophylaxis^† in patients undergoing certain biliary tract procedures,³⁷⁴ colorectal procedures,^{360 374} gynecologic and obstetric procedures (e.g., vaginal, abdominal, or laparoscopic hysterectomy),^{360 374} head and neck surgery,^{360 374} noncardiac thoracic surgery (e.g., lobectomy, pneumonectomy, lung resection, thoracotomy),^{360 374} or urologic procedures (e.g., involving implanted prosthesis).³⁷⁴ Local susceptibility patterns of potential pathogens should be considered when selecting ampicillin sodium and sulbactam sodium for perioperative prophylaxis.^{360 374}

Published guidelines and protocols for perioperative prophylaxis should be consulted for additional information regarding specific procedures.^{360 374}

Prevention of Perinatal Group B Streptococcal Disease

IV ampicillin is used in pregnant women during labor (intrapartum) for prevention of early-onset neonatal group B streptococcal (GBS) disease^†,^{292 359 1164 1307 1308 1309 1817 2130} and is considered an alternative to IV penicillin G for such prophylaxis.^{292 359}

GBS infection is a leading cause of neonatal morbidity and mortality in the US.³⁵⁹ Pregnant women who are colonized with GBS in the genital or rectal areas can transmit GBS infection to their infants during labor and delivery, resulting in invasive neonatal infection that can be associated with substantial morbidity and mortality.^{292 359} GBS infection during pregnancy can cause asymptomatic bacteriuria, urinary tract infection, intra-amniotic infection, or endometritis in the woman and is associated with stillbirths and premature delivery.^{292 359} Neonatal GBS infections are characterized as early-onset GBS disease (usually occurring within the first 24 hours after birth through day 6) or late-onset GBS disease (occurring between 7–90 days of age).^{292 359} GBS disease in neonates usually presents as respiratory distress, apnea, shock, or pneumonia and may involve septicemia or meningitis; other manifestations such as osteomyelitis, septic arthritis, necrotizing fasciitis, adenitis, and cellulitis also can occur.²⁹² Approximately 20% of survivors of neonatal GBS meningitis have moderate to severe neurodevelopmental impairment.²⁹²

Major risk factors for early-onset neonatal GBS disease include maternal GBS colonization in the genitourinary and GI tracts, early membrane rupture (18 hours or more before delivery), intra-amniotic infection, premature delivery (before 37 weeks’ gestation), very low birth weight, intrapartum fever (38°C or higher), and previous delivery of an infant who had GBS disease.^{292 359} The most effective strategy for prevention of early-onset neonatal GBS disease is universal prenatal screening for GBS colonization (e.g., vaginal and rectal cultures) and use of intrapartum anti-infective prophylaxis (i.e., prophylaxis administered after onset of labor or membrane rupture but before delivery) in those with positive results.^{292 359} Following implementation of guidelines for targeted GBS intrapartum anti-infective prophylaxis in the US, the incidence of early-onset GBS disease was reduced by more than 80% (1.8 neonates with early-onset GBS disease per 1000 live births in the 1990s to 0.23 neonates per 1000 live births in 2015).³⁵⁹ Such prophylaxis has no measurable effect on the incidence of late-onset GBS disease.^{292 376 377}

The American College of Obstetricians and Gynecologists (ACOG), AAP, and other experts recommend routine universal prenatal screening for GBS colonization (e.g., vaginal and rectal cultures) in all pregnant women at 36 through 37 weeks of gestation (i.e., performed within the time period of 36 weeks 0 days to 37 weeks 6 days of gestation), unless intrapartum anti-infective prophylaxis is already planned because the woman had known GBS bacteriuria during any trimester of the current pregnancy or has a history of a previous infant with GBS disease.^{292 359} Anti-infective prophylaxis for prevention of early-onset perinatal GBS is indicated in all women identified as having positive GBS cultures during the routine prenatal GBS screening during the current pregnancy, unless a cesarean delivery is performed before the onset of labor in the setting of intact membranes.^{292 359} Intrapartum anti-infective prophylaxis also is indicated in women with unknown GBS status at the time of onset of labor (cultures not performed or results unknown) who have risk factors for perinatal GBS infection (e.g., preterm birth at less than 37 weeks’ gestation, duration of membrane rupture 18 hours or longer, intrapartum fever 38°C or higher).^{292 359} If a women presents in labor at term with unknown GBS status but has a history of GBS colonization during a previous pregnancy, these experts state that the risk for early-onset GBS disease in the infant is increased and it is reasonable to offer intrapartum anti-infective prophylaxis based on the history of GBS colonization.^{292 359}

When intrapartum anti-infective prophylaxis is indicated in the mother for prevention of early-onset GBS disease in the neonate, ACOG, AAP, and other experts recommend IV penicillin G (loading dose of 5 million units followed by 2.5–3 million units every 4 hours until delivery) as the regimen of choice.^{292 359} IV ampicillin (loading dose of 2 g followed by 1 g every 4 hours until delivery) is the preferred alternative for such prophylaxis when penicillin G is not available.^{292 359} Penicillin G is considered the drug of choice since it has a narrower spectrum of activity than ampicillin and is less likely to induce resistance in other vaginal organisms.^{292 359}

If intrapartum prophylaxis is indicated in a penicillin-allergic woman at low risk for anaphylaxis or severe non-IgE-mediated reactions if a penicillin is used (e.g., history of nonspecific symptoms unlikely to be allergic [GI distress, headaches, vaginal candidiasis]; non-urticarial maculopapular [morbilliform] rash without systemic symptoms; pruritus without rash; family history but no personal history of penicillin allergy; patient reports history of penicillin allergy but has no recollection of symptoms or treatment), ACOG, AAP, and others recommend IV cefazolin (loading dose of 2 g followed by 1 g every 8 hours until delivery).³⁵⁹ If intrapartum prophylaxis is indicated in a penicillin-allergic woman at high risk for anaphylaxis or severe non-IgE-mediated reactions if a penicillin is used (e.g., history suggestive of an IgE-mediated event such as pruritic rash, urticaria, immediate flushing, hypotension, angioedema, respiratory distress, or anaphylaxis; recurrent reactions to penicillin, reactions to multiple β-lactam anti-infectives, or positive penicillin allergy test; severe delayed-onset cutaneous or systemic reactions such as eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome, Stevens-Johnson syndrome, or toxic epidermal necrolysis), these experts recommend IV clindamycin (900 mg IV every 8 hours until delivery) if the GBS isolate is tested and found to be susceptible to the drug.³⁵⁹ If the GBS isolate is resistant to clindamycin, IV vancomycin (20 mg/kg [up to 2 g] every 8 hours until delivery) is the recommended alternative in such women.³⁵⁹

Routine use of anti-infective prophylaxis (e.g., penicillin G, ampicillin) in neonates born to women who received adequate GBS intrapartum prophylaxis is not recommended.^{292 359} Regardless of whether intrapartum GBS prophylaxis was administered to the mother, appropriate diagnostic evaluations and anti-infective treatment should be initiated in the neonate if signs or symptoms of active infection develop.^{292 359} Ampicillin in conjunction with an aminoglycoside is the initial regimen of choice for empiric treatment of presumptive neonatal sepsis, including presumptive GBS infection, since it is likely to be active against GBS and other possible causative agents (e.g., other streptococci, enterococci, L. monocytogenes, E. coli).^{292 376 377}

For additional information regarding the prevention of neonatal early-onset GBS disease, the current ACOG guidelines available at [Web] should be consulted.³⁵⁹

Prevention of Bacterial Endocarditis

Amoxicillin^{451 926 932 948 950 1070 1831 1832 1833} and ampicillin^{292 451 929 1195 1408 1831 1832} are used for prevention of α-hemolytic (viridans group) bacterial endocarditis^† in adults and children undergoing certain dental or upper respiratory tract procedures who have cardiac conditions that put them at highest risk of adverse outcomes from endocarditis.⁴⁵¹

The cardiac conditions identified by AHA as those associated with highest risk of adverse outcomes from endocarditis and for which anti-infective prophylaxis is reasonable are prosthetic cardiac valves or prosthetic material used for cardiac valve repair, previous infective endocarditis, cardiac valvulopathy after cardiac transplantation, or congenital heart disease (i.e., unrepaired cyanotic congenital heart disease including palliative shunts and conduits; a completely repaired congenital heart defect where prosthetic material or device was placed by surgery or catheter intervention within the last 6 months; repaired congenital heart disease with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device that inhibit endothelialization).⁴⁵¹

AHA states that anti-infective prophylaxis for prevention of α-hemolytic (viridans group) streptococcal bacterial endocarditis is reasonable for patients with the above cardiac risk factors if they are undergoing any dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa (e.g., biopsies, suture removal, placement of orthodontic bands).⁴⁵¹ AHA states that anti-infective prophylaxis is not needed for routine anesthetic injections through noninfected tissue, dental radiographs, placement of removable prosthodontic or orthodontic appliances, adjustment of orthodontic appliances, placement of orthodontic brackets, shedding of deciduous teeth, or bleeding from trauma to the lips or oral mucosa.⁴⁵¹

AHA states that anti-infective prophylaxis for prevention of bacterial endocarditis also is reasonable for patients with the above cardiac risk factors if they are undergoing invasive procedures of the respiratory tract that involve incision or biopsy of respiratory mucosa (e.g., tonsillectomy, adenoidectomy) or surgical procedures that involve infected skin, skin structure, or musculoskeletal tissue.⁴⁵¹ However, anti-infective prophylaxis solely to prevent infective endocarditis is no longer recommended for GI or genitourinary tract procedures.⁴⁵¹

Oral amoxicillin is the drug of choice when prevention of bacterial endocarditis is indicated in patients undergoing certain dental or upper respiratory tract procedures who have certain cardiac conditions that put them at highest risk of adverse outcomes from endocarditis.⁴⁵¹ If an oral regimen cannot be used in such patients, AHA recommends IM or IV ampicillin or IM or IV cefazolin or ceftriaxone.⁴⁵¹ Alternatives for penicillin-allergic patients include oral cephalexin, oral azithromycin or clarithromycin, oral or parenteral clindamycin, or parenteral cefazolin or ceftriaxone;⁴⁵¹ cephalosporins should not be used in individuals with a history of anaphylaxis, angioedema, or urticaria after receiving a penicillin.⁴⁵¹

When selecting anti-infectives for prophylaxis of bacterial endocarditis, the current recommendations published by AHA should be consulted.⁴⁵¹

Aminopenicillins General Statement Dosage and Administration

Administration

Amoxicillin trihydrate³⁶ and ampicillin trihydrate^{42 45 46 48 49} are administered orally. Ampicillin sodium is administered by IM or IV injection or by IV infusion.^{38 39} Amoxicillin sodium has also been administered IV^{95 447 448 459 1290} but parenteral preparations of the drug are not available in the US.

Since food interferes with GI absorption of ampicillin oral suspension,^{342 457 466} these solutions should be given orally at least 1 hour before or 2 hours after meals for maximal absorption. Amoxicillin³⁶ tablets may be administered orally without regard to meals.

Dosage in Renal Impairment

In patients with renal impairment, doses and/or frequency of administration of aminopenicillins must generally be modified in response to the degree of renal impairment.^{473 510 1320 1373 1374}

Cautions for Aminopenicillins General Statement

The major adverse effects reported with aminopenicillins are GI effects, rash, and hypersensitivity reactions.^{36 38 39 42 45 46 48 49 73 74 614 732 736 804 2205} With the exception of diarrhea (which has been reported most frequently with ampicillin),^{725 727 731 732 741} the frequency and severity of adverse effects are generally similar between ampicillin and amoxicillin.^{73 725 732}

Hypersensitivity Reactions

Hypersensitivity reactions reported with aminopenicillins are similar to those reported with other penicillins.^{74 732} Hypersensitivity reactions to aminopenicillins are manifested most frequently as eosinophilia^{36 38 39 42 45 46 48 49 736} or rash (urticarial, erythematous, morbilliform),^{36 38 39 42 45 46 48 49 74 416 461 732 781 2205} less frequently as angioedema,¹⁴³⁷ exfoliative dermatitis^{38 39 42 45 46 48 49} toxic epidermal necrolysis,²¹³⁵ or erythema multiforme,^{38 39 42 45 46 48 49 2135 2206} and rarely as Stevens-Johnson syndrome.^{36 1437 2206} Serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever) also have been reported.¹⁴³⁷ Eosinophilia has been reported in up to 47% of patients receiving ampicillin.⁷³⁶

Rash has been reported in 1.4–10% of patients receiving amoxicillin or^{73 461 614 708 781 804 2205} or ampicillin.^{61 74 614 708 732 774 804 816 820 821 826 827 829 2205} Two different types of rash have been reported with aminopenicillins.^{781 812 830} One type of rash resembles the hypersensitivity rash seen with other penicillins;^{781 812 830} this rash is usually urticarial, appears within a few days of initiation of therapy with the drugs, and may be associated with other signs of hypersensitivity.^{781 812 830} The second type of rash, is a generalized erythematous, maculopapular rash which, in most cases, appears to be nonimmunologic.^{781 812 830} For more information on the maculopapular rash reported with ampicillin and amoxicillin, see Cautions: Ampicillin Rash.

Positive direct antiglobulin (Coombs’) test results and hemolytic anemia have been reported rarely with ampicillin.⁸⁰⁹ Acute hemolytic anemia, with a negative direct antiglobulin test result, has also been reported in one patient who received ampicillin;⁷⁰⁹ however, it is not clear whether this was a hypersensitivity reaction.⁷⁰⁹

Anaphylaxis has been reported rarely with oral⁸¹¹ or parenteral ampicillin.^{61 713} Anaphylaxis has also been reported in at least one patient who apparently inhaled ampicillin after opening a bottle of the drug for reconstitution.¹²⁷⁶ If a severe hypersensitivity reaction occurs during therapy with an aminopenicillin, the drug should be discontinued and the patient given appropriate treatment (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen) as indicated.^{36 38 39 42 45 46 48 49}

Ampicillin Rash

In addition to the usual urticarial hypersensitivity rash reported with other penicillins (see Cautions: Hypersensitivity Reactions), ampicillin^{781 804 812 830 831} and amoxicillin^{61 73 428 701 708 804 815} frequently cause a generalized erythematous, maculopapular rash. The maculopapular rash, when it occurs, generally appears 3–14 days after initiation of therapy with the drugs,^{61 781 812 816 817 818 819 820 821 824} begins on the trunk, and spreads peripherally to involve most of the body.^{812 816 819 824} The rash may be most intense at pressure areas and elbows and knees;^{812 819 824} mucous membranes may or may not be involved.⁸¹⁶ In most patients, the rash is mild and subsides after 6–14 days despite continued therapy with the drugs;^{61 448 781 812 816 817 824} however, the rash may be severe with coalescence of lesions and purpura.^{812 816 820} If the drug is discontinued, the rash generally resolves in 1–7 days.⁸²⁴

Rash has been reported more frequently with ampicillin and amoxicillin than with other currently available penicillins.^{61 73 614 781 812 827} More than 65% of rashes reported with ampicillin appear to be of the maculopapular type.^{781 824} A maculopapular rash reportedly occurs in 5–10% of children receiving ampicillin.^{817 830} The frequency of rash reported with ampicillin does not appear to be related to dosage of the drug,⁷⁰² but the rash has been reported more frequently in women than in men.⁸¹⁶ In one study, maculopapular rash occurred in 3.7% of males and 13.4% of females receiving ampicillin.⁸¹⁶

A high incidence of rash occurs when aminopenicillins are used in patients with viral disease,^{61 73 428 701 781 812 815 816 819 823 1277} including viral respiratory tract infections,⁸¹⁶ infectious mononucleosis,^{61 73 428 701 722 781 812 815 816 819 822 1277} and cytomegalovirus infections.^{816 823} Rash has been reported in 65–100% of patients with infectious mononucleosis who received ampicillin^{61 819 822} and has also been reported frequently when amoxicillin was used in patients with the disease.^{73 428 701 815} The maculopapular rash has been reported in up to 90% of patients with lymphatic leukemia and a high percentage of patients with reticulosarcoma and other lymphomas who received ampicillin.⁶¹ An increased incidence of rash has also been reported in patients with hyperuricemia receiving allopurinol and concomitant ampicillin or amoxicillin compared with those receiving ampicillin, amoxicillin, or allopurinol alone.^{712 774 812 829} (See Drug Interactions: Allopurinol.)

The mechanism of the maculopapular rash reported with ampicillin and amoxicillin is unknown;^{812 824 831 871} however, in most cases, it appears to be nonimmunologic.^{824 828 831 871} Skin tests for penicillin hypersensitivity have been negative in the majority of patients with these rashes who were tested.^{61 817 821 824 830 871} In addition, many patients have received subsequent treatment with ampicillin or another penicillin without recurrence of the rash or evidence of a hypersensitivity reaction.^{816 821 824 871} Therefore, some clinicians consider the rash nonimmunologic^{61 816 821 824 828} and suggest that the occurrence of a maculopapular rash during aminopenicillin therapy, without other signs of hypersensitivity, does not necessarily imply hypersensitivity to penicillins or contraindicate future use of aminopenicillins or other penicillins.^{61 816 831 906} However, the possibility that the rash is the result of a hypersensitivity reaction to protein impurities contained in commercially available preparations cannot be ruled out^{61 812 871} since, in several studies, a lower incidence of the rash has been reported in patients receiving more purified forms of ampicillin than in those receiving less purified forms of the drug.^{813 814}

The frequency of aminopenicillin-induced adverse dermatologic effects, including rash (morbilliform, macular), urticaria, pruritus, and, rarely, erythema multiforme is substantially higher (about 10-fold) in patients with human immunodeficiency virus (HIV) infections (including those with acquired immunodeficiency syndrome [AIDS]) than in other patients.^{2131 2132 2133} The exact mechanism(s) of this increased risk of aminopenicillin-induced adverse effects has not been determined,^{2132 2133} but may be immunologically based. Limited data indicate that aminopenicillin-associated rash may be associated with absolute helper/inducer (CD4⁺, T4⁺) T-cell counts of 200/mm³ or less.^{2132 2133} It also has been suggested that aminopenicillin-associated rash in such patients may be associated with lymphocyte proliferation and production of lymphokines.²¹³² In patients in whom HIV infection progresses to AIDS, an even further increase in adverse dermatologic reactions has been observed;²¹³¹ however, a causal relationship to drug therapy has not been established, since progressive HIV infection has been associated with increased infectious and noninfectious dermatoses.^{2131 2133 2207 2208} Some clinicians state that further therapy or rechallenge with aminopenicillins should not be contraindicated when such reactions occur in patients with HIV infection.^{2132 2134}

Hematologic Effects

In addition to eosinophilia and hemolytic anemia (see Cautions: Hypersensitivity Reactions), other adverse hematologic effects including anemia, leukopenia,^{36 38 39 42 45 46 48 49 61 62 63 615} neutropenia,^{448 615 674 1028 1030} agranulocytosis,^{36 38 39 42 45 46 48 49 61} thrombocytopenia,^{36 38 39 42 45 46 48 49 61 615 1028} and thrombocytopenic purpura^{36 38 39 42 45 46 48 49} have been reported in patients receiving aminopenicillins. These adverse hematologic effects are usually reversible following discontinuance of the drugs.^{36 38 39 42 45 46 48 49 448 674 1028 1030} Although these hematologic effects are generally considered hypersensitivity reactions to the drugs,^{36 38 39 42 45 46 48 49 615 1030} an immunologic mechanism has not been definitely established.⁶¹⁵

Abnormal platelet aggregation, prolongation of bleeding time, and prolongation of activated partial thromboplastin time (APTT) have been reported in children and healthy adults receiving ampicillin or amoxicillin.^{655 673}

GI Effects

Some of the most frequent adverse reactions to orally administered aminopenicillins are GI effects⁸⁰⁴ including nausea,^{36 38 39 42 45 46 48 49 61 614 725 726} vomiting,^{36 38 39 42 45 46 48 49 461 614 725 728} anorexia,⁷²⁵ epigastric distress,^{61 725 726 728 731} diarrhea,^{36 38 39 42 45 46 48 49 61 461 614 725 726 728 731 732 781 804} and gastritis.⁶¹⁴ Black hairy tongue,^{38 48 49} glossitis,^{38 39 42 45 46 48 49 725} and stomatitis^{38 39 42 45 46 48 49} have also been reported. Adverse GI effects appear to be dose related^{64 614 690 804} and may occasionally be severe enough to require discontinuance of the drugs.^{61 64 461 732}

Diarrhea occurs less frequently during therapy with oral amoxicillin^{61 64 73 804} than during therapy with oral ampicillin, presumably because these derivatives are more completely absorbed from the GI tract than ampicillin^{61 64 73 614 732 804} and therefore have less of an effect on normal flora in the GI tract.^{727 804} Diarrhea reportedly occurs in 9–17% of adults receiving usual doses of oral ampicillin^{61 341 614 732 781 804} and 0.5–5% of adults receiving usual doses of oral amoxicillin.^{61 73 614 804} Aminopenicillins cause diarrhea most frequently in children^{61 690} and in geriatric patients.⁶¹ Diarrhea has been reported to occur in up to 20% of children receiving oral ampicillin and may be severe enough to require discontinuance of therapy in 8% of children receiving the drug.⁶¹ In one study of children receiving usual doses of amoxicillin as an oral suspension, loose stools occurred in 42% of children younger than 8 months of age, 20% of children 8–16 months of age, and 8.5% of children 24–36 months of age.³⁹⁰

The reported incidence of upper GI effects (nausea, vomiting, epigastric pain) following oral administration of the various aminopenicillins appears to be similar.^{73 804} Nausea and vomiting have been reported in 2% of patients receiving amoxicillin^{614 804} and 2–2.9% of patients receiving ampicillin.^{614 804}

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly known as Clostridium difficile).³⁰² C. difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis; CDAD) has been reported during or following discontinuance of ampicillin^{61 63 341 806 807 1287 1289} or amoxicillin.^{61 744 806 1289} C. difficile produces toxins A and B which contribute to development of CDAD.³⁰² Patients should be managed with appropriate anti-infective therapy directed against C. difficile (e.g., fidaxomicin, vancomycin, metronidazole), supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.^{36 302}

Acute, transient enterocolitis with severe abdominal pain and bloody diarrhea, but without evidence of C. difficile-associated diarrhea and colitis, also has been reported in several patients receiving oral ampicillin or oral amoxicillin.^{42 45 46 48 49 685 1032}

Nausea and diarrhea have occurred in up to 3% of patients receiving IV ampicillin.⁶¹ Acute pancreatitis has been reported in at least one patient receiving IV ampicillin therapy.¹⁷¹³

Renal Effects

Acute interstitial nephritis has been reported rarely with ampicillin^{61 341 781 808 1291} and amoxicillin.¹²⁹⁰ In most reported cases, the nephritis resembled that reported with methicillin (no longer commercially available in the US) and appeared to be a hypersensitivity reaction to the drugs.^{61 808 1290} .

At least one case of glomerulonephritis, which occurred as part of Henoch-Schönlein purpura, has been reported with oral ampicillin.⁷⁹³ The syndrome appeared to be a hypersensitivity reaction to the drug and was characterized by urticaria, bloody diarrhea, arthralgia, proteinuria, and hyaline and erythrocyte casts in the urine;⁷⁹³ focal glomerulonephritis was present histologically.⁷⁹³

Crystals of ampicillin have been found rarely in the urine of patients receiving large IV doses of ampicillin.^{781 792 810} Ampicillin, in high concentrations, apparently can crystallize in vitro in urine with a pH of 5 or less.⁷⁹² It is not known if the ampicillin crystals found in the urine of these patients were formed in vitro or in vivo;^{781 792} however, there was no clinical or pathologic evidence of renal damage.^{792 810}

Hepatic Effects

A moderate increase in serum concentrations of AST (SGOT) and/or ALT (SGPT) have been reported rarely during therapy with aminopenicillins,^{36 38 39 42 45 46 48 49 61 73 1437} especially when the drugs were administered to infants.^{38 39 42 45 46 48 49 64} Hepatic dysfunction (cholestatic, hepatocellular, or mixed cholestatic-hepatocellular) has been reported rarely in patients receiving aminopenicillins; signs and symptoms may appear during or after therapy and resolve completely with time.¹⁴³⁷

Nervous System Effects

Headache and dizziness have been reported rarely with ampicillin.

Myoclonic seizures have occurred rarely following IV administration of high doses of ampicillin,^{61 63} especially in patients with impaired renal function.^{61 63} Although a causal relationship has not been definitely established, generalized seizures have also been reported in at least 2 patients receiving oral ampicillin.⁶⁹⁴

Local Reactions

Phlebitis has been reported rarely with IV administration of ampicillin. Pain at the injection site occurs frequently following IM administration of ampicillin.⁶⁷

Precautions and Contraindications

Prior to initiation of therapy with an aminopenicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens.^{36 38 39 42 45 46 48 49} There is clinical and laboratory evidence of partial cross-allergenicity among bicyclic β-lactam antibiotics including penicillins, cephalosporins, cephamycins, and carbapenems.^{611 615 720 769 781 1193 1629 1630} There appears to be little cross-allergenicity between bicyclic β-lactam antibiotics and monobactams (e.g., aztreonam).^{1629 1630 1631 1632 1633} However, the true incidence of cross-allergenicity between penicillins and other β-lactam antibiotics has not been definitely established.^{615 720 1289 1629} Amoxicillin and³⁶ ampicillin^{38 39 42 45 46 48 49} are contraindicated in patients who are hypersensitive to any penicillin. In addition, although it has not been proven that allergic reactions to antibiotics are more frequent in atopic individuals,⁸⁰⁵ the manufacturers state that aminopenicillins should be used with caution in patients with a history of allergy, particularly to drugs.^{36 38 39 42 45 46 48 49} .

Because a high percentage of patients with infectious mononucleosis have developed rash during therapy with aminopenicillins (see Cautions: Ampicillin Rash), aminopenicillins probably should not be used in patients with the disease.^{73 428}

Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with aminopenicillins,^{36 38 39 42 45 46 48 49} especially when the drugs are administered to patients with liver or renal impairment.

Use of aminopenicillins may result in overgrowth of nonsusceptible organisms^{36 38 39 42 45 46 48 49 63 64 341} including Candida.^{36 49 341 683} The majority of bacterial superinfections during therapy with aminopenicillins are caused by Enterobacter,^{36 461} Klebsiella,⁴⁶¹ E. coli,⁴⁶¹ Aerobacter,⁴⁹ or Pseudomonas.^{36 49 64} Oral⁷²⁶ or vaginal^{341 683} candidiasis occurs occasionally with oral aminopenicillins. Superinfections are more likely to occur when large doses of aminopenicillins are used or when therapy is prolonged. Careful observation of the patient is essential during therapy with an aminopenicillin.^{36 38} If suprainfection or superinfection occurs, the drug should be discontinued^{36 38 48 49} and appropriate therapy instituted.^{36 38 39 42 45 46 48 49}

Mutagenicity and Carcinogenicity

Studies to evaluate the mutagenic or carcinogenic potential of aminopenicillins generally have not been performed to date.

Pregnancy, Fertility, and Lactation

Pregnancy

Safe use of amoxicillin or³⁶ ampicillin^{38 39 42 45 46 48 49} during pregnancy has not been definitely established. However, amoxicillin and ampicillin have been administered to pregnant women without evidence of adverse effects to the fetus.^{61 468 723 1145}

Amoxicillin is included in the US Centers for Disease Control and Prevention (CDC) recommendations for the treatment of chlamydial infections^† during pregnancy³⁴⁴ and included in CDC recommendations for the treatment of cutaneous anthrax^† or for postexposure prophylaxis of anthrax^† following exposure to Bacillus anthracis spores.^{672 2499 2506 2509} In addition, ampicillin is recommended by the American College of Obstetricians and Gynecologists (ACOG), AAP, and others for intrapartum anti-infective prophylaxis for prevention of early-onset neonatal group B streptococcal (GBS) disease^†.³⁵⁹

Reproduction studies in mice and rats using amoxicillin doses up to 10 times the usual human dose³⁶ have not revealed evidence of harm to the fetus.³⁶ There are no adequate or controlled studies to date using aminopenicillins in pregnant women, and the drugs should be used during pregnancy only when clearly needed.³⁶

Aminopenicillins generally are poorly absorbed when given orally during labor.³⁶ Although the mechanism is unclear and the clinical importance has not been determined to date, studies using oral ampicillin indicate that, when administered during pregnancy, the drug interferes with metabolism and enterohepatic circulation of steroids resulting in decreased urinary concentrations of estrogen metabolites.^{36 1023 1024 1045} IV administration of ampicillin to guinea pigs slightly decreased uterine tone and frequency of uterine contractions but moderately increased the height and duration of contractions; however, it is not known whether use of the drug in humans during labor or delivery could have any immediate or delayed adverse effects on the fetus, prolong the duration of labor, or increase the likelihood of forceps delivery, other obstetrical intervention, or resuscitation of the neonate.³⁶

Fertility

Reproduction studies in mice and rats using amoxicillin doses up to 10 times the usual human dose³⁶ have not revealed evidence of impaired fertility.³⁶

Lactation

Because aminopenicillins are distributed into milk and may lead to sensitization of infants, the drugs should be used with caution in nursing women.^{36 61 73 355 496}

Drug Interactions

Although not all drug interactions reported with other penicillins have been reported with aminopenicillins, the fact that some of these interactions could occur with aminopenicillins should be considered.

Anti-infective Agents

Aminoglycosides

Synergism with Aminoglycosides

In vitro and animal studies indicate that a synergistic bactericidal effect can occur against some strains of enterococci when ampicillin is used in conjunction with amikacin, gentamicin, streptomycin, or tobramycin.^{80 116 282 300 942 947} The synergistic effect between ampicillin and aminoglycosides is used to therapeutic advantage in the treatment of endocarditis or other severe infections caused by enterococci.^{64 80 282 288 904 947}

A synergistic bactericidal effect has also been reported in vitro against group B streptococci when ampicillin was used in conjunction with amikacin, gentamicin, kanamycin, or tobramycin^{116 295} and against L. monocytogenes when ampicillin was used in conjunction with gentamicin.^{298 1198}

Although the clinical importance has not been determined, in vitro studies indicate that gentamicin and ampicillin may be synergistic against some strains of Enterobacteriaceae (e.g., Enterobacter, P. mirabilis, E. coli).¹¹⁶

Incompatibility with Aminoglycosides

Aminopenicillins are physically and/or chemically incompatible with aminoglycosides and can inactivate the drugs in vitro.^{82 116 341 1035 1115} In vitro inactivation of aminoglycosides by aminopenicillins can occur if the drugs are administered in the same syringe or IV infusion container.^{82 116 341 1035} When concomitant therapy is indicated, in vitro mixing of aminopenicillins and aminoglycosides should be avoided and the drugs administered separately.^{82 341} Ampicillin can also inactivate aminoglycosides in vitro in serum samples obtained from patients receiving concomitant therapy with the drugs.^{1035 1115} This could adversely affect results of serum aminoglycoside assays performed on the serum samples.^{1035 1115}

β-Lactamase Inhibitors

In vitro and in vivo studies indicate that the combination of amoxicillin^{311 312 314 316 318 1298 1311 1437 1446 1450 1453 1454 1473 1486 1494 1501} or ampicillin^{310 312 317} with clavulanic acid or the combination of amoxicillin or ampicillin with sulbactam^{1902 1903 1954 1955 1959 1962 1969 1991 1998 2004 2039} results in a synergistic bactericidal effect against many strains of β-lactamase-producing bacteria. This synergism occurs because clavulanic acid and sulbactam are β-lactamase inhibitors that have a high affinity for and irreversibly bind to certain β-lactamases that can inactivate aminopenicillins.^{143 318 1315 1901 1903 1925 1955 1961 1962 1964 1991 2004 2039 2050} Concomitant use of clavulanic acid with amoxicillin or ampicillin does not result in a synergistic effect against resistant organisms if intrinsic resistance to aminopenicillins rather than β-lactamase production is involved.^{316 318}

The fact that concomitant use of clavulanic acid or sulbactam sodium broadens the spectrum of activity of aminopenicillins is used to therapeutic advantage in the treatment of infections that may be caused by β-lactamase-producing organisms which are generally resistant to aminopenicillins.^{315 318 1312 1313 1437 1457 1475 1486 1488 1901 1902 1903 1954 1955} Amoxicillin is commercially available in fixed combination with clavulanate potassium (amoxicillin/clavulanate) for oral use.¹⁴³⁷ Ampicillin sodium is commercially available in a fixed combination with sulbactam sodium (ampicillin/sulbactam) for parenteral use.¹⁹⁰¹ .

Chloramphenicol

In some in vitro studies, chloramphenicol reportedly antagonized the bactericidal activity of ampicillin against H. influenzae,^{306 1167} N. meningitidis,³⁰⁵ and S. pneumoniae.³⁰⁵ However, indifferent, additive, or synergistic effects have also occurred in vitro when chloramphenicol was used in conjunction with ampicillin against these organisms.^{305 309 1167} In one in vitro study using H. influenzae, chloramphenicol antagonized the bactericidal activity of ampicillin, but ampicillin did not interfere with the antibacterial activity of chloramphenicol.¹¹⁶⁷ Although some clinicians recommend that concomitant use of chloramphenicol and penicillins be avoided,^{306 1153} in vivo antagonism between these drugs has not been demonstrated to date and ampicillin is generally used in conjunction with chloramphenicol for the empiric treatment of bacterial meningitis with no apparent decrease in activity.^{157 305 309 866 905 986 1059 1181 1182 1275}

Rifampin

In one in vitro study using group B streptococci, rifampin used in conjunction with ampicillin resulted in a lower rate of killing than ampicillin alone;³⁸⁸ however, in another in vitro study using H. influenzae, concomitant use of rifampin and ampicillin resulted in an additive or indifferent effect and no synergism or antagonism.¹²⁹⁵ Although in vitro antagonism has also been reported when rifampin was used in conjunction with penicillinase-resistant penicillins, antagonism appears to occur only when high concentrations of the penicillin are present and indifference or synergism appears to occur when low concentrations of the penicillin are present.^{1392 1393}

Sulfasalazine

In one study, administration of oral ampicillin (250 mg 4 times daily for 5 days) prior to administration of sulfasalazine resulted in a decrease in the area under the serum concentration-time curve (AUC) of sulfapyridine (a metabolite of sulfasalazine) compared with administration of sulfasalazine alone.⁷⁷³ Although the mechanism by which ampicillin decreased the AUC of sulfapyridine has not been determined, ampicillin may have altered the GI flora and consequently sulfasalazine metabolism.⁷⁷³

Acetohydroxamic Acid

Results of one in vitro study indicate that the antibacterial activity of acetohydroxamic acid, a urease inhibitor, and ampicillin may be synergistic against some organisms, including Escherichia coli, Klebsiella, Morganella morganii, Providencia rettgeri, and Pseudomonas aeruginosa; however, indifferent or antagonistic effects also occurred.¹¹⁸⁰

Methotrexate

Concomitant use of penicillins (e.g., amoxicillin) may decrease renal clearance of methotrexate,¹⁴⁰⁸ presumably by inhibiting renal tubular secretion of the drug.^{2285 2287} Increased serum concentrations of methotrexate, resulting in GI or hematologic toxicity, have been reported in patients receiving concomitant administration of low- or high-dose methotrexate therapy with penicillins.^{1408 2285 2287} Patients receiving methotrexate and penicillins concomitantly should be monitored carefully.^{1408 2285 2287}

Oral Contraceptives

Concomitant use of ampicillin and estrogen-containing oral contraceptives reportedly may decrease efficacy of the contraceptive and increase the incidence of breakthrough bleeding.^{771 772 781 1043 1153} These effects have also been reported when penicillin V was used in patients receiving oral contraceptives.¹⁰⁴³ Studies in animals indicate that anti-infective agents such as ampicillin may decrease or eliminate enterohepatic circulation of oral contraceptives by disrupting the GI bacterial flora.^{772 1043} GI bacteria produce enzymes which hydrolyze conjugates of estrogens (e.g., ethinyl estradiol) that have been excreted into the GI tract via bile; hydrolysis of these conjugates allows enterohepatic circulation of the pharmacologically active drug.¹⁰⁴³

The clinical importance of this potential interaction between penicillins and oral contraceptives has not been determined.^{772 1153} Pregnancies have occurred in a few patients receiving an oral contraceptive and ampicillin concomitantly.¹¹⁵³ However, in several studies, administration of ampicillin to women receiving oral contraceptives did not affect plasma concentrations of ethinyl estradiol, levonorgestrel, norethisterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), or progesterone,^{771 772 1044} although decreased concentrations of ethinyl estradiol were noted in a few women.^{772 1044 1292} Therefore, although some clinicians suggest that a supplemental method of contraception be used in patients receiving oral contraceptives and ampicillin concomitantly, other clinicians state that most women taking oral contraceptives probably do not need to use alternative contraceptive precautions while receiving ampicillin.^{771 772 1043 1044}

Probenecid

Oral probenecid administered shortly before or simultaneously with aminopenicillins slows the rate of renal tubular secretion of the penicillins and produces higher and prolonged serum concentrations of the drugs.^{36 76 347 447} Studies using amoxicillin indicate that the peak serum concentration and half-life of the drug are generally increased by 30–60% and the area under the serum concentration-time curve (AUC) may be increased by 60%.^{73 229 346 492} In addition, concurrent administration of oral probenecid decreases the volumes of distribution of IM or IV ampicillin or amoxicillin by about 20% which may contribute to higher serum concentrations of the drugs.^{347 447} Concomitant administration of oral probenecid also reportedly increases CSF concentrations of ampicillin and amoxicillin.^{76 447}

Allopurinol

An increased incidence of rash reportedly occurs in patients with hyperuricemia who are receiving allopurinol and concomitant ampicillin or amoxicillin compared with those receiving ampicillin, amoxicillin, or allopurinol alone.^{712 774 812 829 1153} Some clinicians suggest that either allopurinol or hyperuricemia may potentiate aminopenicillin allergenicity.^{712 829} However, other clinicians state that the rash reported in patients receiving allopurinol and aminopenicillins concomitantly is generally the delayed ampicillin rash which appears to be nonimmunologic.⁷⁷⁴ (See Cautions: Ampicillin Rash.) The clinical importance of this effect has not been determined;¹¹⁵³ however, some clinicians suggest that concomitant use of the drugs should be avoided if possible.⁷¹²

Laboratory Test Interferences

Although there is limited information on laboratory test interferences with aminopenicillins and although not all laboratory test interferences reported with other penicillins have been reported with ampicillin, the possibility that these interferences could occur with any of the aminopenicillins should be considered.

Tests for Urinary and Serum Proteins

Ampicillin has caused slightly increased urinary protein concentrations when the Coomassie brilliant blue method is used¹¹¹⁸ and has also reportedly caused falsely increased serum albumin concentrations when the bromcresol green (BCG) procedure was used.⁸⁰³

Tests for Glucose

Like other penicillins, ampicillin reportedly interferes with urinary glucose determinations using cupric sulfate (e.g., Benedict’s solution, Clinitest)⁷⁵⁹ but does not affect glucose oxidase methods (e.g., Clinistix, Tes-Tape).⁷⁵⁹

In one study ampicillin apparently interfered with the Sigma modification of Hall and Tucker’s automated glucose oxidase/peroxidase/ferrocyanide method for serum glucose.¹¹⁵⁸ However, in another study ampicillin did not appreciably interfere with serum glucose methods that used hexokinase, glucose oxidase, or o-toluidine.⁷⁹⁹

Tests for Uric Acid

Ampicillin can cause falsely increased serum uric acid concentrations when the copper-chelate method is used;⁸⁰⁰ however, phosphotungstate and uricase methods for serum uric acid determinations appear to be unaffected by the drug.⁸⁰⁰

Immunohematology Tests

Positive direct antiglobulin (Coombs’) test results have been reported in patients receiving ampicillin.⁸⁰⁹ (See Cautions: Hypersensitivity Reactions.) This reaction may interfere with hematologic studies or transfusion cross-matching procedures and should be considered in patients receiving penicillins.³⁴¹

Serum Aminoglycoside Assays

Because ampicillin inactivates aminoglycosides in vitro (see Drug Interactions: Aminoglycosides), presence of the drug in serum samples to be assayed for aminoglycoside concentrations may result in falsely decreased results.^{1035 1115}

Other Laboratory Tests

Ampicillin in urine reportedly can cause false-positive results for leucine/isoleucine, phenylalanine, and β-aminoisobutyric acid in paper chromatography studies of urinary amino acids and false-positive results for phenylalanine in paper electrophoretograms.⁷⁹²

In one study, ampicillin in urine caused a false-positive result in the iodine-azide spot test used to screen for sulfite oxidase deficiency.¹⁰³⁹ A transient decrease in plasma concentration of total conjugated estriol, estriol glucuronide, conjugated estrone, and estradiol reportedly has occurred in pregnant women taking ampicillin; this effect may also occur with amoxicillin.³⁶ (See Cautions: Pregnancy, Fertility, and Lactation.)

Mechanism of Action

Aminopenicillins have a mechanism of action similar to that of other penicillins.^{61 107} .

Partly because of the presence of a free amino group at R on the penicillin nucleus, aminopenicillins can penetrate the outer membrane of gram-negative bacteria more readily than natural or penicillinase-resistant penicillins and are therefore active against some gram-negative bacteria that are resistant to natural or penicillinase-resistant penicillins.^{61 99 148 575}

Amoxicillin and ampicillin reportedly vary in their rate of bactericidal action and in the completeness of this effect.^{61 76 88 109} Although the clinical importance is unclear, in vitro studies using Escherichia coli and ampicillin and amoxicillin in concentrations twice those of the MIC of the drugs for this organism indicate that amoxicillin causes rapid formation of spheroplasts and lysis of susceptible E. coli, whereas ampicillin produces abnormally elongated or filamentous forms of the organism.^{61 88 109} The elongated or filamentous forms of E. coli are more osmotically stable than spheroplasts and lyse at a slower rate;^{61 88 109} these forms are also capable of rapidly resuming growth if ampicillin is removed before the cells lyse.¹⁰⁹ In one study, ampicillin caused rapid lysis of E. coli only at concentrations 10–20 times the MIC of the drug for the organism.¹⁰⁹

Spectrum

Aminopenicillins are active in vitro against most gram-positive and gram-negative aerobic cocci (except penicillinase-producing strains),^{61 63 64 73 76 116 226 228} some gram-positive aerobic and anaerobic bacilli,^{61 116 228} and some spirochetes.^{61 75} The drugs are also active in vitro against some gram-negative aerobic and anaerobic bacilli.^{61 73 116 228} Aminopenicillins are inactive against Mycoplasma, Rickettsia, fungi, and viruses.⁶¹

Although amoxicillin and ampicillin generally have the same spectrum of activity^{61 64 68 73 75 226 228 229 575} and the same level of activity against susceptible organisms,^{73 75 228 229 575} amoxicillin is more active in vitro on a weight basis than ampicillin against enterococci and Salmonella but less active than ampicillin against Shigella and Enterobacter.^{73 149 150 151 228 229 1314}

Fixed-ratio combinations of amoxicillin and clavulanate potassium^{312 318 1311 1438 1446 1450 1454 1457 1486} or fixed-ratio combinations of ampicillin sodium and sulbactam sodium^{1901 1902 1903 1925 1955 1964 1994 2014 2039} are active in vitro against organisms susceptible to amoxicillin or ampicillin alone. In addition, because clavulanic acid and sulbactam can inhibit certain β-lactamases that generally inactivate aminopenicillins, combinations of amoxicillin and clavulanate potassium^{311 312 314 316 318 1298 1437 1446 1450 1453 1454 1473 1486 1489 1494 1501} or ampicillin sodium and sulbactam sodium^{1901 1902 1903 1925 1955 1961 1962 1964 1986 1991 1994 2004 2014 2039} are active in vitro against many β-lactamase-producing organisms that are resistant to the aminopenicillin alone..

In Vitro Susceptibility Testing

Results of in vitro susceptibility tests with aminopenicillins may be affected by test media,⁷⁶ inoculum size,^{68 76 229 1263} and pH.^{76 229} Susceptibility testing for gram-negative bacilli is particularly affected by inoculum size.⁷³

The Clinical and Laboratory Standards Institute (CLSI) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to aminopenicillins, then an infection caused by this strain may be appropriately treated with the dosage of the drugs recommended for that type of infection and infecting species, unless otherwise contraindicated.²³⁶⁵ If results indicate that a clinical isolate has intermediate susceptibility to aminopenicillins, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue levels and response rates may be lower than for strains identified as susceptible.²³⁶⁵ Therefore, the intermediate category implies clinical applicability in body sites where the drugs are physiologically concentrated (e.g., urine) or when a high dosage of the drugs can be used.²³⁶⁵ This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.²³⁶⁵ If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to aminopenicillins, the strain is not inhibited by systemic concentrations of the drugs achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliably demonstrated in clinical studies.²³⁶⁵

Standard in vitro susceptibility tests cannot detect tolerance to penicillins since these tests do not directly measure bactericidal activity.^{119 120 124 125 133 138 152} This fact should be considered when evaluating results of in vitro susceptibility tests for gram-positive cocci.^{119 120 133 152}

Strains of staphylococci resistant to penicillinase-resistant penicillins also should be considered resistant to aminopenicillins, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drugs.²³⁶⁵

CLSI states that strains of enterococci identified as susceptible to aminopenicillins by in vitro susceptibility tests may be susceptible only if high dosages of the drugs are used for the treatment of serious enterococcal infections; treatment of enterococcal endocarditis caused by susceptible enterococci requires concomitant treatment with an aminoglycoside.²³⁶⁵ In addition, the fact that ampicillin-resistant strains of enterococci that produce β-lactamase may not be reliably detected using the inoculum concentration recommended for routine disk or dilution susceptibility tests should be considered.²³⁶⁵ CLSI recommends that, for enterococcal isolates from blood or CSF, resistance may be detected by a β-lactamase test performed using an inoculum of 10⁷ CFU/mL or greater (or direct colony growth) and a nitrocefin-based substrate.²³⁶⁵ Synergy between ampicillin and an aminoglycoside is best predicted for enterococci by screening for susceptibility to 500 mcg of gentamicin or 1000–2000 mcg of streptomycin per mL.²³⁶⁵

Disk Susceptibility Tests

When disk-diffusion procedures are used to test susceptibility to aminopenicillins, a disk containing 10 mcg of ampicillin is used and results generally can be applied to ampicillin and amoxicillin.²³⁶⁵

CLSI states that, for non-β-lactamase-producing enterococci, results of disk-diffusion in vitro susceptibility tests using the ampicillin disk can be used to predict susceptibility to amoxicillin and clavulanate potassium or ampicillin sodium and sulbactam sodium.²³⁶⁵ However, for staphylococci, Enterobacteriaceae, and Haemophilus, disks containing fixed combinations of amoxicillin and clavulanate potassium or ampicillin sodium and sulbactam sodium should be used.²³⁶⁵

When disk-diffusion procedures are performed according to CLSI standardized procedures to test susceptibility of Enterobacteriaceae using the ampicillin disk, CLSI recommends that organisms with growth inhibition zones of 17 mm or greater be considered susceptible to aminopenicillins and those with zones of 13 mm or less be considered resistant to the drugs.²³⁶⁵ CLSI recommends that Enterobacteriaceae with zones of 14–16 mm be considered to have intermediate susceptibility to aminopenicillins.²³⁶⁵

Enterococci with growth inhibition zones of 17 mm or greater are considered susceptible to aminopenicillins and those with zones of 16 mm or less are considered resistant to the drugs.²³⁶⁵

Susceptibility of staphylococci to aminopenicillins should preferably be tested using a disk containing 10 penicillin G units, with interpretation of results being the same as for natural penicillins.²³⁶⁵ However, if the ampicillin disk is used to test susceptibility of staphylococci, CLSI recommends that staphylococci with growth inhibition zones of 29 mm or greater be considered susceptible to aminopenicillins and those with zones of 28 mm or less be considered resistant to the drugs.²³⁶⁵

When the disk diffusion procedure is performed according to CLSI standardized procedures using the ampicillin disk and Haemophilus Test Media (HTM), CLSI recommends that Haemophilus with growth inhibition zones of 22 mm or greater be considered susceptible to aminopenicillins, those with zones of 19–21 be considered to have intermediate susceptibility, and those with zones of 18 mm or less be considered resistant to the drugs.²³⁶⁵

CLSI recommends that when susceptibility of β-hemolytic streptococci to aminopenicillins is evaluated using the ampicillin disk and Mueller-Hinton agar (with 5% sheep blood), strains with growth inhibition zones of 24 mm or greater be considered susceptible to aminopenicillins.²³⁶⁵ Because strains of β-hemolytic streptococci with growth inhibition zones less than 24 mm have not been reported to date, any such strains should be submitted to a reference laboratory.²³⁶⁵ CLSI states that disk-diffusion susceptibility tests are not reliable for testing susceptibility of S. pneumoniae to aminopenicillins; dilution susceptibility tests should be used for this organism.²²⁶⁵ Because strains of β-hemolytic streptococci with growth inhibition zones less than 24 mm have not been reported to date, any such strains should be submitted to a reference laboratory.²³⁶⁵ CLSI states that disk-diffusion susceptibility tests are not reliable for testing susceptibility of S. pneumoniae to aminopenicillins; dilution susceptibility tests should be used for this organism.²³⁶⁵

When disk-diffusion procedures are performed according to CLSI standardized procedures using the ampicillin disk, Vibrio cholerae with growth inhibition zones of 17 mm or greater are considered susceptible to aminopenicillins, those with zones of 14–16 mm are considered to have intermediate susceptibility, and those with zones of 13 mm or less are considered resistant to aminopenicillins.²³⁶⁵

Dilution Susceptibility Tests

When dilution susceptibility testing (e.g., agar or broth dilution) is used, results of tests using ampicillin generally can be applied to ampicillin and amoxicillin.²³⁶⁵ CLSI states that, for streptococci (including S. pneumoniae) and non-β-lactamase-producing enterococci, results of dilution tests using ampicillin can be used to predict susceptibility to amoxicillin and clavulanate potassium or ampicillin sodium and sulbactam sodium.²³⁶⁵ However, for staphylococci, Enterobacteriaceae, and Haemophilus, dilution susceptibility testing should be performed using combinations of amoxicillin and clavulanate potassium or ampicillin sodium and sulbactam sodium.²³⁶⁵

When dilution susceptibility testing is performed according to CLSI standardized procedures using ampicillin, CLSI recommends that Enterobacteriaceae with MICs of 8 mcg/mL or less be considered susceptible to aminopenicillins, those with MICs of 16 mcg/mL be considered to have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater be considered resistant to the drugs.²³⁶⁵

Enterococci with ampicillin MICs of 8 mcg/mL or less are considered susceptible and those with MICs of 16 mcg/mL or greater are considered resistant to aminopenicillins.²³⁶⁵ Susceptible strains of enterococci require high aminopenicillin dosage for the treatment of serious infections and concomitant use of an aminoglycoside in patients with enterococcal endocarditis.²³⁶⁵

When dilution susceptibility testing is performed according to CLSI standardized procedures, staphylococci with ampicillin MICs of 0.25 mcg/mL or less are considered susceptible to aminopenicillins and those with ampicillin MICs of 0.5 mcg/mL or greater are considered resistant to the drugs.²³⁶⁵

When susceptibility of Haemophilus is tested in a broth dilution procedure according to CLSI standardized procedures using ampicillin and HTM, Haemophilus with MICs of 1 mcg/mL or less are considered susceptible to aminopenicillins, those with MICs of 2 mcg/mL are considered to have intermediate susceptibility, and those with MICs of 4 mcg/mL or greater are considered resistant to the drugs.²³⁶⁵

When testing susceptibility of viridans streptococci using CLSI standardized procedures, CLSI recommends that those with ampicillin MICs of 0.25 mcg/mL or less be considered susceptible to aminopenicillins, those with MICs of 0.5–4 mcg/mL be considered to have intermediate susceptibility, and those with MICs of 8 mcg/mL or greater be considered resistant to the drugs.²³⁶⁵ When testing β-hemolytic streptococci, those with ampicillin MICs of 0.25 mcg/mL or less are considered susceptible to aminopenicillins.²³⁶⁵ Because strains of β-hemolytic streptococci with ampicillin MICs greater than 0.25 mcg/mL have not been reported to date, any such strains should be submitted to a reference laboratory.²³⁶⁵

Vibrio cholerae with ampicillin MICs of 8 mcg/mL or less are considered susceptible to aminopenicillins, those with MICs of 16 mcg/mL are considered to have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater are considered resistant to aminopenicillins.²³⁶⁵

Gram-positive Aerobic Bacteria

Aminopenicillins are active in vitro against many gram-positive aerobic cocci including nonpenicillinase-producing strains of Staphylococcus aureus^{36 38 39 42 45 46 48 49 61 73 76 116 205 226 228} and S. epidermidis;^{36 38 39 42 45 46 48 49 61 76 116 205} groups A, B, C, and G streptococci;^{61 76 116 205 226 228} Streptococcus pneumoniae;^{36 38 39 42 45 46 48 49 61 73 76 116 177 205 226 228} viridans streptococci;^{61 116 176 205 228} and some strains of enterococci.^{36 38 39 42 45 46 48 49 61 73 116 176 196 205 226 228 229 1303} Penicillinase-producing strains of S. aureus and S. epidermidis are resistant to the drugs.^{36 38 39 42 45 46 48 49 61 64 68 75 76 116 226 228 229} In vitro, aminopenicillins are slightly less active on a weight basis than natural penicillins against most susceptible gram-positive cocci;^{64 68} however, the drugs are generally more active in vitro than natural penicillins against enterococci.^{61 64 67}

The MIC₉₀ (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of amoxicillin^{73 226 228} or ampicillin^{73 116 205 226 228} reported for most strains of nonpenicillinase-producing S. aureus is 0.12–0.25 mcg/mL. The MIC₉₀ of the drugs reported for nonpenicillinase-producing S. epidermidis is 0.12–0.4 mcg/mL.^{116 205} In one in vitro study, several strains of S. simulans, S. hominis, and S. warneri were inhibited by ampicillin concentrations of 0.125–0.25 mcg/mL and several strains of S. haemolyticus were inhibited by ampicillin concentrations of 1 mcg/mL.¹¹⁰⁸

Amoxicillin^{61 73 116 177 226 228} or ampicillin^{61 116 175 176 181 205 226 228 1055} concentrations of 0.01–0.25 mcg/mL generally inhibit groups A,^{61 116 176 205 226 228} B,^{61 116 175 176 181 205} C,^{176 205} and G^{176 205 1055} streptococci, S. pneumoniae,^{61 73 116 176 177 205 226 228} and viridans streptococci^{61 116 176 205 228} in vitro.

Amoxicillin reportedly is slightly more active on a weight basis than ampicillin against Enterococcus faecalis,^{73 228 229} and susceptible strains of the organism are generally inhibited in vitro by amoxicillin concentrations of 0.38–3 mcg/mL^{61 73 116 226 228 229} or ampicillin concentrations of 0.5–5 mcg/mL.^{61 73 176 196 205 226 1303} Although some strains of E. faecium are inhibited in vitro by 0.5–8 mcg/mL of ampicillin,^{2091 2093 2099} many strains of the organism require concentrations of 16 mcg/mL or greater for in vitro inhibition and are considered resistant to aminopenicillins.^{2091 2093 2096 2099}

Aminopenicillins are also active in vitro against several gram-positive aerobic bacilli.^{116 228} Corynebacterium diphtheriae is reportedly inhibited in vitro by amoxicillin or ampicillin concentrations of 0.02–0.4 mcg/mL.^{116 228} Susceptible strains of Listeria monocytogenes are inhibited in vitro by 0.1–0.8 mcg/mL of either drug.^{61 116 228 1197 1198}

In vitro, amoxicillin concentrations of 0.25 mcg/mL^{116 228} or ampicillin concentrations of 0.03 mcg/mL¹¹⁶ inhibit some strains of Bacillus anthracis. Erysipelothrix rhusiopathiae is generally inhibited in vitro by amoxicillin or ampicillin concentrations of 0.02–0.05 mcg/mL.^{116 228}

Although most strains of Nocardia are resistant to aminopenicillins, a few strains are reportedly inhibited in vitro by amoxicillin or ampicillin concentrations of 1.6–16 mcg/mL.^{116 163 1104 1302 1412}

Gram-negative Aerobic Bacteria

Neisseria

Aminopenicillins are active in vitro against most strains of Neisseria meningitidis^{36 38 39 42 45 46 48 49 61 116 228} and nonpenicillinase-producing N. gonorrhoeae.^{36 38 39 42 45 46 48 49 61 116 170 171 196 228 1102 1103}

N. meningitidis is generally inhibited in vitro by amoxicillin^{116 228} or ampicillin^{61 116} concentrations of 0.02–0.06 mcg/mL.

Nonpenicillinase-producing strains of N. gonorrhoeae are generally inhibited by amoxicillin or ampicillin concentrations of 0.01–0.35 mcg/mL.^{170 171 196 1102 1103 1263} Some strains of N. gonorrhoeae that are relatively resistant to penicillin G may be susceptible to amoxicillin⁷³ or ampicillin;^{68 1103} however, penicillinase-producing strains of N. gonorrhoeae are usually also resistant to aminopenicillins.^{61 1102 1263}

Haemophilus

Aminopenicillins are active in vitro against many strains of Haemophilus influenzae^{36 38 39 42 45 46 48 49 61 68 73 116 170 196 205 218 226} and some strains of H. parainfluenzae^{1166 1250 1337} and H. ducreyi.^{116 314 1165}

Susceptible strains of H. influenzae or H. parainfluenzae are inhibited in vitro by amoxicillin concentrations of 0.05–0.8 mcg/mL^{61 73 116 226 228 449} or ampicillin concentrations of 0.025–1 mcg/mL;^{61 68 116 170 196 205 218 226 306 309 1167 1250 1295} β-lactamase-producing strains are resistant to aminopenicillins.^{61 170 205 309 449 1166 1167 1250 1275} Although most strains of H. ducreyi are β-lactamase producers and are resistant to aminopenicillins, some strains of the organism are inhibited in vitro by amoxicillin or ampicillin concentrations of 0.25–2 mcg/mL.^{116 314 1165}

Enterobacteriaceae

Aminopenicillins also have some activity against Enterobacteriaceae and are active in vitro against some strains of Escherichia coli,^{36 38 39 42 45 46 48 49 61 73 76 116 217 226 228} Proteus mirabilis,^{36 38 39 42 45 46 48 49 61 76 116 226 228} Salmonella,^{38 39 42 45 46 48 49 61 76 116 226 228 229 1273} and Shigella.^{38 39 42 45 46 48 49 61 76 116 226 228} Although rare strains of P. vulgaris,⁶¹ Enterobacter aerogenes,^{116 149} and Citrobacter freundii¹¹⁶ are reportedly inhibited in vitro by high concentrations of ampicillin, aminopenicillins are inactive against most strains of these organisms.^{61 63 116 226}

Although strains of E. coli resistant to aminopenicillins have been reported with increasing frequency, some strains of the organism are inhibited in vitro by amoxicillin^{61 73 116 226 228} or ampicillin^{61 116 217 226 228} concentrations of 1.25–12.5 mcg/mL. Susceptible strains of P. mirabilis are reportedly inhibited in vitro by amoxicillin^{61 116 226} or ampicillin^{61 116 226} concentrations of 0.8–5 mcg/mL.

Amoxicillin is reportedly slightly more active on a weight basis than ampicillin against susceptible Salmonella;^{72 229} however, ampicillin is reportedly slightly more active on a weight basis than other aminopenicillins against susceptible Shigella.²²⁹ Susceptible strains of Salmonella are generally inhibited in vitro by amoxicillin concentrations of 0.8–3 mcg/mL^{116 226 228 229 454} and ampicillin.^{61 116 226 454 1294} In one study, the MIC₉₀ of ampicillin for S. typhi was 0.5 mcg/mL and the MIC₉₀ for S. enteritidis was 2.5 mcg/mL.¹²⁹³ In vitro, susceptible strains of Shigella are generally inhibited by amoxicillin concentrations of 1.5–12.5^{116 226 228} or ampicillin concentrations of 1–5 mcg/mL.^{116 226}

Other Gram-negative Aerobic Bacteria

Aminopenicillins are active in vitro against Bordetella pertussis^{61 116 182 228} and Eikenella corrodens,¹¹⁶ and most strains of these organisms are reportedly inhibited in vitro by ampicillin concentrations of 0.1–8 mcg/mL.^{61 116 182}

Ampicillin has some activity in vitro against Legionella, although the drug may not be effective clinically.^{116 184 185 1170 1402} In vitro, some strains of L. pneumophila are inhibited by ampicillin concentrations of 0.25–4 mcg/mL.^{116 184 185 1170} Ampicillin concentrations of 0.06–1 mcg/mL inhibit some strains of L. micdadei (the Pittsburgh pneumonia agent), L. bozemanii, and L. gormanii and ampicillin concentrations of 4–16 mcg/mL inhibit some strains of L. dumoffii in vitro.¹⁸⁴

Pasteurella multocida, an organism that can be aerobic or facultatively anaerobic, is usually inhibited in vitro by ampicillin concentrations of 0.1–1.6 mcg/mL.^{68 183} In vitro, amoxicillin^{116 228} or ampicillin^{61 68 116} concentrations of 0.1–2.5 mcg/mL reportedly inhibit some strains of Brucella.

Ampicillin concentrations of 0.13 mcg/mL generally inhibit Gardnerella vaginalis.¹⁹¹

In vitro, ampicillin concentrations of 0.12 mcg/mL generally inhibit strains of Moraxella catarrhalis that do not produce β-lactamase; however, many strains of the organism are β-lactamase producers and are therefore resistant to the drug.¹³⁹⁵

Amoxicillin and ampicillin reportedly have some in vitro activity against Campylobacter fetus, and the MIC₉₀ of the drugs reported for some strains of C. fetus subsp. jejuni is 6.3–12.5 mcg/mL.^{116 187} The MIC₉₀ of ampicillin for Helicobacter pylori reportedly is less than 0.03 mcg/mL.^{1634 1844} Limited data indicate that H. pylori generally is inhibited by amoxicillin concentrations of 0.06 mcg/mL or less;¹⁸⁴⁵ amoxicillin also has demonstrated bactericidal activity against slowly growing H. pylori.¹⁸⁴⁶ The combination of amoxicillin plus metronidazole or its hydroxy metabolite has demonstrated synergism in vitro against H. pylori.¹⁸⁴⁷

Some strains of Vibrio cholerae are reportedly inhibited in vitro by amoxicillin concentrations of 5 mcg/mL.^{116 228}

Aminopenicillins are inactive against Pseudomonas, including Ps. aeruginosa.^{61 73 116 217 226 228 317}

Anaerobic Bacteria

Aminopenicillins are active in vitro against many gram-positive anaerobic bacteria including some strains of Actinomyces,^{61 68 116} Arachnia,⁶¹ Bifidobacterium,^{61 116} Clostridium tetani,^{116 228} C. perfringens,¹¹⁶ Eubacterium,^{61 116} Lactobacillus,^{61 116} Peptococcus,¹¹⁶ Peptostreptococcus,¹¹⁶ and Propionibacterium.⁶¹ The MIC₉₀ of ampicillin reported for Peptococcus and Peptostreptococcus is 0.25 mcg/mL.¹¹⁶ Ampicillin concentrations of 0.25–6.2 mcg/mL reportedly inhibit susceptible strains of Clostridium, including C. perfringens.¹¹⁶ Some strains of C. tetani are reportedly inhibited in vitro by amoxicillin concentrations of 0.05 mcg/mL.²²⁸

Fusobacterium, a gram-negative anaerobe, is generally inhibited in vitro by ampicillin concentrations of 6.2 mcg/mL.¹¹⁶ Many strains of Bacteroides melaninogenicus (Prevotella melaninogenica) are inhibited in vitro by amoxicillin concentrations of 0.5–1 mcg/mL⁶¹ or ampicillin concentrations of 0.5–4 mcg/mL.⁶¹ The B. fragilis group (e.g., B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus) is usually resistant to aminopenicillins.^{61 63 1298}

Spirochetes

Aminopenicillins are active against some spirochetes including Treponema pallidum.^{61 75} T. pallidum is generally inhibited in vitro by amoxicillin concentrations of 0.5 mcg/mL.⁷⁵ Borrelia burgdorferi, the causative organism of Lyme disease, reportedly may be inhibited in vitro by ampicillin concentrations of 0.25–1 mcg/mL or less^{1628 1756} and by amoxicillin concentrations of 0.5 mcg/mL;¹⁷⁵⁴ minimum bactericidal concentrations of amoxicillin for B. burgdorferi generally have ranged from 0.4–3.2 mcg/mL.^{1133 1743 1770}

Resistance

Complete cross-resistance generally occurs between amoxicillin and ampicillin.^{73 75 226 228}

Resistance in Gram-positive Bacteria

Because aminopenicillins are readily inactivated by staphylococcal penicillinases, penicillinase-producing S. aureus and S. epidermidis are resistant to the drugs.^{36 38 39 42 45 46 48 49 61 64 68 75 76 116 226 228 229}

Some strains of S. pneumoniae that are relatively resistant to penicillin G may be susceptible to ampicillin;^{61 1178} however, strains of S. pneumoniae that are completely resistant to penicillin G are also resistant to ampicillin.^{61 177}

Enterococcus faecium generally is resistant to aminopenicillins.^{2091 2092 2093 2096 2097 2099} Resistance to aminopenicillins in some enterococci (e.g., E. faecalis, E. faecium) can result from β-lactamase production^{2090 2091 2092 2094 2095 2096 2097 2098} or from decreased binding to and/or increased production of penicillin-binding proteins with a low affinity for the drugs (e.g., PBP 5 or 6).^{2090 2091 2092 2093 2098 2099} Enterococci that exhibit ampicillin resistance secondary to β-lactamase production may be susceptible in vitro when the aminopenicillin is combined with a β-lactamase inhibitor (e.g., clavulanic acid, sulbactam);^{2092 2095 2097} however, addition of the β-lactamase inhibitor does not necessarily result in susceptibility to the aminopenicillin in such strains.^{2096 2097} Some strains of enterococci with relatively high aminopenicillin resistance secondary to β-lactamase production may remain resistant or be only moderately more susceptible to the aminopenicillin combined with a β-lactamase inhibitor.^{2096 2097} Strains that exhibit ampicillin resistance secondary to alterations in PBPs remain resistant when the drug is combined with a β-lactamase inhibitor such as sulbactam or clavulanic acid,^{2091 2092} and some evidence suggests that such strains occasionally may emerge secondary to high-dose drug exposure.²⁰⁹¹ In addition, enterococci resistant to multiple drugs (e.g., vancomycin, teicoplanin, aminoglycosides, ampicillin, penicillin G, imipenem, tetracyclines, synergistic combinations of β-lactam anti-infectives) have been reported with increasing frequency.^{2090 2091 2092 2093 2094 2095 2096 2098}

Resistance in Gram-negative Bacteria

Penicillinase-producing strains of N. gonorrhoeae that are completely resistant to natural penicillins are usually also resistant to aminopenicillins;^{61 215 241 1263} however, some strains of N. gonorrhoeae that are relatively resistant to natural penicillins may be inhibited in vitro by aminopenicillins.⁶¹

Strains of E. coli that are resistant to aminopenicillins have been reported with increasing frequency.^{61 64 74 139} Approximately 30–50% of clinical isolates of E. coli have been reported to be resistant to the drugs.^{61 64 116 139} Resistance to aminopenicillins in these organisms generally results from the production of β-lactamases^{61 139 229} which can be either plasmid-mediated or chromosomally mediated.^{61 132 139 1177} Strains of P. mirabilis that produce β-lactamases are also generally resistant to aminopenicillins.⁶¹ Resistance to aminopenicillins in Citrobacter¹³⁹ and Enterobacter^{139 150} also generally results from the production of β-lactamases that inactivate the drugs.

Resistance to aminopenicillins has been reported only rarely in Salmonella typhi;^{61 63 1294 1398} however, resistant strains of nontyphoidal Salmonella (e.g., S. typhimurium) have been reported with increasing frequency.^{1272 1273 1305} Approximately 40% of clinical isolates of S. typhimurium are reportedly resistant to aminopenicillins.^{61 74} Strains of Salmonella resistant to aminopenicillins may also be resistant to aminoglycosides, tetracyclines, and sulfonamides.^{1272 1305 1398} Resistance in Salmonella generally results from a plasmid-mediated resistance factor that is acquired by conjugation.^{61 1398}

A large percentage of clinical isolates of Shigella are reportedly resistant to aminopenicillins; however, susceptibility shows considerable geographic variability.^{61 74 1402} Ampicillin resistance occurs more frequently in strains of Sh. sonnei than in strains of Sh. flexneri or Sh. dysenteriae.^{61 74} Resistance to ampicillin in Shigella usually results from a plasmid-mediated resistance factor which can be acquired by conjugation.^{61 116 131} Strains of Shigella resistant to ampicillin are also generally resistant to chloramphenicol, sulfonamides, streptomycin, and tetracyclines,^{61 116} but may be susceptible to co-trimoxazole.¹¹⁶

Ampicillin-Resistant Haemophilus

Ampicillin-resistant strains of H. influenzae and H. parainfluenzae have been reported with increasing frequency;^{61 64 76 155 156 1166 1167 1246 1275 1299 1731} however, susceptibility shows considerable geographic variability.^{116 1166 1169 1275 1389 1731} Approximately 2–35% of clinical isolates of H. parainfluenzae^{61 64 116 156 218 917 972 1169 1275 1389 1391 1731} and 15–86% of clinical isolates of H. parainfluenzae type b, H. influenzae nontype b, and in nonencapsulated (nontypable) strains of the organism.^{61 156 1169 1391 1731}

Ampicillin resistance in H. influenzae or H. parainfluenzae generally results from β-lactamases that are plasmid-mediated and can be acquired by conjugation;^{61 156 306 309 1166 1167 1246 1250 1265 1275 1391 1731} however, resistance has also been reported rarely in strains of H. influenzae that did not produce β-lactamases.^{155 156 1246 1265 1731} Ampicillin-resistant strains of H. influenzae or H. parainfluenzae are also resistant to natural penicillins^{61 155 156 205 218 1166 1167} and extended-spectrum penicillins,^{100 170 205 241} but may be susceptible to chloramphenicol, gentamicin, co-trimoxazole,^{61 155 218 1167 1246 1299 1731} or second or third generation cephalosporins (e.g., cefaclor, cefotaxime, cefoxitin, cefuroxime).^{61 218 249 1246 1299} Strains of H. influenzae that are resistant to both ampicillin and chloramphenicol or ampicillin and co-trimoxazole have been reported rarely.^{1275 1299 1731}

Aminopenicillins General Statement Pharmacokinetics

For additional information on the pharmacokinetics of amoxicillin and ampicillin, see Pharmacokinetics in the individual monographs in 8:12.16.08.

Absorption

Like other penicillins, absorption of orally administered aminopenicillins occurs mainly in the duodenum and upper jejunum⁸¹ and the rate and extent of absorption depends on the particular aminopenicillin derivative,^{64 320 328 351 366 443 466 479 487} dosage form administered,⁷⁶ gastric and intestinal pH,^{341 428} and presence of food in the GI tract.^{61 68 342 428 449 457 478 490}

Aminopenicillins are more resistant to acid-catalyzed hydrolysis than natural penicillins^{64 65 68 90 575} and most penicillinase-resistant penicillins.^{68 575} Amoxicillin,^{36 73 341 428} amoxicillin trihydrate,^{64 81} ampicillin,^{64 68 81 341} and ampicillin trihydrate^{42 45 46 48 49 68} are generally stable in the presence of acidic gastric secretions and are fairly well absorbed following oral administration; however, there are variations in the extent and rate of absorption of the drugs from the GI tract.^{328 351 366 428 433 449 493}

Following oral administration of single doses of the drugs in healthy, fasting adults, peak serum concentrations of ampicillin^{68 81 443 512} or amoxicillin^{36 81 328 346 455 494} are generally attained within 1–2 hours and serum concentrations are usually low or undetectable 6–8 hours later.⁴⁷⁹ Although the drugs are generally absorbed at the same rate, amoxicillin is more completely absorbed from the GI tract than is ampicillin^{73 328 351 366 428 493} and peak serum concentrations of amoxicillin are generally 2–2.5 times higher than those attained with an equivalent oral dose of ampicillin.^{73 81 328 428 479 493} Approximately 74–92% of a single oral dose of amoxicillin^{61 73 320 366 487} is absorbed from the GI tract in fasting adults, but only 30–55% of a single oral dose of ampicillin is absorbed.^{63 67 81 320 341 366 494 487} In one crossover study in healthy, fasting adults who received single 500-mg oral doses of amoxicillin and ampicillin, the area under the serum concentration-time curve (AUC) was approximately 50% larger with amoxicillin than with ampicillin.⁴⁷⁹

As oral dosage of amoxicillin⁴³³ is increased, the fraction of the dose absorbed from the GI tract decreases only slightly and peak serum concentrations and AUCs of the drugs generally increase linearly with increasing dosage. However, as oral dosage of ampicillin is increased from 500 mg to 2 g, the fraction of the dose absorbed decreases and there is a nonlinear relationship between dosage and peak serum concentrations or AUCs of ampicillin.⁴³³

Preliminary data indicate that the volume of water administered with amoxicillin capsules may influence the extent of absorption of the drug.^{455 457 466} In one study, the mean peak serum concentration and AUC of amoxicillin were lower when two 250-mg capsules of the drug were administered with 25 mL of water than when the same dose was administered with 250 mL of water.⁴⁶⁶ This effect did not occur when two 250-mg capsules of ampicillin were administered with 25 mL or 250 mL of water, presumably because ampicillin is more water soluble than amoxicillin.⁴⁶⁶

Oral absorption of aminopenicillins is delayed in neonates compared with absorption of the drugs in children and adults.^{73 340 358} Following oral administration of a single dose of amoxicillin in neonates, peak serum concentrations of the drug are generally attained within 3–4.5 hours^{340 358} compared with 1–2 hours in children^{340 449 462 489} and adults.^{81 328 346 358 455 494} In one study in a limited number of patients with celiac disease, absorption of amoxicillin, but not ampicillin, was reduced following oral administration.¹¹⁰⁸

Presence of food in the GI tract generally decreases the rate and extent of absorption of ampicillin.^{342 457 466} Although presence of food in the GI tract reportedly results in lower and delayed peak serum concentrations of amoxicillin,^{226 228 466} the total amount of drug absorbed does not appear to be affected.^{73 228 342 428 457 466}

Ampicillin sodium is well absorbed following IM administration and peak serum concentrations of the drug are generally higher than those resulting from equivalent doses of the drug given orally.^{67 338 404 453} Following IM administration of a single dose of ampicillin sodium in healthy adults, peak serum concentrations of ampicillin are generally attained within 1 hour^{67 72 404 453} and serum concentrations are low or undetectable 6–8 hours later.^{404 453} Rapid IV administration of ampicillin sodium results in peak serum concentrations of the drug immediately after completion of the infusion and serum concentrations are still detectable 6 hours later.⁵⁵⁶

Ampicillin is absorbed from the peritoneal cavity following local instillation of the drug.³²⁸

Distribution

Aminopenicillins are widely distributed following absorption from the GI tract or injection sites.^{61 73 333} The apparent volumes of distribution of amoxicillin^{455 487} and ampicillin^{453 482} are reportedly 0.267–0.315 L/kg in adults with normal renal function. Studies using IM or IV ampicillin or amoxicillin indicate that concurrent administration of oral probenecid decreases the volumes of distribution of the drugs.^{347 447} (See Drug Interactions: Probenecid.)

Aminopenicillins are generally distributed into ascitic,³³⁹ synovial,^{68 323 326 335} and pleural^{68 435} fluids. The drugs are also distributed into the liver,^{495 511} lungs,⁴⁹⁵ gallbladder,^{483 495} prostate,³³² and muscle.⁴⁹² Amoxicillin and^{73 333 428 431 511} ampicillin^{333 431 511 1171} are generally distributed into middle ear effusions,⁵¹¹ bronchial secretions,^{333 432 1171} sputum,^{73 428 431} maxillary sinus secretions,^{73 599} and tonsils.⁷³ Low concentrations of the drug are also attained in saliva,^{73 321 500} sweat,⁵⁰⁰ and tears.⁵⁰⁰ Aminopenicillins are distributed into bile in varying amounts.^{320 428 495} If biliary obstruction is not present, concentrations of amoxicillin^{63 428 495} or ampicillin^{61 72 320} in bile are generally 1–30 times greater than concurrent serum concentrations of the drugs. Like other penicillins, only negligible amounts of amoxicillin⁷³ or ampicillin^{320 780} have been detected in aqueous humor following oral, IM, or IV administration of the drugs.

Only minimal concentrations of aminopenicillins are attained in CSF following oral, IM, or IV administration in patients with uninflamed meninges;^{61 456} higher concentrations may be attained when meninges are inflamed.⁴⁵⁶ In one study in patients with inflamed meninges who received a single 1-g oral dose of amoxicillin, CSF concentrations of the drug ranged from 0.1–1.5 mcg/mL 2 hours after the dose.⁴⁴⁶ Concurrent administration of oral probenecid with amoxicillin or ampicillin generally results in increased CSF concentrations of the drug.^{76 447} (See Drug Interactions: Probenecid.)

Because aminopenicillins contain a free amino group at R on the penicillin nucleus, these drugs are considerably less protein bound than other currently available penicillins.⁵⁷⁵ Amoxicillin and ampicillin are 17–20^{36 64 81 226 428 491} and 15–25%^{38 39 42 45 46 48 49 68 72 81 336 491} bound to serum proteins, respectively. The drugs bind mainly to serum albumin.³²⁰ Protein binding of the drugs is lower in neonates than in children or adults;^{81 340} ampicillin is reportedly 8–12% bound to serum proteins in neonates.^{81 340}

Amoxicillin^{73 439} and ampicillin^{61 68 320 467} readily cross the placenta. Amoxicillin concentrations in cord blood are reportedly 25–33% of concurrent maternal serum concentrations of the drug.⁷³ Amoxicillin^{61 73 496} and ampicillin^{355 1568} are distributed into milk in low concentrations.

Elimination

Serum concentrations of amoxicillin^{503 601} and ampicillin decline in a biphasic manner. The distribution half-life (t_½α) of amoxicillin is reportedly 0.19–0.39 hours in adults with normal renal function.^{487 601} The elimination half-lives (t_½βs) of amoxicillin^{320 341 428 455 479 493 500 601} and ampicillin^{341 453} are similar and are reportedly 0.7–1.4 hours in adults with normal renal function.

Aminopenicillins are metabolized to varying extents.^{81 366 455 477} The drugs are partially metabolized by hydrolysis of the β-lactam ring to penicilloic acids which are microbiologically inactive.^{73 81 366 455 477} Approximately 19–33% of a single oral dose of amoxicillin,^{73 81 320 341 366 477} 7–11% of a single oral dose of ampicillin,^{81 366 455 477} or 10–12% of a single IM dose of ampicillin sodium^{320 366} is excreted in urine as penicilloic acids. Trace amounts of 6-aminopenicillanic acid (6-APA), formed by removal of the side chain at R on the penicillin nucleus, have also been found in urine following oral administration of ampicillin.³⁶⁶

Aminopenicillins and metabolites of the drugs are rapidly excreted in urine.^{61 76} Like other penicillins, the drugs are excreted by renal tubular secretion and to a lesser extent by glomerular filtration.⁶¹ Small amounts of the drugs are also excreted in feces and bile.^{61 76 509} In adults with normal renal function, approximately 20–64% of a single oral dose of ampicillin^{73 81 336 351 443 479 493} and 43–80% of a single oral dose of amoxicillin^{36 73 81 226 228 428 479 493} are excreted unchanged in urine within 6–8 hours. Approximately 60–70% of a single IM dose of ampicillin sodium^{336 337} or 73–90% of a single IV dose of the drug⁴⁹⁰ is excreted unchanged in urine.

Serum clearance of amoxicillin is reportedly 283 mL/minute⁶⁰¹ and serum clearance of ampicillin is reportedly 259 mL/minute in adults with normal renal function.

Serum concentrations of aminopenicillins are higher and the serum half-lives of the drugs are prolonged in patients with renal impairment.^{61 76 81 320 328 348 438 473 510 601} The serum half-lives of amoxicillin^{438 601} and ampicillin^{61 320 348} reportedly range from 7.4–21 hours in patients with creatinine clearances less than 10 mL/minute.

Serum concentrations of amoxicillin and ampicillin are generally higher and the serum half-lives of the drugs are longer in neonates than in older children or adults.^{340 358 444 470 484} Serum half-lives of the drugs are generally inversely proportional to birthweight, gestational age, and chronologic age.³⁴⁰ This appears to result from immature mechanisms for renal tubular secretion of the drugs.^{340 470} The serum half-life of ampicillin is reportedly 4 hours in neonates 2–7 days of age, 2.8 hours in neonates 8–14 days of age, and 1.7 hours in neonates 15–30 days of age.⁶¹ The serum half-life of amoxicillin is reportedly 3.7 hours in full-term neonates and 0.9–1.9 hours in infants and children.³⁴⁰

Renal clearance of aminopenicillins is also decreased in geriatric patients because of diminished tubular secretory ability; therefore, serum concentrations of the drugs are generally higher and the serum half-lives prolonged in these patients.⁴⁸² In one study in 5 geriatric patients 67–76 years of age, the t_½β of ampicillin ranged from 1.4–6.2 hours.⁴⁸²

Oral probenecid administered shortly before or with aminopenicillins competitively inhibits renal tubular secretion of the penicillins and produces higher and prolonged serum concentrations of the drugs.^{61 73 76 81 226 229 328 346 347} (See Drug Interactions: Probenecid.)

Amoxicillin^{63 73 81 428 438 451 473 601 1373 1554} and ampicillin^{63 64 320 348 510 1373} are removed by hemodialysis. The amount of the drugs removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow-rate); however, a 4- to 6-hour period of hemodialysis generally removes 30–40% of a single oral or IV dose of the drugs into the dialysate when the dose is given immediately prior to dialysis.^{438 510 601} Only minimal amounts of amoxicillin^{509 1373} or ampicillin^{64 328 340 348 1373} appear to be removed by peritoneal dialysis.

Chemistry and Stability

Chemistry

Aminopenicillins are semisynthetic penicillin derivatives produced by acylation of 6-aminopenicillanic acid (6-APA).^{61 76} Aminopenicillins have a free amino group at the α-position at R on the penicillin nucleus^{62 68 74 76 88 297 575} which results in enhanced activity against gram-negative bacteria compared with natural penicillins and penicillinase-resistant penicillins.^{62 68 74 88 297 575} The aminopenicillins group includes amoxicillin and ampicillin.⁷⁶

Ampicillin is the prototype drug of the aminopenicillins.^{64 76 77} Ampicillin differs structurally from penicillin G only in the presence of an amino group at the α-position on the benzene ring at R on the penicillin nucleus.⁸⁸ Amoxicillin is the p-hydroxyl analog of ampicillin.^{68 89 575}

Amoxicillin is commercially available as the trihydrate³⁶ and ampicillin is commercially available as the trihydrate or sodium salt.^{38 39} Amoxicillin also is commercially available in fixed-ratio combinations with clavulanate potassium,¹⁴³⁷ and ampicillin sodium also is commercially available in a fixed-ratio combination with sulbactam sodium.¹⁹⁰¹ Potency of amoxicillin³⁶ and ampicillin^{42 45 46 48 49} is calculated on the anhydrous basis.

Stability

Aminopenicillins are generally stable in the dry state;⁶⁴ however, the drugs are stable only for short periods of time in solution.^{38 39 64 82 94} Like other penicillins, the stability of aminopenicillins is pH and temperature dependent.^{82 90 94} Aminopenicillins are more resistant to acid-catalyzed hydrolysis than natural penicillins^{64 65 68 90 575} and are generally stable in the presence of acidic gastric secretions following oral administration.^{90 228} Amoxicillin and ampicillin reportedly have half-lives of 15–20 hours in solutions with a pH of 2 at 35°C.⁹⁰

Commercially available ampicillin preparations may contain small amounts of polymeric impurities.⁵⁷⁵ In addition, small amounts of ampicillin polymers can form in ampicillin solutions during in vitro storage.⁵⁷⁵ These polymers are potential antigens when combined with protein and appear to play a role in allergic sensitization to penicillins.⁵⁷⁵ .

The stability of ampicillin sodium in solution is concentration dependent and decreases as the concentration of the drug increases.⁸² Ampicillin sodium appears to be especially susceptible to inactivation in solutions containing dextrose, which appears to have a catalytic effect on hydrolysis of the drug.^{82 93} Although solutions of most other penicillins are reportedly stable when frozen,⁸² ampicillin at certain concentrations and in certain solutions rapidly decomposes when frozen.^{82 93} For a more complete discussion of the stability of amoxicillin and ampicillin, and solutions of the drugs, see Chemistry and Stability: Stability, in the individual monographs in 8:12.16.08.

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