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Ampicillin and Sulbactam

Pronunciation

(am pi SIL in & SUL bak tam)

Index Terms

  • Ampicillin Sodium/Sulbactam Na
  • Sulbactam and Ampicillin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution: 1.5 g: Ampicillin 1 g and sulbactam 0.5 g; 3 g: Ampicillin 2 g and sulbactam 1 g; 15 g: Ampicillin 10 g and sulbactam 5 g

Unasyn:

1.5 g: Ampicillin 1 g and sulbactam 0.5 g [contains sodium 115 mg (5 mEq)/1.5 g)]

3 g: Ampicillin 2 g and sulbactam 1 g [contains sodium 115 mg (5 mEq)/1.5 g)]

15 g: Ampicillin 10 g and sulbactam 5 g [bulk package; contains sodium 115 mg (5 mEq)/1.5 g)]

Brand Names: U.S.

  • Unasyn

Pharmacologic Category

  • Antibiotic, Penicillin

Pharmacology

Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested. The addition of sulbactam, a beta-lactamase inhibitor, to ampicillin extends the spectrum of ampicillin to include some beta-lactamase-producing organisms.

Distribution

Sulbactam: Widely distributed to bile, blister, and tissue fluids;poor penetration into CSF with uninflamed meninges; higher concentrations attained with inflamed meninges; Vd (Nahata 1999):

Children 1 to 12 years: ~0.35 L/kg

Adults: 0.25 L/kg

Excretion

Sulbactam: Urine (~75% to 85% as unchanged drug) within 8 hours

Half-Life Elimination

Sulbactam: Children 1 to 12 years (normal renal function): Mean range: ~0.7 to 0.9 hours (Nahata 1999); Adults (normal renal function): 1 to 1.3 hours; Note: Elimination kinetics of both ampicillin and sulbactam are similarly affected in patients with renal impairment, therefore, the blood concentration ratio is expected to remain constant regardless of renal function.

Protein Binding

Sulbactam: 38%

Use: Labeled Indications

Bacterial infections: Treatment of susceptible bacterial infections involved with skin and skin structure, intra-abdominal infections, gynecological infections; spectrum is that of ampicillin plus organisms producing beta-lactamases such as S. aureus, H. influenzae, E. coli, Klebsiella, Acinetobacter, Enterobacter, and anaerobes

Use: Unlabeled

Treatment of acute bacterial rhinosinusitis (ABRS); endocarditis; intravascular catheter-associated bloodstream infection caused by susceptible bacteria; pelvic inflammatory disease; community-acquired pneumonia; early-onset hospital-acquired pneumonia; surgical (perioperative) prophylaxis

Contraindications

Hypersensitivity (eg, anaphylaxis or Stevens-Johnson syndrome) to ampicillin, sulbactam, or to other beta-lactam antibacterial drugs (eg, penicillins, cephalosporins), or any component of the formulations; history of cholestatic jaundice or hepatic dysfunction associated with ampicillin/sulbactam

Dosing: Adult

Unasyn (ampicillin/sulbactam) is a combination product. Note: Dosage recommendations are expressed as grams of ampicillin/sulbactam combination.

Susceptible infections: IM, IV: 1.5 to 3 g every 6 hours (maximum: 12 g ampicillin/sulbactam daily)

Acute bacterial rhinosinusitis, severe infection requiring hospitalization (off-label use): IV: 1.5 to 3 g every 6 hours for 5 to 7 days (Chow 2012)

Amnionitis, cholangitis, diverticulitis, endomyometritis (with doxycycline), endophthalmitis, epididymitis/orchitis, liver abscess (with metronidazole), or peritonitis: IV: 3 g every 6 hours

Bite wounds (animal/human) (off-label use): IV: 1.5 to 3 g every 6 hours (human bites) or every 6 to 8 hours (animal bites) (IDSA [Stevens 2014])

Infective endocarditis, treatment (off-label use): Enterococcus (native or prosthetic valve; resistant to penicillin/susceptible to aminoglycoside and vancomycin): IV: 3 g every 6 hours with a concomitant aminoglycoside for 6 weeks (AHA [Baddour 2015])

Intravascular catheter-associated bloodstream infection, Acinetobacter spp (off-label use) (IDSA 2009): IV: 3 g every 6 hours

Orbital cellulitis: IV: 3 g every 6 hours

Osteomyelitis (diabetic foot) (Lipsky 2004): IV: 3 g every 6 hours

Pelvic inflammatory disease (alternative to preferred therapy): IV: 3 g every 6 hours with doxycycline oral or IV; transition from parenteral to oral therapy can usually be initiated within 24 to 48 hours of clinical improvement for a total treatment duration of 14 days; if tubo-ovarian abscess is present, at least 24 hours of inpatient observation is recommended (CDC [Workowski 2015).

Peritonitis associated with CAPD: Intraperitoneal:

Intermittent: 3 g added to one exchange every 12 hours; allow to dwell for at least 6 hours (Blackwell 1990; Li 2010)

Continuous: Loading dose: 1.5 g per liter of dialysate; maintenance dose: 150 mg per liter of dialysate (Li 2010)

Pneumonia (off-label use):

Aspiration or community-acquired: IV: 1.5 to 3 g every 6 hours for ≥5 days (Geckler 1994; Majcher-Peszynska 2014; Mandell 2007; Rossoff 1995). Note: In ICU patients, use in combination with azithromycin or a fluoroquinolone (Mandell 2007).

Hospital-acquired (empiric, early onset, no known risk for multidrug-resistant pathogens): IV: 3 g every 6 hours for ≥5 days (ATS 2005; Jauregui 1995).

Surgical (perioperative) prophylaxis (off-label use): IV: 3 g within 60 minutes prior to surgical incision. Doses may be repeated in 2 hours if procedure is lengthy or if there is excessive blood loss (Bratzler 2013).

Surgical site infections (intestinal or GI tract) (off-label use): IV: 3 g every 6 hours; in combination with gentamicin or tobramycin (IDSA [Stevens 2014])

Urinary tract infections, pyelonephritis: IV: 3 g every 6 hours for 14 days

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Unasyn (ampicillin/sulbactam) is a combination product. Note: Dosage recommendations are expressed as mg of the ampicillin component.

Susceptible infections: Children and Adolescents: IV: 100 to 200 mg ampicillin/kg/day divided every 6 hours (maximum: 8 g ampicillin daily or 12 g ampicillin/sulbactam daily).

Epiglottitis: Children and Adolescents: IV: 100 to 200 mg ampicillin/kg/day divided in 4 doses

Infective endocarditis, treatment (off-label use) (AHA/IDSA [Baddour 2005]): Infants, Children, and Adolescents:

Bartonella spp. (Native valve): IV: 200 mg ampicillin/kg/day in 4 or 6 divided doses with concomitant gentamicin for 4 to 6 weeks.

Enterococcus organism (resistant to penicillin/susceptible to aminoglycoside and vancomycin): IV: 200 mg ampicillin/kg/day in 4 divided doses with concomitant gentamicin for 6 weeks. Note: If enterococcus is gentamicin resistant, then >6 weeks of ampicillin-sulbactam therapy needed.

HACEK organism: 200 mg ampicillin/kg/day in 4 or 6 divided doses for 4 weeks.

Intravascular catheter-associated bloodstream infection (off-label use) (IDSA 2009): Infants, Children, and Adolescents:

Infants: IV: 100 to 150 mg ampicillin/kg/day in 4 divided doses

Children and Adolescents: IV: 100 to 200 mg ampicillin/kg/day in 4 divided doses

Mild to moderate infections: Children and Adolescents: IV: 100 to 200 mg ampicillin/kg/day divided every 6 hours (maximum: 8 g ampicillin daily or 12 g ampicillin/sulbactam daily)

Peritonsillar and retropharyngeal abscess: Children and Adolescents: IV: 200 mg ampicillin/kg/day in 4 divided doses

Severe infections: Children and Adolescents: IV: 200 mg ampicillin/kg/day divided every 6 hours (maximum: 8 g ampicillin daily or 12 g ampicillin/sulbactam daily)

Surgical (perioperative) prophylaxis (off-label use): Children ≥1 year: IV: 50 mg ampicillin/kg within 60 minutes prior to surgical incision (maximum dose: 2000 mg ampicillin or 3 g ampicillin/sulbactam daily). Doses may be repeated in 2 hours if procedure is lengthy or if there is excessive blood loss (Bratzler 2013).

Dosing: Renal Impairment

Note: Estimation of renal function for the purpose of drug dosing should be done using the Cockcroft-Gault formula. Dosage recommendations are expressed as grams of ampicillin/sulbactam combination:

CrCl ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.

CrCl 15 to 29 mL/minute/1.73 m2: 1.5 to 3 g every 12 hours

CrCl 5 to 14 mL/minute/1.73 m2: 1.5 to 3 g every 24 hours

End stage renal disease (ESRD) on intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days): 1.5 to 3 g every 12 to 24 hours (Heintz 2009). Note: Dosing dependent on the assumption of 3 times weekly, complete IHD sessions.

Continuous renal replacement therapy (CRRT): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug levels in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment (Heintz 2009; Trotman 2005):

CVVH: Initial: 3 g; maintenance: 1.5 to 3 g every 8 to 12 hours

CVVHD: Initial: 3 g; maintenance: 1.5 to 3 g every 8 hours

CVVHDF: Initial: 3 g; maintenance: 1.5 to 3 g every 6 to 8 hours

Dosing: Hepatic Impairment

There is no dosage adjustment provided in the manufacturer’s labeling.

Reconstitution

Direct IV administration and IV infusion: Reconstitute with sterile water for injection (SWFI). Sodium chloride 0.9% (NS) is the diluent of choice for IV infusion use.

IM administration: Reconstitute with SWFI or 0.5% or 2% lidocaine hydrochloride injection.

Administration

Administer around-the-clock to promote less variation in peak and trough serum levels.

IV: Administer by slow injection over 10 to 15 minutes or as an IV infusion over 15 to 30 minutes. Ampicillin and gentamicin should not be mixed in the same IV tubing.

Some penicillins (eg, ampicillin, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate aminoglycosides in vitro. This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater stability against inactivation. Concurrent Y-site administration should be avoided.

IM: Inject deep I.M. into large muscle mass; a concentration of 375 mg/mL ampicillin/sulbactam (250 mg ampicillin/125 mg sulbactam per mL) is recommended; may be diluted in sterile water or lidocaine 0.5% or lidocaine 2% for I.M. administration.

Dietary Considerations

Some products may contain sodium.

Compatibility

Stable in NS.

Y-site administration: Incompatible with aminoglycosides (eg, gentamicin, tobramycin), amiodarone, amphotericin B cholesteryl sulfate complex, ciprofloxacin, idarubicin, nicardipine, ondansetron.

Storage

Prior to reconstitution, store at 20°C to 25°C (68°F to 77°F).

IM: Concentration of 375 mg/mL (250 mg ampicillin/125 mg sulbacatam) should be used within 1 hour after reconstitution.

Intermittent IV infusion: Solutions made in NS are stable up to 72 hours when refrigerated whereas dextrose solutions (same concentration) are stable for only 4 hours. For stability related to specific concentrations and temperatures, see prescribing information.

Drug Interactions

Allopurinol: May enhance the potential for allergic or hypersensitivity reactions to Ampicillin. Monitor therapy

Atenolol: Ampicillin may decrease the bioavailability of Atenolol. Monitor therapy

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Chloroquine: May decrease the serum concentration of Ampicillin. Management: Chloroquine prescribing information recommends separating administration of ampicillin and chloroquine by at least 2 hours to minimize any potential negative impact of chloroquine on ampicillin bioavailability. Consider therapy modification

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Lanthanum: May decrease the serum concentration of Ampicillin. Management: Administer oral ampicillin at least two hours before or after lanthanum. Consider therapy modification

Methotrexate: Penicillins may increase the serum concentration of Methotrexate. Monitor therapy

Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation. Monitor therapy

Probenecid: May increase the serum concentration of Penicillins. Management: Avoid the routine use of penicillins and probenecid, but this combination may be used advantageously in select cases with careful monitoring. Monitor for toxic effects of penicillins if probenecid is initiated or the dose is increased. Consider therapy modification

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Tetracycline Derivatives: May diminish the therapeutic effect of Penicillins. Consider therapy modification

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Penicillins may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Test Interactions

May interfere with urinary glucose tests using cupric sulfate (Benedict's solution, Fehling’s solution, or Clinitest®).

Some penicillin derivatives may accelerate the degradation of aminoglycosides in vitro, leading to a potential underestimation of aminoglycoside serum concentration.

Adverse Reactions

Also see Ampicillin.

>10%: Local: Pain at injection site (IM; 16%)

1% to 10%:

Cardiovascular: Thrombophlebitis (3%), phlebitis (1%)

Dermatologic: Skin rash (<2%)

Gastrointestinal: Diarrhea (3%)

Local: Pain at injection site (IV; 3%)

<1% (Limited to important or life-threatening): Acute generalized exanthematous pustulosis, agranulocytosis, anemia, basophilia, candidiasis, casts in urine (hyaline), chest pain, chills, cholestasis, cholestatic hepatitis, clostridium difficile associated diarrhea, convulsions, decreased neutrophils, decreased serum albumin, decreased serum total protein, dysuria, edema, eosinophilia, erythema, erythema multiforme, erythrocyturia, exfoliative dermatitis, gastritis, glossitis, hairy tongue, headache, hemolytic anemia, hepatic insufficiency, hepatitis, hyperbilirubinemia, hypersensitivity reaction, immune thrombocytopenia, increased blood urea nitrogen, increased lactate dehydrogenase, increased liver enzymes, increased monocytes, increased serum creatinine, injection site reaction, interstitial nephritis, lymphocytopenia, lymphocytosis (abnormal), nausea, positive direct Coombs test, pruritus, pseudomembranous colitis, Stevens-Johnson syndrome, stomatitis, thrombocythemia, thrombocytopenia, urinary retention, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid/hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity or a history of sensitivity to multiple allergens. Patients with a history of penicillin hypersensitivity have experienced severe reactions when treated with cephalosporins. Before initiating therapy, carefully investigate previous penicillin, cephalosporin, or other allergen hypersensitivity. If an allergic reaction occurs, discontinue and institute appropriate therapy.

• Hepatic dysfunction: Hepatitis and cholestatic jaundice have been reported (including fatalities). Toxicity is usually reversible. Monitor hepatic function at regular intervals in patients with hepatic impairment.

• Rash: Appearance of a rash should be carefully evaluated to differentiate a nonallergic ampicillin rash from a hypersensitivity reaction; rash occurs in 5% to 10% of children and is a generalized dull red, maculopapular rash, generally appearing 3-14 days after the start of therapy. It normally begins on the trunk and spreads over most of the body. It may be most intense at pressure areas, elbows, and knees.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Hepatic impairment: Hepatotoxicity has been reported. Monitor hepatic function at regular intervals in patients with hepatic impairment.

• Infectious mononucleosis: A high percentage of patients with infectious mononucleosis have developed rash during therapy; ampicillin-class antibacterials are not recommended in these patients.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended.

Monitoring Parameters

With prolonged therapy, monitor hematologic, renal, and hepatic function; monitor for signs of anaphylaxis during first dose. In patients with preexisting hepatic impairment, monitor hepatic function at regular intervals.

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Both ampicillin and sulbactam cross the placenta. Maternal use of penicillins has generally not resulted in an increased risk of birth defects. When used during pregnancy, pharmacokinetic changes have been observed with ampicillin alone (refer to the Ampicillin monograph for details). Ampicillin/sulbactam may be considered for prophylactic use prior to cesarean delivery (consult current guidelines).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea or injection site irritation. Have patient report immediately to prescriber severe nausea, severe vomiting, vaginal yeast infection, bruising, bleeding, thrush, severe loss of strength and energy, chills, angina, or signs of Clostridium difficile (C. diff)-associated diarrhea (abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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