Continuing Education Activity

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 members of the interprofessional team to use ampicillin-sulbactam appropriately for various indications with an eye towards antimicrobial stewardship.

Objectives:

• Identify the indications for the use of 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 unwarranted use of ampicillin-sulbactam to avoid contributing to antimicrobial resistance.

Indications

Ampicillin/sulbactam combination shows synergy to cover strains of bacteria resistant to ampicillin, thus providing broader coverage.[1]

Lower Respiratory Tract Infections

Ampicillin/sulbactam, when compared with various third-generation cephalosporins (cefuroxime and cefotaxime), second-generation cephalosporin (cefoxitin), mezlocillin, ticarcillin/clavulanate, and imipenem/cilastatin had higher efficacy although not clinically significant in the treatment of lower respiratory tract infections.[2][3][4][5]

Aspiration Pneumonia

In a study by Kadowaki et al., the efficacy of ampicillin/sulbactam, clindamycin, and imipenem/cilastatin was compared.[6] Cure rates for ampicillin/sulbactam were comparable to imipenem/cilastatin being the highest, although clindamycin was the least expensive.

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 important alternate regimen for gynecological infections.[4]

Intra-abdominal Infections

Ampicillin/sulbactam should be used in mild to moderate community-acquired intra-abdominal infections; however, more serious infections require a broader coverage against facultative and gram-negative aerobic bacteria where the combination of antimicrobials may be necessary (carbapenem in combination with vancomycin).[7]

Diabetic Foot Infections

Ampicillin/sulbactam when compared to imipenem/cilastatin[8] 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.[9]

Skin Infections

Ampicillin/sulbactam has an efficacy comparable to third-generation cephalosporins in the treatment of skin infections in patients with or without a history of intravenous drug abuse.[10]

Infection in the Intensive Care Unit (ICU) with Acinetobacter baumannii

It is effective and safe to use ampicillin/sulbactam in multidrug-resistant A. baumannii infections.[11]

Mechanism of Action

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

Ampicillin

The mode of action of ampicillin, like any other beta-lactam antimicrobial, on sensitive organisms, can be considered to be 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, the morphogenetic formation of cell wall peptidoglycan. Inactivation of penicillin-binding proteins by bound antimicrobial 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.[12]

Sulbactam

It is a beta-lactamase inhibitor and inhibits the action of any bacteria producing the enzyme after binding to it and thereby not allowing its action on the antimicrobial.

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%). As ampicillin/sulbactam excretion is primarily renal, its half-life increases in patients with impaired renal function.[13] Pharmacokinetics of ampicillin/sulbactam does not change in the pediatric population as compared to adults.[14] Caution must be observed in the administration to neonates with age less than one week and premature infants due to an underdeveloped urinary system.

Adverse Effects

The primary adverse effects of ampicillin-sulbactam include seizure, diarrhea, enterocolitis, pseudomembranous colitis, vomiting, agranulocytosis, hemolytic anemia, eosinophilia, and immune thrombocytopenia.

Common Adverse Effects

Gastrointestinal

Effects include stomatitis, glossitis, black "hairy" tongue, nausea, vomiting, pseudomembranous colitis, enterocolitis, and diarrhea - this mainly occurs with oral dose administration.

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.

Liver

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

Hemato-Lymphatic Systems

There are reports of anemia, thrombocytopenic purpura, thrombocytopenia, eosinophilia, agranulocytosis, and leukopenia during ampicillin-sulbactam therapy. These reactions are reversible on discontinuation of therapy, the etiology being a hypersensitive phenomenon.

Central Nervous System

Seizures

Opportunistic Infections

During therapy, there is a possibility of superinfection with some bacteria or mycotic organisms. Such cases warrant discontinuation of therapy and substitution of appropriate alternative treatment.

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. Anaphylaxis is more likely in a patient with a previous history of penicillin hypersensitivity and/or reaction to multiple allergens. Before initiating therapy, a careful inquiry is necessary relating to 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 natural flora of the intestine leading to overgrowth of C. difficile. C. difficile-associated diarrhea (CDAD) occurs with nearly all antibacterial agent use, 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. C. difficile-associated diarrhea may be a consideration with all patients after antibacterial use who present with diarrhea. Since it reportedly occurs over two months after the administration of 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 and protein supplementation along with the antimicrobial regimen of C. difficile and surgical evaluation merit consideration if indicated.

Concomitant Infectious Mononucleosis Infection

A high proportion of 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 the majority of 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.

Monitoring

When administering a prolonged therapy, monitor renal, hepatic, and hematologic functions periodically. Monitor also for signs of anaphylaxis during the first dose.

Toxicity

In cases of overdose, discontinuation of the medication, symptomatic treatment, and supportive care institution is necessary. In patients with decreased renal function, the antimicrobial is removable via hemodialysis but not peritoneal dialysis.

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, the drug should not be empirically prescribed for all infections. Resistance to this agent is gradually increasing globally. Even when prescribed, the duration of drug use should be limited. Pharmacists should verify dosing and look into the appropriateness of selecting ampicillin-sulbactam base don the infection type and available antibiogram data, as well as checking for drug-drug interactions.

Nursing will be administering this drug in most cases and must monitor for adverse events as well as assessing therapeutic effectiveness, informing the clinician of their findings as treatment progresses. An interprofessional team, including the clinician (MD, DO, NP, PA) and pharmacist, should work together to minimize the use of this medication to only those individuals that need the drug and make sure the patient understands the importance of completing the course. This interprofessional team approach to antimicrobial therapy with ampicillin/sulbactam ensures optimal patient outcomes with minimal adverse effects. [Level 5]