Continuing Education Activity

The ampicillin/sulbactam combination shows synergy to cover strains of bacteria resistant to ampicillin, thus providing broader coverage. This combo adds a beta-lactamase inhibitor to ampicillin to provide extended coverage against potentially resistant bacteria. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent to interprofessional team members to use ampicillin-sulbactam appropriately for various indications with an eye towards antimicrobial stewardship.

Objectives:

• Identify the indications for ampicillin-sulbactam.
• Describe the mechanism of action of ampicillin-sulbactam.
• Review the possible adverse effects associated with the use of ampicillin-sulbactam.
• Outline the role of interprofessional coordination to restrict the unwarranted use of ampicillin-sulbactam to avoid contributing to antimicrobial resistance.

Indications

The ampicillin/sulbactam combination shows synergy to cover strains of bacteria resistant to ampicillin, thus providing broader coverage.[1] Bacteria susceptible to ampicillin-sulbactam are Haemophilus influenzae, Escherichia coli, Acinetobacter, Klebsiella Staphylococcus aureus, Enterobacter, and anaerobes. Consequently, ampicillin/sulbactam is approved for the following conditions caused by susceptible bacteria. 

FDA-approved Indications

• Skin and skin structure infections: Ampicillin/sulbactam has an efficacy comparable to third-generation cephalosporins in treating skin infections in patients with or without a history of intravenous drug abuse.[2]

• Intra-abdominal infections: Ampicillin/sulbactam should be used in mild to moderate community-acquired intra-abdominal infections; however, more severe infections require broader coverage against facultative and gram-negative aerobic bacteria antimicrobials may be combined necessary (carbapenem in combination with vancomycin).[3]

• Gynecological infections:  Pelvic inflammatory disease results from sexually transmitted organisms (Neisseria gonorrhoeae or Chlamydia trachomatis) or anaerobic vaginal flora. First-line treatment includes cefoxitin or cefotetan with doxycycline or clindamycin with gentamycin plus doxycycline. Ampicillin/sulbactam is comparable in efficacy and is an essential alternate regimen for gynecological infections.[4]

Off-label Clinical Uses

• Lower respiratory tract infections: Ampicillin/sulbactam, compared with various third-generation cephalosporins (cefuroxime and cefotaxime), second-generation cephalosporin (cefoxitin), mezlocillin, and imipenem/cilastatin, had higher efficacy although not clinically significant in the treatment of lower respiratory tract infections.[5][6][7]

• Aspiration pneumonia: In a study by Kadowaki et al., researchers compared the efficacy of ampicillin/sulbactam, clindamycin, and imipenem/cilastatin. Cure rates for ampicillin/sulbactam were comparable to imipenem/cilastatin. Although clindamycin was the least expensive.[8] 

• Diabetic foot infections: Ampicillin/sulbactam, compared to imipenem/cilastatin[9] and piperacillin/tazobactam, are comparably effective. However, piperacillin/tazobactam has broader coverage, and the most common gram-negative bacterium isolated was Pseudomonas aeruginosa.

• Pediatric infections: In the pediatric population, indications for ampicillin/sulbactam include epiglottitis, periorbital infections, acute fulminant meningococcemia, and sepsis management.[10]

• Infection in the intensive care unit (ICU) with Acinetobacter baumannii: Effective and safe to use ampicillin/sulbactam in multidrug-resistant Acinetobacter baumannii infections.[11]

• Endocarditis: Ampicillin can be combined with aminoglycosides for infections caused by susceptible strains of Enterococcus.[12]

Mechanism of Action

Ampicillin is a beta-lactam antimicrobial, and sulbactam is a beta-lactamase inhibitor.

Mechanism of Ampicillin

• Like any other beta-lactam antimicrobial, the mode of action of ampicillin on sensitive organisms can be considered a two-step process. In the first step, the drug binds to primary receptors called membrane-bound penicillin-binding proteins. These proteins perform vital roles in cell cycle-related morphogenetic formation of cell wall peptidoglycan. Therefore, the inactivation of penicillin-binding proteins by bound antimicrobials has immediate arresting actions on their function.

• The second stage comprises the physiological effects caused by this receptor-ligand interaction. Penicillin-binding proteins are involved in the late stages of peptidoglycan synthesis in the cell wall. Because peptidoglycan maintains the integrity of the cell wall, which resides in a hypotonic environment, its disruption causes lysis and cell death.[13]

Mechanism of Sulbactam

• Beta-Lactamase production is of critical importance for the evolution of drug-resistant bacteria. Combinations of β-lactams with β-lactamase inhibitors, such as ampicillin/sulbactam, extend the spectrum of β-lactams by preventing the hydrolysis by β-lactamases.[14]

Mechanism of Resistance

• A study demonstrated that in acinetobacter baumannii, the strains with pbp3(penicillin-binding protein-3) mutations demonstrated higher levels of resistance to sulbactam. Lower levels of resistance to sulbactam had mutations in cell wall metabolism or stress response genes.[15]

Pharmacokinetics

Absorption: The peak serum concentrations of ampicillin and sulbactam are attained after a 15-minute intravenous infusion. The steady-state volumes of distribution ranged from 14.2 to 15.1 and 12.2 to 16.3 l for ampicillin and sulbactam. Penetration of ampicillin and sulbactam in CSF is augmented in the presence of inflamed meninges.[16]

Distribution: Ampicillin and sulbactam have extensive distribution in the extracellular fluids and tissues. Ampicillin is approximately 28% reversibly bound to human serum protein, and sulbactam has approximately 38% plasma protein binding. The steady-state volumes of distribution ranged from 14.2 to 15.1 and 12.2 to 16.3 liters for ampicillin and sulbactam.

Metabolism: Ampicillin is metabolized by penicillinase to penicilloic acid and other metabolites.[17]

Elimination: Ampicillin and sulbactam are primarily excreted in urine via glomerular filtration and tubular excretion. The half-life of ampicillin and sulbactam is approximately one hour in healthy subjects.[18]

Administration

Ampicillin/sulbactam is not absorbed adequately after oral absorption. In intravenous formulations, penetration into tissue/fluids includes intraperitoneal fluid (60%), myometrium (64%), sputum (12% to 14%), cerebrospinal fluid (CSF) (11% to 14%).

Dosage and Administration

• Ampicillin/sulbactam administration can be through intramuscular or intravenous route.

• For IV administration, administer the dose by slow intravenous injection over at least 10 to 15 minutes.

• Administer ampicillin/sulbactam by deep intramuscular injection within one hour of preparation.

• The recommended adult dosage of ampicillin/sulbactam is 1.5 grams (1 gram ampicillin + 0.5 gram sulbactam) to 3 grams (2 grams ampicillin + 1 gram sulbactam) every six hours. The total dose of sulbactam should not exceed 4 grams per day.

• IDSA 2022 guidelines suggest that for infection caused by carbapenem-resistant acinetobacter baumannii(CRAB) infections, ampicillin/sulbactam 9 g IV q8h over 4 hours is recommended. For mild infections caused by CRAB organisms sensitive to ampicillin-sulbactam, 3g IV q4h is recommended.[19] The strains of CRAB, which are nonsusceptible to ampicillin-sulbactam, still ampicillin-sulbactam may remain a useful treatment option based on the potential for sulbactam to saturate altered penicillin-binding proteins targets.

Pediatric Patients

• One Year of age or older: The recommended daily dose of ampicillin/sulbactam in pediatric patients is 300 mg per kg of body weight administered via intravenous infusion in equally divided doses every 6 hours. Caution must be observed in the administration to neonates with age less than one week and premature infants due to an underdeveloped urinary system.

• Dosage recommendations for pediatric patients weighing 40 kg or more are the same as for adult patients.

• The course of intravenous therapy should not routinely exceed 14 days.

• The pharmacokinetics of ampicillin/sulbactam does not change in the pediatric population compared to adults.[20] 

Use in Specific Patient Population

Patients with Hepatic Impairment: No dose adjustment is suggested.

Patients with Renal Impairment: Excretion of ampicillin/sulbactam is primarily by renal route; hence its half-life increases in patients with impaired renal function. 

• If creatine clearance is>30 mL/minute, the recommended dose of ampicillin/sulbactam is 1.5 to 3 grams every six hours. (No dosage adjustment is necessary)

• If creatine clearance is between 15 to 29 mL/minute, the recommended dose of ampicillin/sulbactam is 1.5 to 3 grams every twelve hours.

• If creatine clearance is between 15 to 29 mL/minute, the recommended dose of ampicillin/sulbactam is 1.5 to 3 grams daily.

• It is important to note that in patients with impaired renal function, the elimination kinetics of ampicillin and sulbactam are similarly affected; hence the ratio of one to the other will remain constant at a given renal function.[21]

Pregnancy Considerations: For patients With preterm pre-labor rupture of membranes < 34 weeks of gestation, treatment with intravenous ampicillin and erythromycin is suggested by the ACOG(American College of Obstetricians and Gynecologists) to prevent group B streptococcal perinatal infection.[22]

Breastfeeding Considerations: Clinical data suggest that ampicillin-sulbactam is present in low levels in milk that are not expected to cause adverse effects in breastfed infants. Disruption of the infant's gastrointestinal flora can result in diarrhea or thrush. Ampicillin-sulbactam is acceptable in nursing mothers.[23]

Adverse Effects

Local Adverse Reactions

• Pain at IM/IV injection site 

• Thrombophlebitis 

Gastrointestinal Adverse Drug Reactions

• Stomatitis

• Nausea and vomiting

• Pseudomembranous colitis

• Enterocolitis

• Black hairy tongue[24]

Hypersensitivity Reactions

• There are frequent reports of skin rashes and urticaria.

• Reports also exist of some cases of erythema multiforme and exfoliative dermatitis.

• Anaphylaxis is the most serious complication experienced and is usually associated with the parenteral form, which requires prompt treatment.[25]

Hepatotoxicity

• A moderate elevation of serum glutamic oxaloacetic transaminase (SGOT) is reported, commonly in infants; its significance is unknown. In addition, mild transient elevation occurs with repeated intramuscular administration in individuals receiving larger than usual doses.

• Evidence indicates that SGOT(AST) gets released in the intramuscular injection site, and the increased quantities seen in the blood may not necessarily be from the liver as a source.[26] 

Hemato-lymphatic Systems

• These reactions are reversible on discontinuation of therapy, the etiology being a hypersensitive phenomenon.

• Hemolytic anemia

• Thrombocytopenia

• Eosinophilia

• Thrombocytopenic purpura

• Agranulocytosis[27]

Neurological Adverse Drug Reactions

• Headache

• Seizures[28]

Opportunistic Infections

• Superinfection with Clostridium difficile-associated diarrhea(CDAD) and fungal infections

• Such cases warrant discontinuation of therapy and substitution of appropriate alternative treatment.[29]

Drug-Drug Interactions

• The administration of the cholera vaccine is not recommended during systemic antibiotic treatment as it reduces the efficacy of the cholera vaccine. Prolonged antibiotic treatment with intravesical BCG adversely impacts bladder cancer disease recurrence and outcomes. Avoid simultaneous use.[30]

• Concomitant use of allopurinol with ampicillin increases the risk of Stevens-Johnson syndrome.[31]

• Ampicillin is a bactericidal drug; combining bactericidal drugs with bacteriostatic drugs like doxycycline is generally not recommended.[32]

Contraindications

Hypersensitivity

• There are reports of serious and life-threatening anaphylactoid reactions with ampicillin-sulbactam therapy. Although anaphylaxis is more common following parenteral therapy, it can also occur after oral administration. In addition, anaphylaxis is more likely in a patient with a previous history of penicillin hypersensitivity and/or reaction to multiple allergens. Therefore, a careful inquiry is necessary before initiating therapy regarding hypersensitivity reactions to cephalosporins, allergens, or penicillin.

• If a hypersensitivity reaction occurs, the clinician should discontinue therapy and alternative treatment initiated. Anaphylactoid reactions require immediate emergency treatment with oxygen, epinephrine, steroids, and airway management, including intubation if indicated.

Clostridioides difficile Infection

• Antibacterial treatment alters the intestine's natural flora, leading to the overgrowth of Clostridium difficile. Clostridium difficile-associated diarrhea(CDAD) occurs when using nearly all antibacterial agents, especially ampicillin. The resulting severity may range from mild diarrhea to fulminant colitis. Hypertoxin-producing C. difficile strains cause increased morbidity and mortality, as these strains are refractory to the recommended antimicrobial therapy and may require colectomy. Therefore, Clostridium difficile-associated diarrhea may be a consideration for all patients present with diarrhea after antibacterial use. Since it reportedly occurs over two months after administering antibacterial agents, a careful medical history is necessary in these cases.

• If CDAD is confirmed, ongoing antimicrobial use not directed against the organism might require therapy discontinuation. Adequate fluid and electrolyte management, protein supplementation, the antimicrobial regimen of C. difficile, and surgical evaluation merit consideration if indicated.[33]

Concomitant Infectious Mononucleosis Infection

• Many patients with infectious mononucleosis started on ampicillin-sulbactam to develop a rash. Ideally, the rash appears 7 to 10 days following the initiation of ampicillin-sulbactam therapy and remains for a few days to one week after discontinuing the drug. In most cases, the rash is maculopapular, generalized, and pruritic. Therefore, ampicillin-sulbactam administration is not a recommended agent in these patients. Whether these patients are truly allergic to penicillin remains unknown.[34]

 Hepatic Dysfunction

• Ampicillin reexposure can lead to the recurrence of drug-induced liver injury(DILI). Avoid the use of ampicillin in patients with a history of aminopenicillin-induced hepatitis.[27]

Monitoring

• When administering prolonged therapy, monitor renal, hepatic, and hematologic parameters periodically.

• Monitor for signs of anaphylaxis during the first dose.[35]

Toxicity

• Patients with impaired renal function have an increased risk of overdose due to decreased clearance.

• Neurological adverse reactions, including convulsions, may occur with attaining high CSF levels of ampicillin.

• In overdose, discontinuation of the ampicillin/sulbactam, symptomatic treatment, and supportive care are necessary.

• In severe overdose, initiate hemodialysis for removal of ampicillin from circulation. The molecular weight and degree of protein binding of sulbactam are also compatible with hemodialysis.[36][37]

• Corticosteroids can be used to manage the allergic manifestations of immunoallergic hepatitis due to ampicillin.[27]

Enhancing Healthcare Team Outcomes

Ampicillin/sulbactam is a widely prescribed antimicrobial by primary care providers, nurse practitioners, internists, surgeons, and other healthcare professionals. While the antimicrobial is effective, clinicians should not empirically prescribe for all infections as the resistance to this agent is increasing globally. Therefore, clinicians should initiate this medication only for precise indications and ensure the appropriate duration of drug use. Antimicrobial stewardship is a coordinated program that promotes the appropriate use of antimicrobials. Studies indicate that antimicrobial stewardship programs reduce antimicrobial resistance and decrease the spread of infections caused by multidrug-resistant organisms.[38]

Pharmacists should verify dosing, look into the appropriateness of selecting ampicillin-sulbactam based on the infection type and available antibiogram data, and check for drug-drug interactions. In most cases, nurses administer this drug, monitor for adverse events, and assess therapeutic effectiveness, informing the clinician of their findings as treatment progresses. In the case of an overdose, emergency department physicians and nurses should rapidly stabilize the patient. Nephrology consultation is essential for extracorporeal removal in severe overdose. A psychiatrist consultation is necessary if the overdose is intentional. Infectious disease consultation is vital for superinfections. Gastroenterology consultation is crucial for colitis and toxic megacolon. A psychiatrist consultation is necessary if the overdose is intentional. Infectious disease consultation is vital for superinfections. A retrospective cohort study suggests that infectious disease consultation decreases one month and one-year all-cause mortality for multidrug-resistant organisms.[39] [Level 3]

Multiple healthcare providers may be involved in caring for patients requiring ampicillin therapy, including clinicians (MDs, DOs, NPs, PAs), specialists, pharmacists, and nurses. In such a scenario, the entire team should work together in close collaboration to maximize efficacy and minimize adverse drug reactions. Pharmacists will perform medication reconciliation, verify dosing, and offer patients counsel on their medication administration. Nurses will administer the drug in the hospital setting, watch for adverse events, counsel patients, and serve as liaisons between all interprofessional team members. Open communication lines between all team members are essential to the interprofessional model. In summary, an interprofessional team approach optimizes patient outcomes related to ampicillin/sulbactam therapy. [Level 5]