Continuing Education Activity

The ampicillin/sulbactam combination demonstrates synergy in addressing bacterial strains resistant to ampicillin, thus providing broader coverage. This drug combination incorporates a β-lactamase inhibitor into ampicillin, extending coverage against potentially resistant bacteria. The ampicillin/sulbactam combination has been approved by the U.S. Food and Drug Administration (FDA) for treating skin and skin structure infections, intra-abdominal infections, and gynecological infections. This activity emphasizes the appropriate use of ampicillin/sulbactam by providing information on its indications, mechanism of action, adverse events, and drug interactions, which is crucial for the interprofessional healthcare team to ensure the delivery of optimal patient care.

Objectives:

• Identify the appropriate indications for ampicillin/sulbactam combination therapy, considering bacterial resistance patterns and the spectrum of coverage.

• Assess patient responses and monitor for adverse events during ampicillin/sulbactam therapy by adjusting treatment as needed.

• Apply knowledge of the mechanism of action and pharmacokinetics of ampicillin/sulbactam in clinical decision-making for optimal patient care.

• Collaborate with pharmacists, infectious disease specialists, and other interprofessional healthcare professionals for a coordinated approach to ampicillin/sulbactam therapy, contribute to antimicrobial stewardship efforts, and address antibiotic resistance concerns.

Indications

Ampicillin is a β-lactam antimicrobial, whereas sulbactam is a β-lactamase inhibitor. The combination of ampicillin and sulbactam demonstrates synergy in addressing bacterial strains resistant to ampicillin, thus providing broader coverage.[1] Bacteria susceptible to ampicillin/sulbactam include Haemophilus influenzae, Escherichia coli, Acinetobacter, Klebsiella, Staphylococcus aureus, Enterobacter, and anaerobes. This drug combination incorporates a β-lactamase inhibitor into ampicillin, extending coverage against potentially resistant bacteria. 

FDA-Approved Indications

The U.S. Food and Drug Administration (FDA) has approved the combination of ampicillin and sulbactam to treat the conditions below that are caused by susceptible bacteria. 

Skin and skin structure infections: The ampicillin/sulbactam combination demonstrates efficacy comparable to third-generation cephalosporins in treating skin infections, whether in patients with or without a history of intravenous (IV) drug abuse.[2]

Intra-abdominal infections: The ampicillin/sulbactam combination is recommended for mild to moderate community-acquired intra-abdominal infections. However, in cases of more severe infections that demand broader coverage against facultative and gram-negative aerobic bacteria, the use of combination antimicrobials, such as carbapenem in conjunction with vancomycin, may be necessary.[3]

Gynecological infections: Pelvic inflammatory disease arises from sexually transmitted organisms (Neisseria gonorrhoeae or Chlamydia trachomatis) or anaerobic vaginal flora. First-line treatment typically involves cefoxitin or cefotetan with doxycycline or clindamycin with gentamicin plus doxycycline. The ampicillin/sulbactam combination demonstrates comparable efficacy and is a crucial alternative regimen for gynecological infections.[4]

Off-Label Uses

Lower respiratory tract infections: In the treatment of lower respiratory tract infections, ampicillin/sulbactam exhibits higher efficacy compared to various third-generation cephalosporins (cefuroxime and cefotaxime), second-generation cephalosporin (cefoxitin), mezlocillin, and imipenem/cilastatin. Although the difference is not clinically significant, it suggests a favorable performance of ampicillin/sulbactam.[5][6][7]

Aspiration pneumonia: In a study by Kadowaki et al, the efficacy of ampicillin/sulbactam, clindamycin, and imipenem/cilastatin was compared. Cure rates for ampicillin/sulbactam were found to be comparable to those of imipenem/cilastatin despite clindamycin being the least expensive option.[8]

Diabetic foot infections: Ampicillin/sulbactam demonstrates comparable effectiveness to imipenem/cilastatin [9] and piperacillin/tazobactam, which 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, ampicillin/sulbactam is indicated for conditions such as epiglottitis, periorbital infections, acute fulminant meningococcemia, and sepsis management.[10]

Infection in the intensive care unit (ICU) with Acinetobacter baumannii: Ampicillin/sulbactam is proven to be effective and safe for use in multidrug-resistant A baumannii infections.[11]

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

Osteonecrosis of the jaw (ONJ): Ampicillin/sulbactam has demonstrated effectiveness against ONJ caused by Streptococcus and Staphylococcus, primarily found within the biofilm of ONJ.[13]

The literature review indicates that ampicillin/sulbactam may be beneficial in managing infectious pulmonary artery pseudoaneurysms.[14]

Mechanism of Action

Ampicillin is a β-lactam antimicrobial, whereas sulbactam is a β-lactamase inhibitor.

Mechanism of Ampicillin

Similar to other β-lactam antimicrobials, the mode of action of ampicillin on susceptible organisms can be considered a 2-step process. In the initial step, the drug binds to primary receptors known as membrane-bound penicillin-binding proteins (PBPs). These proteins play crucial roles in the cell cycle–related morphogenetic formation of the cell wall peptidoglycan. Consequently, the inactivation of PBPs by bound antimicrobials immediately arrests their function.

The second stage involves the physiological effects resulting from this receptor-ligand interaction. PBPs are involved in the late stages of peptidoglycan synthesis in the cell wall. As peptidoglycan is crucial for maintaining the integrity of the cell wall, any disruption leads to lysis and eventual cell death, especially in the context of the hypotonic environment in which the cell resides.[15]

Mechanism of Sulbactam

The production of β-lactamase is critically essential for the evolution of drug-resistant bacteria. Combinations of β-lactams with β-lactamase inhibitors, such as ampicillin/sulbactam, broaden the spectrum of β-lactams by inhibiting their hydrolysis by β-lactamases.[16]

Mechanism of Resistance

A study demonstrated that in A baumannii, strains with PBP-3 mutations exhibited elevated levels of resistance to sulbactam. Conversely, strains with mutations in cell wall metabolism or stress response genes displayed lower resistance to sulbactam.[17]

Pharmacokinetics

Absorption: Peak serum concentrations of ampicillin and sulbactam are reached following a 15-minute IV infusion. The steady-state volumes of distribution range from 14.2 to 15.1 L for ampicillin and 12.2 to 16.3 L for sulbactam. The penetration of ampicillin and sulbactam into the cerebrospinal fluid (CSF) is enhanced in the presence of inflamed meninges.[18]

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

Metabolism: Ampicillin undergoes metabolism by penicillinase, leading to the formation of penicilloic acid and other metabolites.[19]

Elimination: Ampicillin and sulbactam are primarily excreted in urine via glomerular filtration and tubular excretion. The half-life of ampicillin and sulbactam is approximately 1 hour in healthy subjects.[20]

Administration

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

Adult Dosage and Administration

• Ampicillin/sulbactam administration can be administered via intramuscular (IM) or IV routes.

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

• Administer ampicillin/sulbactam by deep intramuscular injection within 1 hour of preparation.

• The recommended adult dosage of ampicillin/sulbactam is 1.5 g (1 g ampicillin + 0.5 g sulbactam) to 3 g (2 g ampicillin + 1 g sulbactam) every 6 hours. The total dosage of sulbactam should not exceed 4 g/d.

• The 2022 guidelines from the Infectious Diseases Society of America (IDSA) recommend ampicillin/sulbactam at a dosage of 9 g IV administered q8h over 4 hours infusion for infections caused by carbapenem-resistant A baumannii (CRAB). In cases of mild infections caused by CRAB organisms sensitive to ampicillin/sulbactam, a recommended dosage is 3 g IV every q4h.[21] Notably, even in cases where CRAB strains show nonsusceptibility to ampicillin/sulbactam, this combination may still be a viable treatment option due to the potential for sulbactam to saturate altered PBP targets. 

Specific Patient Populations

Hepatic impairment: No dosage adjustment is suggested.

Renal impairment: The excretion of ampicillin/sulbactam is primarily through the renal route, resulting in an increased half-life in patients with impaired renal function. 

• If creatine clearance exceeds 30 mL/min, the recommended dosage of ampicillin/sulbactam is 1.5 to 3 g administered every 6 hours, and no dosage adjustment is necessary.

• If the creatine clearance is between 15 and 29 mL/min, the recommended dosage of ampicillin/sulbactam is 1.5 to 3 g administered every 12 hours.

• If the creatine clearance is between 15 and 29 mL/min, the recommended dosage of ampicillin/sulbactam is 1.5 to 3 g daily.

• Ampicillin and sulbactam elimination kinetics are similarly affected in patients with impaired renal function. Therefore, the ratio of one to the other will remain constant at a given level of renal function.[22]

Pregnancy considerations: The American College of Obstetricians and Gynecologists (ACOG) recommends the use of IV ampicillin and erythromycin for patients with preterm pre-labor rupture of membranes less than 34 weeks of gestation to prevent group B streptococcal perinatal infection.[23]

Breastfeeding considerations: Clinical data suggest that ampicillin/sulbactam is present in low levels in breast milk, which are not expected to cause adverse effects in breastfed infants. However, the disruption of the infant's gastrointestinal flora can result in diarrhea or thrush. Overall, ampicillin/sulbactam is acceptable for use by nursing mothers.[24]

Pediatric patients: In pediatric patients, administering ampicillin/sulbactam involves tailored dosing based on age and body weight, with specific considerations for neonates and premature infants.

• For children aged 1 year or older: The recommended daily dosage of ampicillin/sulbactam in pediatric patients is 300 mg/kg of body weight administered via IV infusion in equally divided doses every 6 hours. Caution must be exercised when administering ampicillin/sulbactam to neonates younger than 1 week and premature infants due to their underdeveloped urinary system.

• Dosage recommendations for pediatric patients with a body weight of 40 kg or more align with those for adult patients.

• The duration of IV therapy should not routinely exceed 14 days.

• The pharmacokinetics of ampicillin/sulbactam remain consistent in the pediatric population compared to adults.[25]

Older patients: The product labeling lacks specific dosage recommendations for using ampicillin/sulbactam in older individuals. Therefore, dosing should be determined based on renal function.

Adverse Effects

Adverse Reactions

Local adverse reactions: These reactions may include pain at the IM or IV injection site and thrombophlebitis.

Gastrointestinal adverse drug reactions: These drug reactions may include stomatitis, nausea and vomiting, pseudomembranous colitis, enterocolitis, and black hairy tongue.[26]

Hypersensitivity reactions: These reactions may manifest as frequent reports of skin rashes and urticaria. Additionally, there are documented cases of erythema multiforme and exfoliative dermatitis. The most severe complication is anaphylaxis, primarily associated with the parenteral form, necessitating prompt treatment.[27]

Hepatotoxicity: Hepatotoxicity may involve a moderate elevation of serum glutamic oxaloacetic transaminase (SGOT), commonly observed in infants, with its significance remaining unknown. Furthermore, mild and transient elevations have been noted with repeated intramuscular administration in individuals receiving larger-than-usual doses.

Evidence indicates that SGOT or aspartate aminotransferase is released at the intramuscular injection site, and the increased quantities observed in the blood may not necessarily originate from the liver as a source.[28]

Hemato-lymphatic system reactions: These reactions are attributed to a hypersensitive phenomenon and are generally reversible upon discontinuation of therapy. These reactions may include hemolytic anemia, thrombocytopenia, eosinophilia, thrombocytopenic purpura, and agranulocytosis.[29]

Neurological adverse drug reactions: These reactions may include headaches and seizures.[30]

Opportunistic infections: These infections may manifest as superinfection with Clostridium difficile–associated diarrhea (CDAD) and fungal infections. In such cases, discontinuation of therapy and substitution with appropriate alternative treatment are warranted.[31]

Drug-Drug Interactions

• The administration of the cholera vaccine is not recommended during systemic antibiotic treatment, as it can reduce its efficacy. Prolonged antibiotic treatment with intravesical BCG adversely impacts bladder cancer disease recurrence and outcomes. Simultaneous use should be avoided.[32]

• The concurrent use of allopurinol with ampicillin increases the risk of Stevens-Johnson syndrome.[33]

• Ampicillin is a bactericidal drug, and combining bactericidal drugs with bacteriostatic drugs, such as doxycycline, is generally not recommended.[34]

Contraindications

Hypersensitivity

Reports exist of severe 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 thorough inquiry is essential before initiating therapy concerning hypersensitivity reactions to cephalosporins, allergens, or penicillin.

In the event of a hypersensitivity reaction, clinicians should promptly discontinue therapy and initiate alternative treatment. Anaphylactoid reactions necessitate immediate emergency treatment with oxygen, epinephrine, steroids, and airway management, including intubation if indicated.

Clostridioides difficile Infection

Antibacterial treatment disrupts the natural flora of the intestine, leading to the overgrowth of C difficile. CDAD occurs when using nearly all antibacterial agents, especially ampicillin. The resulting severity of CDAD 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, CDAD may be a consideration for all patients with diarrhea after antibacterial use. Therefore, CDAD should be considered for all patients with diarrhea after antibacterial use. A thorough medical history is essential in these cases because it may reportedly occur over 2 months after administering antibacterial agents.

If CDAD is confirmed, discontinuing ongoing antimicrobial therapy not directed against the organism may be necessary. Considerations should include adequate fluid and electrolyte management, protein supplementation, the appropriate antimicrobial regimen for C difficile, and surgical evaluation if indicated.[35]

Concomitant Infectious Mononucleosis Infection

Many patients diagnosed with infectious mononucleosis and initiated on ampicillin/sulbactam therapy develop a rash. Ideally, the rash manifests 7 to 10 days after initiating ampicillin/sulbactam therapy and persists for a few days to one week after discontinuing the drug. In most cases, the rash is maculopapular, generalized, and pruritic. Therefore, the administration of ampicillin/sulbactam is not recommended in these patients. The actual allergic status of these patients to penicillin remains unknown.[36]

Hepatic Dysfunction

As reexposure to ampicillin can result in the recurrence of drug-induced liver injury (DILI), it is advised to avoid ampicillin use in patients with a history of aminopenicillin-induced hepatitis.[29]

Monitoring

During prolonged therapy, it is advisable to monitor renal, hepatic, and hematologic parameters periodically. In addition, monitoring for signs of anaphylaxis should be maintained, particularly during the first dose.[37]

A recent observational cohort study involving 150 patients (intervention: n=75; control: n=75) investigated DILI caused by ampicillin/sulbactam. The study explored the correlation between DILI and the albumin-bilirubin (ALBI) score, which indicates hepatic functional reserve. Results revealed a 9.5% incidence of DILI, notably showing that patients with a baseline ALBI score of ≥-2.00 had a significantly elevated risk for ampicillin/sulbactam–induced DILI. The ALBI score emerged as a valuable predictor of DILI in patients undergoing ABPC/SBT therapy, emphasizing its clinical relevance for therapeutic monitoring.[38]

Toxicity

Signs and Symptoms of Overdose

Patients with impaired renal function face an elevated risk of overdose due to decreased clearance. Neurological adverse reactions, such as convulsions, may occur when high CSF levels of ampicillin are reached.

Management of Overdose

In cases of overdose, it is imperative to discontinue ampicillin/sulbactam, provide symptomatic treatment, and offer supportive care. In severe overdoses, hemodialysis should be initiated to remove ampicillin from circulation, considering that the molecular weight and degree of protein binding of sulbactam are compatible with hemodialysis.[39][40] Corticosteroids can manage the allergic manifestations of immunoallergic hepatitis due to ampicillin.[29] 

In a recent study investigating DILI caused by ampicillin/sulbactam, researchers examined the correlation between DILI and the ALBI score—an indicator of hepatic functional reserve. The study, including 380 patients, revealed an incidence of DILI at 9.5%. The results of Cox regression analysis demonstrated a significantly increased risk of ampicillin/sulbactam–induced DILI in patients with a baseline ALBI score of ≥-2.00. Therefore, the ALBI score emerges as a practical and valuable tool for predicting the likelihood of DILI attributed to ampicillin/sulbactam, especially in patients with an ALBI score ≥-2.00. This underscores the need for vigilant and routine liver function monitoring in these individuals.[38]

Enhancing Healthcare Team Outcomes

Ampicillin/sulbactam is extensively prescribed by primary care providers, nurse practitioners, internists, surgeons, and other healthcare professionals. Despite its efficacy, clinicians should avoid empirical prescriptions for all infections due to the increasing global resistance to this agent. Hence, healthcare professionals should initiate this medication only for specific indications, ensuring the appropriate duration of drug use. Antimicrobial stewardship is a coordinated program designed to promote the proper use of antimicrobials. Studies indicate that implementing antimicrobial stewardship programs effectively reduces antimicrobial resistance and mitigates the spread of infections caused by multidrug-resistant organisms.[41]

Pharmacists are critical in medication management by verifying dosing, assessing the appropriateness of selecting ampicillin/sulbactam based on infection type and available antibiogram data, counseling patients on medication administration, and evaluating potential drug-drug interactions.

In many instances, nurses are responsible for administering drugs in the hospital setting, monitoring for adverse events, providing patient counseling, liaising with all interprofessional team members, and assessing therapeutic effectiveness. The nursing staff communicates their observations to the clinician to facilitate ongoing treatment adjustments. 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 cases. 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 required if the overdose is intentional. Consultation with infectious disease specialists is vital for addressing superinfections, while gastroenterology consultation is crucial for managing colitis and toxic megacolon.[42] Clinical pharmacists play a significant role in preventing drug-induced complications, such as acute kidney injury, showcasing their crucial impact on patient care.

Clinical pharmacists contribute significantly to therapeutic outcomes by providing expert recommendations on drug selection, administration, dosage adjustments, and monitoring for potential interactions or adverse effects. In addition, these observational findings emphasize the crucial role of ampicillin—a commonly used antibiotic in inpatient care. The involvement of a clinical pharmacist can significantly reduce the incidence of acute kidney injury related to medications such as ampicillin, highlighting the vital contribution of pharmacists in enhancing overall patient safety and well-being in critical care settings.[43]

Multiple healthcare providers may be involved in caring for patients requiring ampicillin therapy, including physicians, specialists, pharmacists, and nurses. In such a scenario, the team should collaborate closely to maximize efficacy and minimize adverse drug reactions. Open communication lines between all healthcare team members are essential to the interprofessional model. In summary, an interprofessional team approach optimizes patient outcomes related to ampicillin/sulbactam therapy.