Penicillins and Beta-Lactamase Inhibitors (Systemic)

This monograph includes information on the following:

1) Amoxicillin and Clavulanate
2) Ampicillin and Sulbactam 
3) Piperacillin and Tazobactam
4) Ticarcillin and Clavulanate


INN:
Amoxicillin— Amoxicilline

BAN:
Amoxicillin—Amoxycillin

VA CLASSIFICATION
Amoxicillin and Clavulanate
Primary: AM112

Ampicillin and Sulbactam
Primary: AM112

Piperacillin and Tazobactam
Primary: AM114

Ticarcillin and Clavulanate
Primary: AM114


Commonly used brand name(s): Augmentin1; Clavulin-125F1; Clavulin-2501; Clavulin-250F1; Clavulin-500F1; Tazocin3; Timentin4; Unasyn2; Zosyn3.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antibacterial (systemic)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations
Ampicillin and amoxicillin have activity against Haemophilus influenzae , Escherichia coli , and Salmonella and Shigella species, and also retain activity against penicillin-sensitive gram-positive bacteria. However, many Enterobacteriaceae and H. influenzae are resistant as a result of beta-lactamase production. {11} Amoxicillin has the same spectrum of activity as ampicillin, although amoxicillin has slightly better activity against Enterococcus faecalis , E. coli , and Salmonella sp., and slightly less activity against Shigella sp. {11} {48}

Ticarcillin combines the gram-negative spectrum of ampicillin with activity against most species of Enterobacter , Providencia , and Morganella sp. It also has some activity against Pseudomonas aeruginosa and some indole-positive Proteus sp. {11}

Piperacillin is more active than ticarcillin against P. aeruginosa and Klebsiella sp., but has activity similar to that of ticarcillin against most other gram-negative bacteria. {11} {29} Piperacillin also inhibits Pseudomonas cepacia , Pseudomonas maltophilia , and Pseudomonas fluorescens . {11}

Resistance to penicillins is thought to be due to three main mechanisms. The first is alteration of the antibiotic target sites' penicillin-binding proteins (PBPs); the second is inactivation of the penicillin by bacterially produced enzymes (beta-lactamases); and the third is decreased permeability of the cell wall to penicillins. Of these three mechanisms, production of beta-lactamase is the most common and the most important. {11} {29}

When combined with a penicillin, beta-lactamase inhibitors, which include clavulanic acid (clavulanate), sulbactam, and tazobactam, have effectively extended the penicillin's spectrum of activity. Like penicillins, the beta-lactamase inhibitors are beta-lactam compounds; however, they have minimal intrinsic antibacterial activity. {25} Instead of being hydrolyzed by beta-lactamases, they irreversibly bind to these enzymes, thereby protecting the penicillin from hydrolysis (`suicide' inhibition). Beta-lactamase inhibitors only work when a beta-lactamase enzyme is present. They will not alter the susceptibility of organisms inherently resistant to the penicillin; nor will they alter resistance patterns due to other causes, e.g., alteration of the penicillin-binding proteins (PBPs) (the mechanism of resistance for methicillin-resistant staphylococci). {25}

Clavulanate, sulbactam, and tazobactam are irreversible inhibitors of a wide variety of plasmid-mediated and some chromosomally mediated bacterial beta-lactamases. {11} {17} {19} Clavulanate and tazobactam are highly active, and sulbactam is moderately active, against transferable plasmid-mediated beta-lactamases. The inhibitory effect on chromosomally mediated type I enzymes is variable. Any beta-lactam agent, including beta-lactamase inhibitors and penicillins, may induce beta-lactamase production. {19} {21} Therefore, organisms such as Enterobacter , Serratia , Morganella , and Pseudomonas species may produce more beta-lactamase enzyme when they are exposed to a penicillin or a beta-lactamase inhibitor. Clavulanate is a moderate inducer of the chromosomal enzymes in these organisms; sulbactam and tazobactam are weaker inducers. {25} Also, if the complex with the beta-lactamase inhibitor is not stable, regeneration of the beta-lactamase may occur. If so, the enzyme must be repeatedly inactivated for inhibition to be maintained. It is also easier to protect a beta-lactam antibiotic against organisms that produce a small amount of enzyme than it is to protect against organisms producing a large amount. {19}

All three beta-lactamase inhibitors inactivate staphylococcal penicillinase. {12} Beta-lactamase inhibitors inactivate the chromosomally mediated beta-lactamases of Proteus vulgaris and Bacteroides sp., and the class IV beta-lactamases present in some Klebsiella sp. {19} Resistance in H. influenzae and Neisseria gonorrhoeae that produce TEM beta-lactamases is rare since these organisms produce only a small quantity of enzyme and are very permeable to the inhibitor. {19}

Clavulanate is a potent inhibitor of plasmid-mediated enzymes, most commonly found in Enterobacteriaceae. {08} However, all beta-lactamases are not equally susceptible. The class I beta-lactamases of the Richmond-Sykes classification are often resistant, including beta-lactamases typically produced by Enterobacter , Citrobacter , and Serratia species, and P. aeruginosa . {08} {17} Clavulanic acid is available as a combined product with both amoxicillin and ticarcillin, resulting in products with broad-spectrum antibacterial activity against beta-lactamase–producing strains of E. coli , H. influenzae , Moraxella (Branhamella) catarrhalis , many Klebsiella sp., most Bacteroides sp., Staphylococcus aureus , and Staphylococcus epidermidis , except methicillin-resistant staphylococcal strains. {08} Combining ticarcillin with clavulanic acid increases the activity of ticarcillin to include 60 to 80% of ticarcillin-resistant strains of Enterobacteriaceae and all beta-lactamase–producing strains of S. aureus , H. influenzae , and Bacteroides sp. No increase in activity is provided against P. aeruginosa . {11} {29}

Sulbactam also inhibits many beta-lactamases, including those produced by Bacteroides , Haemophilus , and Klebsiella sp., and N. gonorrhoeae , but it appears to be less potent than clavulanic acid against several beta-lactamases, including staphylococcal beta-lactamases, TEM-type enzymes, especially strains of E. coli and other pathogens producing TEM-1 and TEM-2 beta-lactamases, and the beta-lactamases typically present in Bacteroides fragilis . {08} {17} {19}

Tazobactam also has a broad spectrum of activity, and appears to be at least as effective as clavulanic acid against a wide variety of beta-lactamases. {08} {17} Tazobactam may have greater activity than clavulanate against some Enterobacteriaceae class I chromosomally mediated beta-lactamases, such as those of Morganella morganii , E. coli , Klebsiella pneumoniae , Citrobacter diversus , Proteus mirabilis , Providencia stuartii , and P. aeruginosa . {19} {26} Both tazobactam and clavulanate have greater activity against these organisms than sulbactam has. {26} The piperacillin and tazobactam combination also has good activity against staphylococci, streptococci, H. influenzae , Moraxella catarrhalis , Enterococcus faecalis , and Listeria monocytogenes . {21} {26} Greater resistance was seen with Enterococcus faecium , Enterobacter sp., Citrobacter freundii , Serratia sp., and Xanthomonas maltophilia . {21} {26}

Accepted

Bone and joint infections (treatment)—Ticarcillin and clavulanate combination and [ampicillin and sulbactam combination]1 are indicated in the treatment of bone and joint infections caused by susceptible organisms. {04} {05} {11} {29} {56} {59} {71}

Intra-abdominal infections (treatment)—Ampicillin and sulbactam combination, piperacillin and tazobactam combination, and ticarcillin and clavulanate combination are indicated in the treatment of intra-abdominal infections caused by susceptible organisms. {01} {04} {06} {23} {49} {56} {61} {69} {70} {71}

Otitis media, acute (treatment)—Amoxicillin and clavulanate combination is indicated in the treatment of acute otitis media caused by susceptible organisms. {02} {03} {43} {44} {67} {68}

Pelvic infections, female (treatment)—Ampicillin and sulbactam combination, piperacillin and tazobactam combination, and ticarcillin and clavulanate combination are indicated in the treatment of female pelvic infections caused by susceptible organisms. {01} {04} {06} {21} {53} {56} {62} {69} {70} {71}

Pneumonia, bacterial (treatment)—Amoxicillin and clavulanate combination, piperacillin and tazobactam combination, and ticarcillin and clavulanate combination are indicated in the treatment of bacterial pneumonia caused by susceptible organisms. {01} {02} {03} {04} {05} {34} {55} {59} {63} {64} {67} {68} {70} {71}

Pneumonia, nosocomial (treatment)—Piperacillin and tazobactam combination is indicated in the treatment of nosocomial pneumonia caused by susceptible organisms. {70}

Septicemia, bacterial (treatment)—Ticarcillin and clavulanate combination and [piperacillin and tazobactam combination]1 are indicated in the treatment of bacterial septicemia caused by susceptible organisms. {04} {05} {22} {59} {71}

Sinusitis (treatment)—Amoxicillin and clavulanate combination is indicated in the treatment of sinusitis caused by susceptible organisms. {02} {03} {42} {67} {68}

Skin and soft tissue infections (treatment)—Amoxicillin and clavulanate combination, ampicillin and sulbactam combination, piperacillin and tazobactam combination, and ticarcillin and clavulanate combination are indicated in the treatment of skin and soft tissue infections caused by susceptible organisms. {01} {02} {03} {04} {05} {06} {24} {32} {33} {50} {67} {68} {69} {70} {71}

Urinary tract infections, bacterial (treatment)—Amoxicillin and clavulanate combination and ticarcillin and clavulanate combination are indicated in the treatment of bacterial urinary tract infections caused by susceptible organisms. {02} {03} {04} {05} {35} {36} {37} {38} {59} {67} {68} {71}

[Bronchitis (treatment)]1—Amoxicillin and clavulanate combination is used in the treatment of bronchitis caused by susceptible organisms. {39} {40} {41}

[Chancroid (treatment)]1—Amoxicillin and clavulanate combination is used in the treatment of chancroid caused by Haemophilus ducreyi . {45} {46}

[Gonorrhea, endocervical and urethral (treatment)]1—Ampicillin and sulbactam combination is used in the treatment of uncomplicated endocervical and urethral gonorrhea caused by Neisseria gonorrhoeae . {11} {51} {52}

[Perioperative infection prophylaxis for colorectal surgery, abdominal hysterectomy, and high-risk cesarean section]—Ticarcillin and clavulanate combination is used prophylactically to help prevent perioperative infections that may result from colorectal surgery, abdominal hysterectomy, and high-risk cesarean section {05} {56}; however, other agents (i.e., cefazolin for hysterectomy and high-risk cesarean section, and neomycin plus erythromycin base for colorectal surgery) are preferred for use as perioperative prophylaxis in these procedures. {66}

Unaccepted
Piperacillin and tazobactam combination should not be used for the treatment of complicated urinary tract infections because of inadequate efficacy at the usual dose (3.375 grams every six hours). {01}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Clavulanate: Naturally occurring compound produced by Streptomyces clavuligerus {48}.
    Sulbactam: Synthetic penicillanic acid sulfone {08} {17}.
    Tazobactam: Analog of sulbactam {08} {17}.

Chemical group—
    Amoxicillin: Aminopenicillin. {11}
    Ampicillin: Aminopenicillin. {11}
    Piperacillin: Acylureidopenicillin. {11}
    Ticarcillin: Carboxypenicillin. {11}
Molecular weight—
    Amoxicillin: 419.46 {58}
    Ampicillin sodium: 371.39 {58}
    Clavulanate potassium: 237.25 {58}
    Piperacillin sodium: 539.55 {58}
    Sulbactam sodium: 255.23 {58}
    Tazobactam sodium: 322.28 {58}
    Ticarcillin disodium: 428.4 {58}

Mechanism of action/Effect:

Penicillins—Bactericidal; inhibit bacterial cell wall synthesis. Action is dependent on the ability of penicillins to reach and bind penicillin-binding proteins (PBPs) located on the inner membrane of the bacterial cell wall. PBPs (which include transpeptidases, carboxypeptidases, and endopeptidases) are enzymes that are involved in the terminal stages of assembling the bacterial cell wall and in reshaping the cell wall during growth and division. {29} Penicillins bind to, and inactivate, PBPs, resulting in the weakening of the bacterial cell wall and lysis. {11} {29}

Beta-lactamase inhibitors—Act by irreversibly binding to the beta-lactamase enzyme, preventing hydrolysis of the beta-lactam ring of the penicillin. The inhibitor first forms a noncovalent complex, which is fully reversible, with a beta-lactam agent. Beta-lactamase inhibitors then act by recognizing the serine residue at the active site of the beta-lactamase enzyme. The structure of the inhibitor is opened and a covalent acyl-enzyme complex is formed with the serine residue. This prevents the beta-lactamase enzyme from hydrolyzing the penicillin and the liberation of the beta-lactamase enzyme. {19} {47}

Absorption:

Amoxicillin and clavulanate are both well absorbed after oral administration and are stable in the presence of gastric acid. {02} {03} This combination product may be given without regard to meals; however, the absorption of clavulanate is greater when taken with food than in a fasting state. {68} Oral bioavailability of amoxicillin and clavulanic acid is approximately 90% and 75%, respectively. {11} Orally administered sulbactam is poorly absorbed. {17}

Distribution:

The penicillins and beta-lactamase inhibitors are widely distributed to most tissues and body fluids, including peritoneal fluid, blister fluid, urine (high concentrations), pleural fluid, middle ear fluid, intestinal mucosa, bone, gallbladder, lung, female reproductive tissues, and bile. Distribution into the cerebrospinal fluid (CSF) is low in subjects with noninflamed meninges, as is penetration into purulent bronchial secretions. {01} {02} {04} {06} {11}

Penicillins also cross the placenta and are distributed into breast milk. {01} {02} {04} {06}


Volume of distribution (Vol D) {13}:

Amoxicillin: 0.36 L/kg.

Ampicillin: 0.29 L/kg.

Piperacillin: 0.23 L/kg.

Ticarcillin: 0.16 L/kg.


Protein binding:

Amoxicillin—Low (17 to 20%). {02} {03} {11}

Ampicillin—Low (20 to 28%). {06} {11}

Clavulanic acid—Low (22 to 30%). {02} {03} {11}

Piperacillin—Low (Approximately 16 to 30%). {01} {11}

Sulbactam—Moderate (38%). {06} {11}

Tazobactam—Low (Approximately 30%). {01}

Ticarcillin—Moderate (45 to 60%). {04} {11}

Biotransformation:


Hepatic:

Amoxicillin: Approximately 10% of a dose is metabolized. {60}

Ampicillin: Approximately 10% of a dose is metabolized to inactive penicilloic acid. {11} {60}

Clavulanic acid: Less than 50% of a dose is metabolized. {11}

Piperacillin: Metabolized to the desethyl metabolite, which has minor activity. {01}

Sulbactam: Less than 25% of a dose is metabolized. {60}

Tazobactam: Metabolized to a single, inactive metabolite. {01}

Ticarcillin: Less than 15% of a dose is metabolized. {60}


Half-life:


Normal renal function:

Amoxicillin: Approximately 1.3 hours. {02} {03}

Ampicillin: Approximately 1 hour. {06}

Clavulanic acid: Approximately 1 hour. {02} {03} {04}

Piperacillin: 0.7 to 1.2 hours. {01}

Sulbactam: Approximately 1 hour. {06}

Tazobactam: 0.7 to 1.2 hours. {01}

Ticarcillin: 1 to 1.2 hours. {04}



Impaired renal function (severe):

Amoxicillin: Approximately 12 hours. {13}

Ampicillin: 9 to 19 hours. {06} {13}

Clavulanate: Approximately 3 hours. {05}

Piperacillin: 1.4 to 2.8 hours. {01} {13}

Sulbactam: Approximately 9 hours. {06}

Tazobactam: 2.8 to 4.8 hours. {01}

Ticarcillin: Approximately 9 hours. {13}


Time to peak serum concentration

Amoxicillin and clavulanic acid combination—1 to 2 hours. {02} {03}

Ampicillin and sulbactam combination—End of infusion. {06}

Piperacillin and tazobactam combination—End of infusion. {01}

Ticarcillin and clavulanate combination—End of infusion. {04}

Peak serum concentration:


Amoxicillin and clavulanic acid combination:

Chewable tablets and oral suspension: Approximately 6.9 mcg per mL (mcg/mL) amoxicillin and 1.6 mcg/mL clavulanic acid after an oral dose of 250 mg amoxicillin and 62.5 mg clavulanic acid. {02} {03}

Tablets (film-coated): Approximately 4.4 to 4.7 mcg/mL amoxicillin and 2.3 to 2.5 mcg/mL clavulanic acid after an oral dose of 250 mg amoxicillin and 125 mg clavulanic acid. {02} {03}



Ampicillin and sulbactam combination:

Intramuscular: Approximately 8 to 35 mcg/mL ampicillin and 6 to 25 mcg/mL sulbactam following an intramuscular dose of 1.5 grams (1 gram of ampicillin and 500 mg of sulbactam). {06}

Intravenous: Approximately 40 to 70 mcg/mL ampicillin and 20 to 40 mcg/mL sulbactam following an intravenous dose of 1.5 grams (1 gram of ampicillin and 500 mg of sulbactam). {06}



Piperacillin and tazobactam combination:

Approximately 242 mcg/mL piperacillin and 24 mcg/mL tazobactam following an intravenous dose of 3.375 grams (3 grams of piperacillin and 0.375 gram of sulbactam). {01}



Ticarcillin and clavulanic acid combination:

Approximately 330 mcg/mL ticarcillin and 8 mcg/mL clavulanic acid following an intravenous dose of 3.1 grams (3 grams of ticarcillin and 0.1 gram of clavulanic acid). {04}


Elimination:


Primarily renal (glomerular filtration and tubular secretion) {13}


Amoxicillin and clavulanic acid combination—
        50 to 78%, and 25 to 40% of an administered dose of amoxicillin and clavulanic acid, respectively, are excreted unchanged in the urine within the first 6 hours after administration. {02} {03}



Ampicillin and sulbactam combination—
        75 to 85% of an administered dose of both ampicillin and sulbactam is excreted unchanged in the urine within the first 8 hours after administration. {06}



Piperacillin and tazobactam combination—
        Approximately 68% and 80% of an administered dose of piperacillin and tazobactam, respectively, are excreted unchanged in the urine. {01}



Ticarcillin and clavulanic acid combination—
        60 to 70%, and 35 to 45% of an administered dose of ticarcillin and clavulanic acid, respectively, are excreted unchanged in the urine within the first 6 hours after administration. {04}




Biliary—


Ampicillin and sulbactam—
        Less than 1%. {54}



Piperacillin and tazobactam combination—
        Less than 2%. {21}




In dialysis—


Hemodialysis—
        Hemodialysis removes amoxicillin, ampicillin, clavulanate, piperacillin, sulbactam, tazobactam, and ticarcillin from the blood. {01} {02} {04} {06} {14}
        Piperacillin and tazobactam combination—30 to 40% of an administered dose is removed, plus an additional 5% of the tazobactam dose as the metabolite. {01}



Peritoneal dialysis—
        Piperacillin and tazobactam combination—6 to 21% of an administered dose is removed, plus an additional 16% of the tazobactam dose as the metabolite. {01}




Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to one penicillin may be allergic to other penicillins also. {01} {02} {03} {04} {05} {06}

Patients allergic to cephalosporins, cephamycins, or beta-lactamase inhibitors may be allergic to penicillin and beta-lactamase inhibitor combinations also. {01} {02} {03} {04} {05} {06}

Carcinogenicity

Long-term carcinogenicity studies in animals have not been done on any of the penicillin and beta-lactamase inhibitor combinations. {01} {02} {04} {06} {67} {68} {69} {70} {71}

Mutagenicity

Amoxicillin and clavulanic acid combination—The mutagenic potential of amoxicillin and clavulanic acid combination was studied in vitro with an Ames test, a human lymphocyte cytogenetic assay, a yeast test, and a mouse lymphoma forward mutation assay, and in vivo with mouse micronucleus tests and a dominant lethal test. All results were negative with the exception of the in vitro mouse lymphoma assay, in which weak activity was found at very high, cytotoxic concentrations. {67}

Ampicillin and sulbactam combination—Long-term studies in animals have not been done to evaluate the mutagenic potential of this combination. {06} {69}

Piperacillin and tazobactam combination—Microbial mutagenicity studies with piperacillin and tazobactam combination at concentrations of up to 14.84 and 1.86 mcg, respectively, per plate were negative. Negative results were also found in the unscheduled DNA synthesis (UDS) test at concentrations of up to 5689 and 711 mcg per mL (mcg/mL), respectively, in the mammalian point mutation (Chinese hamster ovary cell HPRT) assay at concentrations of up to 8000 and 1000 mcg/mL, respectively, and in the mammalian cell (BALB/c-3T3) transformation assay at concentrations of up to 8 and 1 mcg/mL, respectively. In vivo , piperacillin and tazobactam combination did not induce chromosomal aberrations in rats administered intravenous doses of 1500 and 187.5 mg per kg of body weight (mg/kg), respectively; this dose is similar to the maximum recommended human daily dose based on mg per square meter of body surface area (mg/m 2). {01} {70}

Ticarcillin and clavulanic acid combination—Studies performed in vitro and in vivo did not indicate a potential for mutagenicity. {04} {71}

Pregnancy/Reproduction
Fertility—
Amoxicillin and clavulanic acid combination: Studies in rats given doses of up to 5.7 times the usual human dose (dosed with a 2:1 ratio formulation of amoxicillin:clavulanate) have not shown that amoxicillin and clavulanate combination impairs fertility. {67} {68}

Ampicillin and sulbactam combination: Studies in mice, rats, and rabbits given doses of up to 10 times the human dose have not shown that ampicillin and sulbactam combination adversely affects fertility. {06} {69}

Piperacillin and tazobactam combination: Reproduction studies in rats revealed no evidence of impaired fertility when piperacillin and tazobactam combination was administered at doses similar to the maximum recommended human daily dose based on body surface area (mg/m 2). There was also no evidence of impaired fertility when tazobactam was administered at doses of up to three times the maximum recommended human daily dose based on body surface area (mg/m 2). {01} {70}

Ticarcillin and clavulanic acid combination: Studies in rats given daily doses of up to 1050 mg/kg have not shown that ticarcillin and clavulanate combination impairs fertility. {04} {71}

Pregnancy—
Penicillins cross the placenta. {01} {02} {04} {06} {48} {57} Clavulanic acid also crosses the placenta. {48} {57} Adequate and well-controlled studies in humans have not been done; however, problems in humans have not been documented.

Amoxicillin and clavulanate combination: Studies in rats and mice given oral dosages of up to 1200 mg per kg of body weight per day, equivalent to 7200 and 4080 mg per square meter of body surface area per day, respectively (4.9 and 2.8 times the maximum human oral dose, based on body surface area), caused no adverse effects in the fetus. {67} {68}

FDA Pregnancy Category B.

Ampicillin and sulbactam combination: Studies in mice, rats, and rabbits given doses of up to 10 times the human dose have not shown that ampicillin and sulbactam combination causes adverse effects in the fetus. {06} {69}

FDA Pregnancy Category B.

Piperacillin and tazobactam combination: Teratology studies performed in mice and rats given piperacillin and tazobactam combination at doses one to two times, respectively, the human dose based on body surface area (mg/m 2) revealed no evidence of harm to the fetus. In addition, no evidence of harm to the fetus was found when tazobactam was administered to mice and rats at doses of up to 6 and 14 times the human dose, respectively, based on body surface area (mg/m 2). Tazobactam crosses the placenta in mice; concentrations in the fetus are 10% or less of those found in maternal plasma. {01} {70}

FDA Pregnancy Category B.

Ticarcillin and clavulanate combination: Studies in rats given daily doses of up to 1050 mg/kg have not shown that ticarcillin and clavulanate combination causes adverse effects in the fetus. {04} {71}

FDA Pregnancy Category B.


Labor and delivery—

Amoxicillin and clavulanate combination and ampicillin and sulbactam combination: Oral ampicillin class antibiotics generally are poorly absorbed during labor. Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, the frequency of contractions, the height of contractions, and the duration of contractions. However, it is not known whether the use of these medications in humans during labor or delivery has any immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary. {67} {68} {69}

Breast-feeding

Penicillins and sulbactam are distributed into breast milk in low concentrations {01} {02} {03} {04} {05} {06}; it is not known whether clavulanic acid and tazobactam are distributed into breast milk. {01} {05} {70} Although significant problems in humans have not been documented, the use of penicillins by nursing mothers may lead to sensitization, diarrhea, candidiasis, and skin rash in the infant. {09}

Pediatrics

Many penicillins have been used in pediatric patients, and no pediatrics-specific problems have been documented to date. However, the incompletely developed renal function of neonates and young infants may delay the excretion of renally eliminated penicillins. {54}

Amoxicillin and clavulanate combination: The 200-mg and the 400-mg chewable tablets contain 2.1 mg and 4.2 mg phenylalanine, respectively, produced through the metabolism of aspartame. The 200-mg-per-5 mL and the 400-mg-per-5 mL strengths of the oral suspension contain 7 mg of phenylalanine per 5 mL. {67} These dosage forms should be used with caution, if at all, in patients with phenylketonuria. The other strengths and dosage forms of amoxicillin and clavulanate combination do not contain phenylalanine {67}.

Piperacillin and tazobactam combination: Although safety and efficacy have not been established in pediatric patients, the results of one study found the clearance and elimination half-life to be increased in infants < 6 months of age. Piperacillin and tazobactam combination had no effect on bilirubin-albumin binding in vitro . {21}


Geriatrics


Penicillins have been used in geriatric patients and no geriatrics-specific problems have been documented to date. However, elderly patients are more likely to have an age-related decrease in renal function, which may require an adjustment in dosage in patients receiving penicillins. {01}


Dental

Prolonged use of penicillins may lead to the development of oral candidiasis. {01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Allopurinol{06}{28}{69}    (concurrent use with ampicillin may significantly increase the possibility of skin rash, especially in hyperuricemic patients; however, it has not been established that allopurinol, rather than the presence of hyperuricemia, is responsible for this effect)


Aminoglycosides{01}{04}{05}{70}    (concurrent administration of piperacillin and tazobactam combination with tobramycin decreased the urinary recovery of tobramycin by 38%; concurrent administration of tobramycin and ticarcillin resulted in a decrease in serum tobramycin concentration by 11%)


» Anticoagulants, coumarin- or indanedione-derivative or
» Heparin or
» Thrombolytic agents{01}{04}{05}{70}    (concurrent use of these medications with high-dose piperacillin or ticarcillin may increase the risk of hemorrhage because these penicillins inhibit platelet aggregation; patients should be monitored carefully for signs of bleeding; concurrent use of piperacillin or ticarcillin with thrombolytic agents may increase the risk of severe hemorrhage and is not recommended; increases in prothrombin time have been reported in patients taking amoxicillin and clavulanate combination concurrently with anticoagulants {68})


» Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially aspirin or
Diflunisal, very high doses or
Other salicylates or
» Platelet aggregation inhibitors, other (see Appendix II ) or
» Sulfinpyrazone{01}{04}{05}    (concurrent use of these medications with high-dose piperacillin or ticarcillin may increase the risk of hemorrhage because of additive inhibition of platelet function; in addition, hypoprothrombinemia induced by large doses of salicylates and the gastrointestinal ulcerative or hemorrhagic potential of NSAIDs, salicylates, or sulfinpyrazone may also increase the risk of hemorrhage when these medicines are used concurrently with piperacillin or ticarcillin)


Chloramphenicol or
Erythromycins or
Sulfonamides or
Tetracyclines{07}    (since bacteriostatic drugs may interfere with the bactericidal effect of penicillins in the treatment of meningitis or in other situations in which a rapid bactericidal effect is necessary, it is best to avoid concurrent therapy; however, chloramphenicol and ampicillin are sometimes administered concurrently in pediatric patients)


» Oral contraceptives{67}    (as with other broad spectrum antibiotics, penicillins and beta-lactamase inhibitors may decrease the efficacy of oral contraceptives)


» Probenecid{01}{02}{03}{04}{05}{06}{31}{67}{68}{69}{70}{71}    (probenecid decreases renal tubular secretion of penicillins, sulbactam, and tazobactam [but not clavulanic acid, which is cleared primarily by glomerular filtration] when used concurrently; this effect results in increased and more prolonged serum concentrations, prolonged elimination half-life [half-life of piperacillin increased by 21%, that of tazobactam by 71% {01}, and that of sulbactam by 40% {54}], and increased risk of toxicity. Penicillins and probenecid are often used concurrently to treat sexually transmitted diseases [STDs] or other infections in which high and/or prolonged antibiotic serum and tissue concentrations are required)


Vecuronium{70} or
Nondepolarizing muscle relaxants{70} , other    (concurrent use with piperacillin and tazobactam combination may prolong neuromuscular blockade {70})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
» Glucose, urine{01}{02}{06}{27}{68}{69}{70}    (high urinary concentrations of a penicillin may produce false-positive or falsely elevated test results with copper-reduction tests [Benedict's, Clinitest, or Fehling's]; glucose enzymatic tests [ Clinistix or Testape] are not affected)


Direct antiglobulin (Coombs') tests{01}{04}{05}{06}{18}{71}    (false-positive result may occur during therapy with any penicillin)


Protein, urine{01}{04}{05}{71}    (high urinary concentrations of piperacillin or ticarcillin may produce false-positive protein reactions [pseudoproteinuria] with the sulfosalicylic acid and boiling test, the acetic acid test, the biuret reaction, and the nitric acid test; bromophenol blue reagent test strips [ Multi-stix] are reportedly unaffected)

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT]) and
Lactate dehydrogenase (LDH), serum{01}{02}{03}{04}{05}{06}{18}{67}{68}{69}{70}{71}    (values may be increased)


Bilirubin, serum{67}{68}{70}{71}    (concentrations may be increased)


Blood urea nitrogen (BUN) and
Creatinine, serum{01}{18}{69}{70}{71}    (increased concentrations have been associated with ampicillin and sulbactam, piperacillin, and ticarcillin)


Estradiol or
Estriol, total conjugated or
Estriol-glucuronide or
Estrone, conjugated{02}{06}{68}{69}    (concentrations may be decreased transiently in pregnant women following administration of amoxicillin and ampicillin)


Hematocrit or
Hemoglobin concentrations    (may be decreased with the piperacillin and tazobactam combination {70})


» Partial thromboplastin time (PTT) and
» Prothrombin time (PT){01}{04}{05}{18}{70}{71}    (an increase has been associated with piperacillin and ticarcillin)


Potassium, serum{01}{04}{05}{21}{70}{71}    (hypokalemia may occur following administration of piperacillin or ticarcillin, either of which may act as a nonreabsorbable anion in the distal renal tubules; this may cause an increase in pH and result in increased urinary potassium loss; the risk of hypokalemia increases with use of larger doses)


Sodium, serum{04}{05}{71}    (hypernatremia may occur following administration of large doses of ticarcillin because of the medication's high sodium content)


Uric acid, serum{04}{05}{71}    (ticarcillin may transiently decrease the serum concentration in some patients)


White blood count{01}{02}{03}{04}{05}{06}{10}{67}{68}{69}{70}{71}    (leukopenia or neutropenia is associated with the use of all penicillins; the effect is more likely to occur with prolonged therapy and severe hepatic function impairment)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, these medications should not be used when the following medical problems exist:
» Allergy to penicillins or beta-lactamase inhibitors{01}{02}{03}{04}{05}{06}{67}{68}{69}{70}{71}
» Cholestatic jaundice, amoxicillin and clavulanate combination–associated, history of{67}{68} or
» Hepatic dysfunction, amoxicillin and clavulanate combination–associated, history of{67}{68}    (severe heptotoxicity resulting in death has occurred with the amoxicillin and clavulanate combination, usually associated with serious underlying diseases or concomitant medications)


Risk-benefit should be considered when the following medical problems exist
Allergy, general, history of, such as asthma, eczema, hay fever, hives    (serious hypersensitivity reactions are more likely to occur in patients with sensitivity to multiple allergens {68})


» Allergy to cephalosporins{69}
» Bleeding disorders, history of{01}{04}{05}{70}{71}    (some penicillins, especially piperacillin and ticarcillin, may cause platelet dysfunction and hemorrhage)


» Congestive heart failure (CHF) or
Hypertension{04}{05}    (the sodium content of the parenteral dosage forms of penicillins and beta-lactamase combinations should be considered in patients who require sodium restriction {70} {71})


» Cystic fibrosis{01}{70}    (patients with cystic fibrosis may be at increased risk for fever and skin rash when given piperacillin)


» Gastrointestinal disease, active or a history of, especially antibiotic-associated colitis    (penicillins may cause pseudomembranous colitis)


» Hepatic dysfunction{67}{68}    (the amoxicillin and clavulanate combination may exacerbate hepatic dysfunction and should be used with caution in these patients; heptotoxicity with this combination is usually reversible; however, rare cases have resulted in death {67} {68})


» Mononucleosis, infectious{02}{03}{06}{67}{68}{69}    (a morbilliform skin rash may occur in a high percentage of patients taking ampicillin)


» Phenylketonuria    (the 200-mg-per-5 mL and the 400-mg-per-5 mL formulations, as well as the 200-mg and the 400-mg chewable tablets, of amoxicillin and clavulanate combination contain aspartame {67}, which is metabolized to phenylalanine, and may be hazardous to patients with phenylketonuria)


» Renal function impairment{01}{02}{03}{04}{05}{06}{67}{68}{69}{70}{71}    (because most penicillins are excreted through the kidneys, a reduction in dosage, or an increase in dosing interval, is recommended in patients with renal function impairment; also, the sodium content of high doses of ticarcillin should be considered in patients with severe renal function impairment)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


For amoxicillin and clavulanate combination and ticarcillin and clavulanate
Hepatic function{67}{68}{71} and
Renal function{67}{68}{71}    (periodic monitoring is advisable during prolonged therapy)


For amoxicillin and clavulanate combination, piperacillin and tazobactam combination, and ticarcillin and clavulanate combination
Hematopoietic function{67}{68}{70}{71}    (periodic monitoring is advisable during prolonged therapy)


For piperacillin and tazobactam combination and ticarcillin and clavulanate combination
» Partial thromboplastin time (PTT) and
» Prothrombin time (PT){01}{04}{05}{18}    (may be required prior to and during prolonged therapy in patients with renal function impairment who are receiving high doses, since hemorrhagic manifestations may occur, although the effect is rare)


Potassium, serum{01}{04}    (determinations may be required periodically during therapy in patients with low potassium reserves and in patients receiving cytotoxic medications or diuretics, since hypokalemia may occur)


For all penicillin and beta-lactamase inhibitor combinations (if Clostridium difficile colitis occurs)
» Stool toxin assays{15}{16}    (enzyme immunoassay of stool samples for the presence of C. difficile toxins may be required prior to treatment of patients with antibiotic-associated colitis to document the presence of C. difficile toxins; however, C. difficile and its toxins may persist following treatment with oral vancomycin, metronidazole, or cholestyramine, despite clinical improvement; follow-up cultures and toxin assays are not recommended if clinical improvement is complete)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Allergic reactions, specifically anaphylaxis {01}{02}{03}{04}{05}{06}(fast or irregular breathing; puffiness or swelling around face; shortness of breath; sudden, severe decrease in blood pressure )
    
elevated liver function tests {67} {68} {69} {70} {71}
    
oral candidiasis {02} {03} (sore mouth or tongue; white patches in mouth and/or on tongue)
    
serum sickness–like reactions (skin rash; joint pain; fever){02}{03}
    
skin rash, hives, or itching {01}{02}{03}{04}{05}{06}{18}
    
thrombophlebitis {69} (pain, redness, and swelling at site of injection)
    
vaginal candidiasis {01} {02} {03} (vaginal itching and discharge)

Incidence rare
    
Chest pain {69} {70}
    
clostridium difficile colitis (severe abdominal or stomach cramps and pain; abdominal tenderness; watery and severe diarrhea, which may also be bloody; fever){01}{02}{03}{04}{05}{06}
    
dysuria or urinary retention {69} (trouble in urinating)
    
edema {69} (swelling of face, fingers, lower legs, or feet ; weight gain)
    
erythema multiforme or Stevens-Johnson syndrome {70} ( blistering, peeling, or loosening of skin and mucous membranes; fever; malaise [general feeling of illness or discomfort ; red skin lesions, often with a purple center)
    
hepatic dysfunction, including cholestatic hepatitis {67} {68} {70} (abdominal pain; nausea or vomiting ; yellow eyes or skin)
    
glossitis {69} (redness, swelling, or soreness of tongue)
    
leukopenia or neutropenia ( sore throat and fever){01}{02}{03}{04}{05}{06}
    
platelet dysfunction (unusual bleeding or bruising)
{01}{04}{05}    
proteinuria or pyuria {70} (cloudy urine)
    
seizures {01} {04} {05}
    
toxic epidermal necrolysis ( blistering, peeling, loosening of skin ; chills; cough ; diarrhea ; itching; joint or muscle pain; red, irritated eyes ; red skin lesions, often with a purple center ; sore throat ; sores, ulcers, or white spots in mouth or on lips ; unusual tiredness or weakness){75}

Note: Platelet dysfunction is primarily associated with piperacillin and ticarcillin. {01} {04} {05}
Clotridium difficile colitis may occur up to several weeks after discontinuation of these medications. {01} {02} {03} {04} {05} {06}
Seizures are more likely to occur in patients receiving high doses of a penicillin and/or patients with severe renal function impairment. {01} {04} {05}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Gastrointestinal reactions (gas; mild diarrhea; nausea or vomiting; stomach pain ; swelling of abdomen)
{01}{02}{03}{04}{05}{06}{18}    
headache {01} {02} {03} {04} {05} {06} {18}

Incidence rare
    
Chills {69}
    
epistaxis {69} (nosebleed)
    
fatigue {69} (unusual tiredness or weakness)
    
malaise {69} (general feeling of discomfort or illness)
    
prolonged muscle relaxation — with piperacillin and tazobactam combination





Overdose
For specific information on the agents used in the management of penicillins and beta-lactamase inhibitors overdose, see:    • Barbiturates (Systemic)monograph and/or
   • Diazepam in Benzodiazepines (Systemic) monograph.


For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Since there is no specific antidote, treatment of penicillin overdose should be symptomatic and supportive. {68} {71}

If motor excitability or convulsions occur, general supportive measures, including the administration of anticonvulsive agents (e.g., diazepam or barbiturates) may be considered. {70}

Specific treatment—Hemodialysis may aid in the removal of penicillins from the blood. {01} {68} {69} {70}

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Penicillins and Beta-lactamase Inhibitors (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergy to penicillins, cephalosporins, cephamycins, or beta-lactamase inhibitors

Pregnancy—Penicillins and clavulanic acid cross the placenta





Breast-feeding—Penicillins and sulbactam are distributed into breast milk





Use in children—Neonates and young infants may have reduced elimination of renally eliminated penicillins due to incompletely developed renal function; aspartame-containing amoxicillin and clavulanate combination products should be used with caution, if at all, in patients with phenylketonuria

Other medications, especially aminoglycosides; coumarin- or indanedione-derivative anticoagulants; heparin; nonsteroidal anti-inflammatory drugs (NSAIDs), especially aspirin; oral contraceptives; other platelet aggregation inhibitors; probenecid; sulfinpyrazone; or thrombolytic agents
Other medical problems, especially a history of bleeding disorders; cholestatic jaundice; congestive heart failure; cystic fibrosis; active or history of gastrointestinal disease, especially antibiotic-associated colitis; hepatic dysfunction; infectious mononucleosis; phenylketonuria; or renal function impairment

Proper use of this medication
Taking amoxicillin and clavulanate combination on a full or empty stomach; administration with food may decrease the incidence of gastrointestinal side effects (diarrhea, nausea, and vomiting) {30}

Proper administration technique for oral liquids:


Using a specially marked measuring spoon or other device to measure each dose


Not using after expiration date

Chewing or crushing chewable tablets before swallowing

» Importance of taking at evenly spaced times and not missing doses

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Checking with physician if no improvement within a few days or if symptoms become worse

» For severe diarrhea, checking with physician before taking any antidiarrheals; for mild diarrhea, kaolin- or attapulgite-containing, but not other, antidiarrheals may be tried; checking with physician or pharmacist if mild diarrhea continues or worsens

» Patients with diabetes: False-positive reactions with copper sulfate urine glucose tests may occur, especially with amoxicillin and clavulanate, ampicillin and sulbactam, and piperacillin and tazobactam combinations

Possible interference with diagnostic tests


Side/adverse effects
Signs of potential side effects, especially allergic reactions; oral candidiasis; serum sickness-like reactions; skin rash, hives, or itching; thrombophlebitis; vaginal candidiasis; chest pain; clostridium difficile colitis; dysuria or urinary retention; edema; erythema multiforme or Stevens-Johnson syndrome; hepatic dysfunction; glossitis; leukopenia or neutropenia; platelet dysfunction; and seizures


General Dosing Information
As with other antibacterials, the possiblility of superinfection with mycotic or bacterial pathogens should be kept in mind during therapy with a penicillin and beta-lactamase inhibitor combination. If superinfection occurs, the penicillin and beta-lactamase inhibitor combination should be discontinued and appropriate treatment instituted. {67} {68} {69} {70} {71}

Appropriate culture and susceptibility tests should be performed before treatment with a penicillin and beta-lactamase inhibitor combination in order to isolate and identify the organism(s) causing infection and determine their susceptibility to antimicrobials. {69} {70} {71} Once the results of culture and antimicrobial testing are known, therapy should be adjusted as appropriate. {70}

There are insufficient data to support the use of ticarcillin and clavulanate combination in the treatment of septicemia or infections in pediatric patients when the suspected or proven pathogen is Haemophilus influenzae type b. {71}

For oral dosage forms only
Amoxicillin and clavulanate combination may be taken on a full or empty stomach. Administration with food may decrease the incidence of gastrointestinal side effects (diarrhea, nausea, and vomiting). {30}

For treatment of adverse effects
Serious anaphylactoid reactions require immediate emergency treatment, which consists of the following: {01} {02} {03} {67} {68} {69} {70} {71}

   • Parenteral epinephrine.
   • Oxygen.
   • Intravenous corticosteroids.
   • Airway management (including intubation).
For Clostridium difficile colitis—

   • Some patients may develop C. difficile colitis during or following administration of penicillins.
   • C. difficile colitis may result in severe watery diarrhea, which may occur during therapy or up to several weeks after therapy is discontinued. If diarrhea occurs, administration of antiperistaltic antidiarrheals (e.g., opioids, diphenoxylate and atropine combination, loperamide, paregoric) is not recommended since they may delay the removal of toxins from the colon, thereby prolonging and/or worsening the condition. {15}
   • Mild cases may respond to discontinuation of the medication alone. Moderate to severe cases may require fluid, electrolyte, and protein replacement. {01} {02} {04} {06} {67} {68} {69} {70} {71}
   • In cases not responding to the above measures or in more severe cases, oral doses of vancomycin, metronidazole, or cholestyramine may be used. Oral vancomycin is effective in doses of 125 mg every 6 hours for 5 to 10 days. The dose of metronidazole is 250 to 500 mg every 8 hours, and the dose of cholestyramine is 4 grams four times a day. Recurrences, which occur in approximately 25% of patients treated with vancomycin or metronidazole, may be treated with a second course of these medications. {15} {16}
   • Cholestyramine resin has been shown to bind C. difficile toxin in vitro . If cholestyramine resin is administered in conjunction with oral vancomycin, the medications should be administered several hours apart since the resin has been shown to bind oral vancomycin also. {16}

AMOXICILLIN AND CLAVULANATE

Summary of Differences


Precautions:
Pediatrics—Patients with phenylketonuria should be aware that the 200-mg and the 400-mg chewable tablets contain 2.1 mg and 4.2 mg phenylalanine, respectively, as a component of aspartame. The 200-mg-per-5-mL and the 400-mg-per-5-mL strengths of the oral suspension contain 7 mg of phenyalanine. Other dosage forms and strengths do not contain aspartame.

Drug interactions and/or related problems—Clavulanic acid does not interact with probenecid.

Laboratory value alterations—Amoxicillin may decrease total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol concentrations in pregnant women.

Medical considerations/Contraindications—Hepatic dysfunction and phenylketonuria.

Patient monitoring—Periodic monitoring of hepatic function and renal function is advisable during prolonged therapy.



Additional Dosing Information
Amoxicillin and clavulanate combination may be taken on a full or empty stomach. {67} {68} However, clavulanate absorption is greater when administered at the beginning of a meal. Also, administration with food may decrease the incidence of gastrointestinal side effects (diarrhea, nausea, and vomiting). {30} {67} {68}

Patients with hepatic impairment should be dosed with caution and hepatic function should be monitored at regular intervals. {67} {68}

Severe diarrhea has been reported less frequently when amoxicillin and clavulanate combination is dosed every twelve hours compared with every eight hours {67} {68}.

The 200-mg-per-5 mL and the 400-mg-per-5 mL formulations of amoxicillin and clavulanate oral suspension, as well as the 200-mg and the 400-mg chewable tablets, contain phenylalanine. {67}

Amoxicillin and clavulanate 250-mg tablets and 250-mg chewable tablets do not contain the same amount of clavulanate. The 250-mg tablets contain 125 mg of clavulanate, and the 250-mg chewable tablets contain 62.5 mg of clavulanate. Therefore, these products should not be substituted for each other or used interchangeably. This is important to ensure that there is a sufficient concentration of clavulanate at the site of infection to inhibit the beta-lactamase that is present. {68}

Because the 250-mg tablet and the 250-mg chewable tablet have different amoxicillin-to-clavulanic acid ratios, the 250-mg tablet should not be used in children who weigh less than 40 kg. {68}

Since the 250-mg and the 500-mg strengths of amoxicillin and clavulanate combination tablets contain the same amount of clavulanate (125 mg), two 250-mg tablets are not equivalent to one 500-mg tablet. {02} {68} {03}

Patients with impaired renal function generally do not require dosage reduction unless the renal impairment is severe. Adults and adolescents with severely impaired renal function may receive 500 mg or 250 mg with the dosing interval increased as follows {68}:

Creatinine clearance
(mL/min)/(mL/sec)
Dosing interval
(hours)
> 30/0.5
8
10–30/0.17–0.5
12
< 10/< 0.17
24


Patients on hemodialysis should receive 500 mg or 250 mg every 24 hours, depending on the severity of the infection. They should receive an additional dose both during and at the end of dialysis. {68}

Patients with severe renal impairment (glomerular filtration rate < 30 mL per minute) should not receive the 875-mg tablet. {68}


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

AMOXICILLIN AND CLAVULANATE POTASSIUM FOR ORAL SUSPENSION USP

Usual adult and adolescent dose
Antibacterial


Pneumonia and other severe infections:
Oral, 875 mg of amoxicillin and 125 mg of clavulanic acid every twelve hours or 500 mg of amoxicillin and 125 mg of clavulanic acid every eight hours. {68}



Other infections:
Oral, 500 mg of amoxicillin and 125 mg of clavulanic acid every twelve hours or 250 mg of amoxicillin and 125 mg of clavulanic acid every eight hours. {68}


Note: Adults who have difficulty swallowing may be given the 125-mg-per-5 mL or the 250-mg-per-5 mL formulation of oral suspension in place of the 500-mg tablet. The 200-mg-per-5 mL or the 400-mg-per-5 mL formulation of oral suspension may be used in place of the 875-mg tablet. {67}



Usual pediatric dose
Antibacterial
Dosage is based on the amoxicillin component.


Neonates and infants up to 12 weeks (3 months) of age:
Oral, 15 mg of amoxicillin per kg of body weight every twelve hours. {67}

Note: Use of the formulation containing 125 mg of amoxicillin per 5 mL of oral suspension is recommended by the manufacturer since experience is limited with the 200-mg-per-5 mL formulation. {67}




Infants 3 months of age and older and children up to 40 kg of body weight :
Otitis media, acute

Pneumonia

Sinusitis

Other severe infections—

Oral, 22.5 mg of amoxicillin per kg of body weight every twelve hours (using the formulation containing either 200 mg of amoxicillin per 5 mL or 400 mg of amoxicillin per 5 mL) or 13.3 mg of amoxicillin per kg of body weight every eight hours (using the formulation containing either 125 mg of amoxicillin per 5 mL or 250 mg of amoxicillin per 5 mL).

Less severe infections—Oral, 12.5 mg of amoxicillin per kg of body weight every twelve hours (using the formulation containing either 200 mg of amoxicillin per 5 mL or 400 mg of amoxicillin per 5 mL) or 6.7 mg of amoxicillin per kg of body weight every eight hours (using the formulation containing either 125 mg of amoxicillin per 5 mL or 250 mg of amoxicillin per 5 mL).




Children weighing more than 40 kg of body weight:
See Usual adult and adolescent dose.



Strength(s) usually available
U.S.—


125 mg of amoxicillin and 31.25 mg of clavulanic acid per 5 mL (when reconstituted according to manufacturer"s instructions) (Rx) [Augmentin{67}]


200 mg of amoxicillin and 28.5 mg of clavulanic acid per 5 mL (when reconstituted according to manufacturer"s instructions) (Rx) [Augmentin{67} (aspartame)]


250 mg of amoxicillin and 62.5 mg of clavulanic acid per 5 mL (when reconstituted according to manufacturer"s instructions) (Rx) [Augmentin{67}]


400 mg of amoxicillin and 57 mg of clavulanic acid per 5 mL (when reconstituted according to manufacturer"s instructions) (Rx) [Augmentin{67} (aspartame)]

Note: The amoxicillin and clavulanate combination products with 200 mg of amoxicillin per 5 mL of oral suspension and 400 mg of amoxicillin per 5 mL contain 7 mg of phenylalanine per 5 mL {67}, as a component of aspartame.


Canada—


125 mg of amoxicillin and 31.25 mg of clavulanic acid per 5 mL (when reconstituted according to manufacturer"s instructions) (Rx) [Clavulin-125F{72}]


250 mg of amoxicillin and 62.5 mg of clavulanic acid per 5 mL (when reconstituted according to manufacturer"s instructions) (Rx) [Clavulin-250F{72}]

Packaging and storage:
Prior to reconstitution, store at or below 25 °C (77 °F). Store in a tight container. {67}

Stability:
After reconstitution, suspensions retain their potency for 10 days if refrigerated. {67}

Auxiliary labeling:
   • Refrigerate.
   • Shake well.
   • Continue medication for full time of treatment.
   • Beyond-use date.

Note: When dispensing, include a calibrated liquid-measuring device.



AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS USP

Usual adult and adolescent dose
Antibacterial


Pneumonia and other severe infections:
Oral, 875 mg of amoxicillin and 125 mg of clavulanic acid every twelve hours or 500 mg of amoxicillin and 125 mg of clavulanic acid every eight hours. {68}



Other infections:
Oral, 500 mg of amoxicillin and 125 mg of clavulanic acid every twelve hours or 250 mg of amoxicillin and 125 mg of clavulanic acid every eight hours. {68}



[Chancroid]1:
Oral, 500 mg of amoxicillin and 125 mg of clavulanic acid, or 500 mg of amoxicillin and 250 mg of clavulanic acid every eight hours for three to seven days. {45} {46}



Usual pediatric dose
Antibacterial


Infants and children up to 40 kg of body weight {02} {03}:
See Amoxicillin and Clavulanate Potassium for Oral Suspension .

Note: Because the 250-mg tablet and the 250-mg chewable tablet have different amoxicillin-to-clavulanic acid ratios, the 250-mg tablet should not be used in children who weigh less than 40 kg. {68}




Children 40 kg of body weight and over:
See Usual adult and adolescent dose.



Strength(s) usually available
U.S.—


250 mg of amoxicillin and 125 mg of clavulanic acid (Rx) [Augmentin{68}]


500 mg of amoxicillin and 125 mg of clavulanic acid (Rx) [Augmentin{68}]


875 mg of amoxicillin and 125 mg of clauvulanic acid (Rx) [Augmentin{68}]

Canada—


250 mg of amoxicillin and 125 mg of clavulanic acid (Rx) [Clavulin-250{72}]


500 mg of amoxicillin and 125 mg of clavulanic acid (Rx) [Clavulin-500F{72}]

Note: Two 250-mg tablets are not equivalent to one 500-mg tablet since both strengths contain equal amounts of clavulanate potassium. {68}


Packaging and storage:
Store at or below 25 °C (77 °F). Store in a tight container. {68}

Auxiliary labeling:
   • Continue medication for full time of treatment.


AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS (CHEWABLE) USP

Usual adult and adolescent dose
See Amoxicillin and Clavulanate Potassium for Oral Suspension .

Usual pediatric dose
See Amoxicillin and Clavulanate Potassium for Oral Suspension .

Strength(s) usually available
U.S.—


125 mg of amoxicillin and 31.25 mg of clavulanic acid (Rx) [Augmentin{67}]


200 mg of amoxicillin and 28.5 mg of clavulanic acid (Rx) [Augmentin{67} (aspartame [containing 2.1 mg of phenylalanine])]


250 mg of amoxicillin and 62.5 mg of clavulanic acid (Rx) [Augmentin{67}]


400 mg of amoxicillin and 57 mg of clavulanic acid (Rx) [Augmentin{67} (aspartame [containing 4.2 mg of phenylalanine])]

Canada—
Not commercially available.

Packaging and storage:
Store at or below 25 °C (77 °F) Store in a tight container. {68}

Auxiliary labeling:
   • Should be chewed or crushed.
   • Continue medication for full time of treatment.


AMPICILLIN AND SULBACTAM

Summary of Differences


Precautions:
Drug interactions and/or related problems—Concurrent use with allopurinol may increase the risk of skin rash.

Laboratory value alterations—Ampicillin may decrease total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol concentrations in pregnant women.

Medical considerations/contraindications—Use in patients with infectious mononucleosis may increase the risk of skin rash.



Additional Dosing Information
Ampicillin and sulbactam combination should be administered by deep intramuscular injection or by direct, slow intravenous injection over at least a 10- to 15-minute period. It may also be administered by intravenous infusion in 50 to 100 mL of a suitable diluent over a 15- to 30-minute period. {06} {69}

Adults with impaired renal function may require an increase in the dosing interval as follows {06} {14}:

Creatinine clearance
(mL/min)/(mL/sec)
Dosing interval
(hours)
³ 30/0.5
6 to 8
15–29/0.25–0.48
12
5–14/0.08–0.23
24
< 5/0.08
48



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

AMPICILLIN SODIUM AND SULBACTAM SODIUM STERILE USP

Usual adult and adolescent dose
Antibacterial
Intramuscular or intravenous, 1.5 to 3 grams (1 to 2 grams of ampicillin and 500 mg to 1 gram of sulbactam) every six hours. {06} {69}
[Gonorrhea: ]1
Intramuscular, 1.5 grams (1 gram of ampicillin and 500 mg of sulbactam) as a single dose with 1 gram of oral probenecid. {51} {52}



Usual adult prescribing limits
4 grams of sulbactam daily. {06} {69}

Usual pediatric dose
Antibacterial
Children up to 1 year of age: Safety and efficacy have not been established. {69}

Children 1 to 12 years of age: Dosage has not been established. {06} {69} However, doses of 200 to 400 mg per kg of body weight of ampicillin and 100 to 200 mg per kg of body weight of sulbactam per day, administered in divided doses, have been used. {56}


Size(s) usually available:
U.S.—


1.5 grams (1 gram of ampicillin and 500 mg of sulbactam) (Rx) [Unasyn{69} (sodium 5 mEq [5 mmol])]


3 grams (2 grams of ampicillin and 1 gram of sulbactam) (Rx) [Unasyn{69} (sodium 10 mEq [10 mmol])]

Canada—
Not commercially available.

Packaging and storage:
Prior to reconstitution, store below 30 °C (86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
To prepare initial dilution for intramuscular use, add 3.2 mL of sterile water for injection or of 0.5 or 2% lidocaine hydrochloride injection (without epinephrine) to each 1.5-gram vial and 6.4 mL of diluent to each 3-gram vial to provide an ampicillin concentration of 250 mg per mL and a sulbactam concentration of 125 mg per mL. {06}

To prepare initial dilution for direct intermittent intravenous use, add 3.2 mL of sterile water for injection to each 1.5-gram vial and 6.4 mL of diluent to each 3-gram vial to provide an ampicillin concentration of 250 mg per mL and a sulbactam concentration of 125 mg per mL. The resulting solution should be immediately diluted with a suitable diluent (see manufacturer"s package insert) to a final ampicillin concentration of 2 to 30 mg per mL and a final sulbactam concentration of 1 to 15 mg per mL. {06} {69}

Solutions should be allowed to stand following dissolution, allowing any foaming to dissipate, in order to permit visual inspection for complete solubilization. {06} {69}

For reconstitution of piggyback infusion bottles or ADD-Vantage Vials®, consult manufacturer"s labeling.

Stability:
After reconstitution for intramuscular use, solutions retain their potency for 1 hour. {06} {69}

After reconstitution for intravenous infusion, solutions containing 30 mg of ampicillin and 15 mg of sulbactam per mL retain their potency for 8 hours at 25 °C (77 °F) or for 48 hours at 4 °C (39 °F) in sterile water for injection or 0.9% sodium chloride injection. Solutions containing 20 mg of ampicillin and 10 mg of sulbactam per mL retain their potency for 72 hours at 4 °C (39 °F) in sterile water for injection or 0.9% sodium chloride injection. Solutions containing 20 mg of ampicillin and 10 mg of sulbactam per mL retain their potency for 2 hours at 25 °C (77 °F) or for 4 hours at 4 °C (39 °F) in 5% dextrose injection. Solutions containing 2 mg of ampicillin and 1 mg of sulbactam per mL retain their potency for 4 hours at 25 °C (77 °F) in 5% dextrose injection. For stability in other diluents, consult manufacturer"s package insert. {06} {69}

Solutions (250 mg of ampicillin and 125 mg of sulbactam per mL) may vary in color from pale yellow to yellow. Dilute solutions (up to 30 mg of ampicillin and 15 mg of sulbactam per mL) may vary in color from colorless to pale yellow. {06} {69}

Incompatibilities:
Extemporaneous admixtures of beta-lactam antibacterials (penicillins) and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered at separate sites at least 1 hour apart. Do not mix them in the same intravenous bag, bottle, or tubing. {06} {69}

When aminoglycosides and penicillins are administered separately by different routes, a reduction in aminoglycoside serum concentration may occur. Usually this is clinically significant only in patients with severely impaired renal function in whom the excretion of both medications is delayed.

Additional information:
The sodium content (derived from ampicillin sodium and sulbactam sodium) is approximately 5 mEq (5 mmol) per 1.5 grams (1 gram of ampicillin and 500 mg of sulbactam). This must be considered in patients on a restricted sodium intake when calculating total daily sodium intake. {06} {69}


PIPERACILLIN AND TAZOBACTAM

Summary of Differences


Precautions:
Drug interactions and/or related problems—Piperacillin also interacts with anticoagulants and other medications that affect blood clotting.

Laboratory value alterations—May cause false-positive protein reaction in various urine protein tests; may decrease serum potassium concentrations; may increase prothrombin time and partial thromboplastin time.

Medical considerations/contraindications—Caution required in patients with history of bleeding problems; patients with cystic fibrosis may be at increased risk of fever and skin rash.



Side/adverse effects:
Increased risk of platelet dysfunction. Prolonged muscle relaxation may occur.



Additional Dosing Information
Piperacillin and tazobactam combination should be administered by intravenous infusion over a 30-minute period. {01}

The half-life of piperacillin and tazobactam is increased by 25% and 18%, respectively, in patients with hepatic cirrhosis. However, this difference does not warrant an adjustment in dose. {01}

Patients with nosocomial pneumonia should be treated with both piperacillin and tazobactam combination and an aminoglycoside antibiotic. If Pseudomonas aeruginosa is isolated from the patient, treatment with the aminoglycoside should continue. If P. aeruginosa is not isolated, the aminoglycoside may be discontinued if determined appropriate by the physician based upon the severity of the infection as well as the patient"s clinical and bacteriological progress. {70}

Patients with impaired renal function may require a reduction in dose and should be observed for hemorrhagic complications. {01} Reductions in dose for adults and adolescents with impaired renal function are as follows {01}:

Creatinine clearance
(mL/min)/(mL/sec)
Dose/Dosing interval
(piperacillin and tazobactam)
> 40/0.67
3.375 grams every 6 hours
20–40/0.33–0.67
2.25 grams every 6 hours
< 20/0.33
2.25 grams every 8 hours
Hemodialysis patients
2.25 grams every 8 hours
and 0.75 gram after
each dialysis

Note: If an aminoglycoside is being used concurrently with piperacillin and tazobactam combination, the dose of the aminoglycoside should be reduced in patients with renal function impairment according to the recommendations of the manufacturer. {70}




Parenteral Dosage Forms

PIPERACILLIN SODIUM AND TAZOBACTAM SODIUM STERILE

Usual adult and adolescent dose
Antibacterial
Nosocomial pneumonia: Intravenous infusion, 3.375 grams (3 grams of piperacillin and 0.375 grams of tazobactam) every four hours in addition to therapy with an aminoglycoside for seven to fourteen days. {70}
Other infections: Intravenous infusion, 3.375 grams to 4.5 grams (3 to 4 grams of piperacillin and 0.375 to 0.5 grams of tazobactam) every six to eight hours for seven to ten days. {01} {21}


Usual pediatric dose
Antibacterial
Infants and children up to 12 years of age: Dosage has not been established. {01}

Children 12 years of age and older: See Usual adult and adolescent dose . {01}


Size(s) usually available:
U.S.—


2.25 grams (2 grams of piperacillin and 0.25 grams of tazobactam) (Rx) [Zosyn{70} (sodium 4.7 mEq [4.7 mmol])]


3.375 grams (3 grams of piperacillin and 0.375 grams of tazobactam) (Rx) [Zosyn{70} (sodium 7.1 mEq [7.1 mmol])]


4.5 grams (4 grams of piperacillin and 0.5 grams of tazobactam) (Rx) [Zosyn{70} (sodium 9.4 mEq [9.4 mmol])]

Canada—


2.25 grams (2 grams of piperacillin and 0.25 grams of tazobactam) (Rx) [Tazocin{74} (sodium 4.7 mEq [4.7 mmol])]


3.375 grams (3 grams of piperacillin and 0.375 grams of tazobactam) (Rx) [Tazocin{74} (sodium 7 mEq [7 mmol])]


4.5 grams (4 grams of piperacillin and 0.5 grams of tazobactam) (Rx) [Tazocin{74} (sodium 9.4 mEq [9.4 mmol])]

Packaging and storage:
Prior to reconstitution, store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
To prepare initial dilution for intravenous use, add 5 mL of compatible reconstituion diluent per gram of piperacillin to each vial and shake well until dissolved. Compatible reconstitution diluents include the following: {70} 0.9% Sodium chloride for injection, Sterile water for injection, Dextrose 5%, Bacteriostatic saline/parabens, Bacteriostatic water/parabens, Bacteriostatic saline/benzyl alcohol, Bacteriostatic water/benzyl alcohol. This solution should be further diluted to the desired final volume (50 to 150 mL) with compatible intravenous diluents. Compatible intravenous diluents include the following: {70}

• 0.9% Sodium chloride for injection, Sterile water for injection, Dextrose 5%, Dextran 6% in saline
Note: The maximum recommended volume per dose of sterile water for injection is 50 mL. {70}


Lactated Ringer"s injection is not compatible with piperacillin and tazobactam combination. {70}

The prepared solution should be inspected for particulate matter and discoloration prior to administration, whenever the solution and container permit. {70}

For reconstitution of ADD-Vantage® vials, consult the manufacturer"s labeling.

Stability:
After reconstitution for intravenous use, solutions retain their potency for 24 hours at room temperature (21 to 24 °C [70 to 75 °F]) or for up to 7 days if refrigerated at 4 °C (39 °F). {70}

Incompatibilities:
Lactated Ringer"s injection is not compatible with piperacillin and tazobactam combination. {70}

Extemporaneous admixtures of beta-lactam antibacterials (penicillins) and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered in separate sites at least 1 hour apart. Do not mix them in the same intravenous bag, bottle, or tubing. {04}

When aminoglycosides and penicillins are administered separately by different routes, a reduction in aminoglycoside serum concentration may occur. Usually this is clinically significant only in patients with severely impaired renal function in whom the excretion of both medications is delayed. {04}

Additional information:
The sodium content is approximately 2.35 mEq (2.35 mmol) per gram of piperacillin. This must be considered in patients on a restricted sodium intake when calculating total daily sodium intake. {70}


PIPERACILLIN SODIUM AND TAZOBACTAM SODIUM INJECTION

Usual adult and adolescent dose
Antibacterial
See Piperacillin Sodium and Tazobactam Sodium Sterile


Usual pediatric dose
Antibacterial
See Piperacillin Sodium and Tazobactam Sodium Sterile


Strength(s) usually available
U.S.—


2.25 grams (2 grams of piperacillin and 0.25 grams of tazobactam) (Rx) [Zosyn{70} (sodium 5.7 mEq [5.7 mmol])]


3.375 grams (3 grams of piperacillin and 0.375 grams of tazobactam) (Rx) [Zosyn{70} (sodium 8.6 mEq [8.6 mmol])]


4.5 grams (4 grams of piperacillin and 0.5 grams of tazobactam) (Rx) [Zosyn{70} (sodium 11.4 mEq [11.4 mmol])]

Note: The 2.25-gram and 3.375-gram strengths are available in 50-mL containers. The 4.5-gram strength is available in a 100-mL container. {70}


Canada—
Not commercially available.

Packaging and storage:
Store at or below -20 °C (-4 °F). {70}

Incompatibilities:
Extemporaneous admixtures of beta-lactam antibacterials (penicillins) and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered in separate sites at least 1 hour apart. Do not mix them in the same intravenous bag, bottle, or tubing. {71}

When aminoglycosides and penicillins are administered separately by different routes, a reduction in aminoglycoside serum concentration may occur. Usually this is clinically significant only in patients with severely impaired renal function in whom the excretion of both medications is delayed. {04}

Additional information:
The sodium content is approximately 2.85 mEq (2.85 mmol) per gram of piperacillin. This must be considered in patients on a restricted sodium intake when calculating total daily sodium intake. {70}


TICARCILLIN AND CLAVULANATE

Summary of Differences


Precautions:
Drug interactions and/or related problems—Ticarcillin interacts with anticoagulants and other medications that affect blood clotting; clavulanic acid does not interact with probenecid.

Laboratory value alterations—May cause false-positive protein reaction for various urine protein tests; may decrease serum potassium concentrations; may increase prothrombin time and partial thromboplastin time; may increase serum sodium concentrations; may decrease uric acid.

Medical considerations/contraindications—Caution required in patients with history of bleeding problems; caution also required in patients with congestive heart failure, hypertension, or renal function impairment because of sodium content.



Side/adverse effects:
Increased risk of platelet dysfunction.



Additional Dosing Information
Sterile ticarcillin disodium and clavulanate potassium and ticarcillin disodium and clavulanate potassium injection should be administered by intravenous infusion over a 30-minute period. {04} {05}

Based on in vitro synergism between ticarcillin and clavulanic acid combination and aminoglycoside antibiotics against P. aeruginosa , combined therapy has been successful, especially in patients who have impaired host defenses. When used in combination, both drugs should be used in their full therapeutic doses. When results of culture and susceptibility tests become available, antimicrobial therapy should be adjusted as appropriate. {71}

In those patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented, or in patients who require prophylaxis against central nervous system infection, an alternate agent with demonstrated clinical efficacy in this setting should be used instead of ticarcillin and clavulanate combination. {71}

Patients with impaired renal function may require a reduction in dose and should be observed for hemorrhagic complications. {04} After an initial loading dose of 3 grams of ticarcillin and 100 mg of clavulanic acid, adults with impaired renal function may require a reduction in dose as follows: {71}

Creatinine clearance
(mL/min)/(mL/sec)
Dose/Dosing interval
> 60/1
3.1 grams every 4 hours
30–60/0.5–1
2 grams every 4 hours
10–30/0.17–0.5
2 grams every 8 hours
< 10/0.17
2 grams every 12 hours
< 10 with hepatic dysfunction
2 grams every 24 hours
Peritoneal dialysis patients
3.1 grams every 12 hours
Hemodialysis patients
2 grams every 12 hours;
and 3.1 grams after
each dialysis



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

TICARCILLIN AND CLAVULANIC ACID FOR INJECTION USP

Usual adult
Antibacterial
Adults 60 kg of body weight and over—

• Gynecologic infections (treatment):

• Moderate infection—Intravenous infusion, 50 mg of ticarcillin and 1.7 mg of clavulanic acid per kg of body weight every six hours. {71}


• Severe infection—Intravenous infusion, 50 mg of ticarcillin and 1.7 mg of clavulanic acid per kg of body weight every four hours. {71}



• Other infections (treatment): Intravenous infusion, 3 grams of ticarcillin and 100 mg of clavulanic acid every four to six hours. {71}

Adults weighing less than 60 kg—

• Gynecologic and other infections (treatment): Intravenous infusion, 50 mg of ticarcillin and 1.7 mg of clavulanic acid per kg of body weight every four to six hours. {71}.

[Surgical prophylaxis]: Intravenous infusion, 3 grams of ticarcillin and 100 mg of clavulanic acid one-half to one hour prior to the start of surgery, or (for cesarean section) as soon as the umbilical cord is clamped, then 3.1 grams (3 grams of ticarcillin and 100 mg of clavulanic acid) at four-hour intervals for a total of three doses. {05}


Usual pediatric dose
Antibacterial


Infants less than 1 month of age:
Dosage has not been established. {04} {05}



Infants and children 1 month to 12 years of age:
Intravenous infusion, 50 mg of ticarcillin and 1.7 mg of clavulanic acid per kg of body weight every four to six hours. {05} {56}

Note: Children with cystic fibrosis—Intravenous infusion, 350 to 450 mg of ticarcillin and 11.7 to 17 mg of clavulanic acid per kg of body weight a day in divided doses. {20}




Children 12 years of age and older:
See Usual adult and adolescent dose (Adults and adolescents up to 60 kg of body weight) .



Size(s) usually available:
U.S.—


3.1 grams (3 grams of ticarcillin and 100 mg of clavulanic acid) (Rx) [Timentin{71} (sodium 4.75 mEq [4.75 mmol] per gram )]


31 grams (30 grams of ticarcillin and 1 gram of clavulanic acid) (Rx) [Timentin{71}]

Canada—


3.1 grams (3 grams of ticarcillin and 100 mg of clavulanic acid) (Rx) [Timentin{73} (sodium 4.75 mEq [4.75 mmol] per gram )]


31 grams (30 grams of ticarcillin and 1 gram of clavulanic acid) (Rx) [Timentin{73}]

Packaging and storage:
Prior to reconstitution, store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
To prepare initial dilution for direct intravenous use, add 13 mL of sterile water for injection or sodium chloride injection to each 3.1-gram vial to provide a ticarcillin concentration of approximately 200 mg per mL and a clavulanic acid concentration of approximately 6.7 mg per mL. The resulting solution should be further diluted to desired volume in sodium chloride injection, 5% dextrose injection, or lactated Ringer"s injection and administered over a 30-minute period by direct infusion or through a Y-type intravenous infusion set. {71}

Once reconstituted, the ticarcillin and clavulanate solution should be visually inspected for particulate matter prior to administration. If particulate matter is present, the solution should be discarded. The color of ticarcillin and clavulanate reconstituted solution normally ranges from light to dark yellow, depending on the concentration of the solution and the duration and temperature of storage. {71}

For reconstitution of piggyback infusion bottles or pharmacy bulk vials, see manufacturer"s labeling for instructions. If the Y-type method of administration is used, the primary infusion should be temporarily discontinued during infusion of ticarcillin and clavulanate combination. {04} {71}

Stability:
After reconstitution for intravenous use, solutions containing 200 mg of ticarcillin per mL retain their potency for 6 hours at room temperature (21 to 24 °C [70 to 75 °F]) or for up to 72 hours if refrigerated at 4 °C (39 °F). {04} {71}

Solutions containing 10 to 100 mg of ticarcillin per mL in sodium chloride injection or lactated Ringer"s injection retain their potency for 24 hours at room temperature (21 to 24 °C [70 to 75 °F]) or for 7 days if refrigerated at 4 °C (39 °F). Solutions containing 10 to 100 mg of ticarcillin per mL in 5% dextrose injection retain their potency for 24 hours at room temperature or for 3 days if refrigerated. {04} {71}

After reconstitution, solutions containing 100 mg of ticarcillin or less per mL in sodium chloride injection or lactated Ringer"s injection may be frozen and stored for up to 30 days. Solutions in 5% dextrose injection may be frozen for 7 days. Thawed solutions should be used within 8 hours. {04} Solutions should not be refrozen once they have been thawed. {71}

Incompatibilities:
Extemporaneous admixtures of beta-lactam antibacterials (penicillins) and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered in separate sites at least 1 hour apart. Do not mix them in the same intravenous bag, bottle, or tubing. {04} {71}

When aminoglycosides and penicillins are administered separately by different routes, a reduction in aminoglycoside serum concentration may occur. Usually this is clinically significant only in patients with severely impaired renal function in whom the excretion of both medications is delayed. {04}

Sterile ticarcillin disodium and clavulanate potassium combination is incompatible with sodium bicarbonate. {04} {71}

Additional information:
The sodium content is approximately 4.75 mEq (4.75 mmol) per gram of ticarcillin. This must be considered in patients on a restricted sodium intake when calculating total daily sodium intake. {71}

The potassium content is approximately 0.15 mEq (6 mg) per 100 mg of clavulanic acid. {04}


TICARCILLIN AND CLAVULANIC ACID INJECTION

Usual adult and adolescent dose
See Sterile Ticarcillin Disodium and Clavulanate Potassium USP .

Usual pediatric dose
See Sterile Ticarcillin Disodium and Clavulanate Potassium USP .

Strength(s) usually available
U.S.—


3.1 grams (3 grams of ticarcillin and 100 mg of clavulanic acid) in 100 mL (Rx) [Timentin{71} (sodium 4.75 mEq [4.75 mmol] per gram)]

Canada—
Not commercially available.

Packaging and storage:
Do not store above -10 °C (14 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
Thaw container at room temperature before administration, making sure that all ice crystals have melted.

Minibags should not be used in series connections. Doing so may result in air embolism because of residual air being drawn from the primary container before administration of intravenous solution from the secondary container is complete.

Stability:
Thawed solutions should be used within 8 hours. {04} Once thawed, solutions should not be refrozen.

Incompatibilities:
Extemporaneous admixtures of beta-lactam antibacterials (penicillins) and aminoglycosides may result in substantial mutual inactivation. If these groups of antibacterials are administered concurrently, they should be administered in separate sites at least 1 hour apart. Do not mix them in the same intravenous bag, bottle, or tubing. {04}

When aminoglycosides and penicillins are administered separately by different routes, a reduction in aminoglycoside serum concentration may occur. Usually this is clinically significant only in patients with severely impaired renal function in whom the excretion of both medications is delayed. {04}

Additional information:
The sodium content is approximately 4.75 mEq (4.75 mmol) per gram of ticarcillin. This must be considered in patients on a restricted sodium intake when calculating total daily sodium intake.

The potassium content is approximately 0.15 mEq (6 mg) per 100 mg of clavulanic acid. {04}



Revised: 12/12/2000



References
  1. Piperacillin and tazobactam package insert (Zosyn, Lederle—US), Rev 10/93, Rec 2/94.
  1. Amoxicillin and clavulanate (Augmentin, SmithKline Beecham). In: PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company; 1994. p. 2242-4.
  1. Amoxicillin and clavulanate (Clavulin, SmithKline Beecham). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association; 1993. p. 247-8.
  1. Ticarcillin and clavulanate (Timentin, SmithKline Beecham). In: PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company; 1994. p. 2292-5.
  1. Ticarcillin and clavulanate (Timentin, SmithKline Beecham). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association; 1993. p. 1228-9.
  1. Ampicillin and sulbactam (Unasyn, Roerig). In: PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company; 1994. p. 1995-8.
  1. Tatro DS, editor. Drug interaction facts. St Louis: Facts and Comparisons; 1983. p. 376.
  1. Segreti J, Trenholme GM. Beta-lactamase inhibitors and new cephalosporins. Curr Opin Infect Dis 1993; 6: 731-6.
  1. Anderson PO. Drug use during breast-feeding. Clin Pharm 1991; 10: 594-624.
  1. Singh N, Yu VL, Mieles LA, et al. Beta-lactam antibiotic-induced leukopenia in severe hepatic dysfunction: risk factors and implications for dosing in patients with liver disease. Am J Med 1993; 94: 251-6.
  1. Nathwani D, Wood MJ. Penicillins: a current review of their clinical pharmacology and therapeutic use. Drugs 1993; 45(6): 866-94.
  1. Turnidge J, Grayson ML. Optimum treatment of staphylococcal infections. Drugs 1993; 45(3): 353-66.
  1. St. Peter WL, Redic-Kill KA, Halstenson CE. Clinical pharmacokinetics of antibiotics in patients with impaired renal function. Clin Pharmacokinet 1992; 22(3): 169-210.
  1. Fillastre J-P, Singlas E. Pharmacokinetics of newer drugs in patients with renal impairment (part I). Clin Pharmacokinet 1991; 20(4): 293-310.
  1. Bartlett JG. Antibiotic-associated diarrhea. Clin Infect Dis 1992; 15: 573-81.
  1. Fekety R, Shah AB. Diagnosis and treatment of Clostridium difficile colitis. JAMA 1993; 269(1): 71-5.
  1. Rolinson GN. Evolution of beta-lactamase inhibitors. Rev Infect Dis 1991; 13 Suppl 9: S727-S732.
  1. Kuye O, Teal J, DeVries VG, et al. Safety profile of piperacillin/tazobactam in phase I and III clinical studies. J Antimicrob Chemother 1993; 31 Suppl A: 113-24.
  1. Livermore DM. Determinants of the activity of beta-lactamase inhibitor combinations. J Antimicrob Chemother 1993; 31 Suppl A: 9-21.
  1. Lindsay CA, Bosso JA. Optimisation of antibiotic therapy in cystic fibrosis patients. Clin Pharmacokinet 1993; 24(6): 496-506.
  1. Bryson HM, Brogden RN. Piperacillin/tazobactam: a review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Drugs 1994; 47(3): 506-35.
  1. Wise R. The efficacy and safety of piperacillin/tazobactam in the therapy of bacteraemia. J Antimicrob Chemother 1993; 31 Suppl A: 97-104.
  1. Brismar B, Malmborg AS, Tunevall G, et al. Piperacillin-tazobactam versus imipenem-cilastatin for treatment of intra-abdominal infections. Antimicrob Agents Chemother 1992; 36(12): 2766-73.
  1. Tan JS, Wishnow RM, Talan DA, et al. Treatment of hospitalized patients with complicated skin and skin structure infections: double-blind, randomized, multicenter study of piperacillin-tazobactam versus ticarcillin-clavulanate. Antimicrob Agents Chemother 1993; 37(8): 1580-6.
  1. Williams JD. Interaction between antibiotics and beta-lactamase inhibitors. Infections in Medicine 1993; 10 Suppl A: 15-21.
  1. Fuchs PC, Barry AL. In vitro activity of piperacillin/tazobactam: a review. Infect Med 1993; 10 Suppl A: 22-7.
  1. LeBel M, Paone RP, Lewis GP. Effect of ten new beta-lactam antibiotics on urine glucose test methods. Drug Intell Clin Pharm 1984; 18: 617-20.
  1. Saxon A, Beall GN, Rohr AS, et al. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med 1987; 107(2): 204-15.
  1. Donowitz GR, Mandell GL. Beta-lactam antibiotics (Pt 1). N Engl J Med 1988; 318(7): 419-26.
  1. Personal communication, Mark F. McMahon, SmithKline Beecham Pharmaceuticals [letter] 6/11/93.
  1. Staniforth DH, Jackson D, Clarke HL, et al. Amoxycillin/clavulanic acid: the effect of probenecid. J Antimicrob Chemother 1983; 12: 273-5.
  1. Pien FD. Double-blind comparative study of two dosage regimens of cefaclor and amoxicillin-clavulanic acid in the outpatient treatment of soft tissue infections. Antimicrob Agents Chemother 1983; 24(6): 856-9.
  1. Jaffe AC, O'Brien CA, Reed MD, et al. Randomized comparative evaluation of Augmentin and cefaclor in pediatric skin and soft-tissue infections. Curr Therap Res 1985; 38(1): 160-8.
  1. Wallace RJ, Steele LC, Brooks DL, et al. Amoxicillin-clavulanic acid in the treatment of lower respiratory tract infections caused by beta-lactamase-positive Haemophilus influenzae and Branhamella catarrhalis. Antimicrob Agents Chemother 1985; 27(6): 912-5.
  1. Brumfitt W, Hamilton-Miller JMT. Amoxicillin plus clavulanic acid in the treatment of recurrent urinary tract infections. Antimicrob Agents Chemother 1984; 25(2): 276-8.
  1. Pedler SJ, Bint AJ. Comparative study of amoxicillin-clavulanic acid and cephalexin in the treatment of bacteriuria during pregnancy. Antimicrob Agents Chemother 1985; 27(4): 508-10.
  1. Martinelli R, da Silva Lopez AA, de Oliveira MMMG, et al. Amoxicillin-clavulanic acid in treatment of urinary tract infection due to gram-negative bacteria resistant to penicillin. Antimicrob Agents Chemother 1981; 20(6): 800-2.
  1. Iravani A, Richard GA. Amoxicillin-clavulanic acid versus cefaclor in the treatment of urinary tract infections and their effects on the urogenital and rectal flora. Antimicrob Agents Chemother 1986; 29(1): 107-11.
  1. Beeuwkes H, Rutgers VH. A combination of amoxicillin and clavulanic acid in the treatment of respiratory tract infections caused by amoxicillin-resistant Haemophilus influenzae. Infection 1981; 9(5): 244-8.
  1. Aigner K, Schindl R, Mittermayer H. Augmentin in acute exacerbations of chronic bronchitis. J Int Med Res 1984; 12: 321-6.
  1. Maesen FPV, Davies BI, Baur C. Amoxycillin/clavulanate in acute purulent exacerbations of chronic bronchitis. J Antimicrob Chemother 1987; 19: 373-83.
  1. Wald ER, Chiponis D, Ledesma-Medina J. Comparative effectiveness of amoxicillin and amoxicillin-clavulanate potassium in acute paranasal sinus infections in children: a double-blind, placebo-controlled trial. Pediatrics 1986; 77(6): 795-800.
  1. Odio CM, Kusmiesz H, Shelton S, et al. Comparative treatment trial of Augmentin versus cefaclor for acute otitis media with effusion. Pediatrics 1985; 75(5): 819-26.
  1. Marchant CD, Shurin PA, Johnson CE, et al. A randomized controlled trial of amoxicillin plus clavulanate compared with cefaclor for treatment of acute otitis media. J Pediatr 1986; 109: 891-6.
  1. Fast MV, D'Costa LJ, Karasira P, et al. Treatment of chancroid by clavulanic acid with amoxycillin in patients with beta-lactamase-positive Haemophilus ducreyi infection. Lancet 1982; 2: 509-11.
  1. Ndinya-Achola JO, Nsanze H, Karasira P, et al. Three day oral course of Augmentin to treat chancroid. Genitourin Med 1986; 62: 202-4.
  1. Labia R, Barthelemy M, Peduzzi J. Molecular aspects of beta-lactamase inhibition and inactivation by clavulanic acid: a review. Drugs Exp Clin Res 1985; 11(11): 765-70.
  1. Weber DJ, Tolkoff-Rubin NE, Rugin RH. Amoxicillin and potassium clavulanate: an antibiotic combination. Pharmacotherapy 1985; 4: 122-36.
  1. Mehtar S, Croft RJ, Hilas A. A non-comparative study of parenteral ampicillin and sulbactam in intra-thoracic and intra-abdominal infections. J Antimicrob Chemother 1986; 17: 389-96.
  1. Nichols RL, Smith JW, Adinolfi MF, et al. Inhibition of beta-lactamase-induced resistance in soft-tissue infections. Arch Surg 1985; 120: 36-42.
  1. Odugbemi T. An open evaluative study of sulbactam/ampicillin with or without probenecid in gonococcal infections in Lagos. Curr Therap Res 1987; 41(4): 542-51.
  1. Ngeow YF, Ramachandran S, Cheong YM. Treatment of gonorrhea with sulbactam/ampicilin. Sex Transm Dis 1991; 18(3): 192-4.
  1. Abbassi AF, Said A, Gaber A. Intramuscular sulbactam/ampicillin combination therapy in gynaecological and obstetric bacterial infections. J Int Med Res 1991; 19 Suppl 1: 44A-49A.
  1. Benson JM, Nahata MC. Sulbactam/ampicillin, a new beta-lactamase inhibitor/beta-lactam antibiotic combination. Drug Intell Clin Pharm 1988; 22: 534-41.
  1. Mouton Y, Leroy O, Beuscart C, et al. Efficacy, safety and tolerance of parenteral piperacillin/tazobactam in the treatment of patients with lower respiratory tract infections. J Antimicrob Chemother 1993; 31 Suppl A: 87-95.
  1. Itoazu GS, Danziger LH. Ampicillin-sulbactam and ticarcillin-clavulanic acid: a comparison of their in vitro activity and review of their clinical efficacy. Pharmacotherapy 1991; 11(5): 382-414.
  1. Fortunato SJ, Bawdon RE, Swan KF, et al. Transfer of Timentin (ticarcillin and clavulanic acid) across the in vitro perfused human placenta: comparison with other agents. Am J Obstet Gynecol 1992; 167: 1595-9.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 52-3, 175, 578, 690, 708, 733.
  1. Roselle GA, Bode R, Hamilton B, et al. Clinical trial of the efficacy and safety of ticarcillin and clavulanic acid. Antimicrob Agents Chemother 1985; 27(3): 291-6.
  1. Mandell GL, Douglas RG, Bennett JE, editors. Principles and practice of infectious diseases. 3rd ed. New York: Churchill Livingstone; 1990. p. 236, 262.
  1. Polk HC, Fink MP, Laverdiere M, et al. Prospective randomized study of piperacillin/tazobactam therapy of surgically treated intra-abdominal infection. Am Surg 1993; 59: 598-605.
  1. Sweet RL, Roy S, Faro S, et al. Piperacillin and tazobactam versus clindamycin and gentamicin in the treatment of hospitalized women with pelvic infection. Obstet Gynecol 1994; 83: 280-6.
  1. Shales DM, Norden, Pneumonia Study Group. Piperacillin/tazobactam (P/T) compared to ticarcillin/clavulanate (T/C) in community-acquired bacterial lower respiratory tract infection. Presented at the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 1993; New Orleans, Louisianna. Poster #646.
  1. Joshi M, Solomkin JS, Bernstein JM, et al. Open, randomized, multicenter comparison of piperacillin/tazobactam (PIP/TAZ) vs ceftazidime (CAZ), both plus tobramycin (TM), in 300 patients with hospital-acquired lower respiratory tract infections (LRTI). Presented at the 6th International Congress for Infectious Disease (ICID); 1994; Prague, Czech Republic. Poster #856.
  1. Roberts GW, Nation RL, Jarvinen AO, et al. An in vivo assessment of the tobramycin/ticarcillin interaction in cystic fibrosis patients. Br J Clin Pharmacol 1993; 36: 372-5.
  1. Antimicrobial prophylaxis in surgery. Med Lett Drugs Ther 1993; 35(906): 91-4.
  1. Augmentin Powder for Oral Suspension and Chewable Tablets (SmithKline Beecham). In: PDR Physicians' desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 3028-31.
  1. Augmentin Tablets (SmithKline Beecham). In: PDR Physicians' desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 3031-4.
  1. Unasyn (Pfizer). In: PDR Physicians' desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 2421-4.
  1. Zosyn (Lederle). In: PDR Physicians' desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 1557-62.
  1. Timentin (SmithKline Beecham). In: PDR Physicians' desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 3106-9.
  1. Clavulin (SmithKline Beecham). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 328-9.
  1. Timentin (SmithKline Beecham). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 1679-80.
  1. Tazocin (Wyeth-Ayerst). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 1639-41.
  1. Package Insert Timentin®, ticarcillin disodium and clavulanate potassium. SmithKline Beecham, Philadelphia, PA (PI revised 07/2000) reviewed 12/2000.
Hide
(web5)