Continuing Education Activity

Ampicillin is a medication used to manage and treat certain bacterial infections. It is in the penicillin class of medications. Ampicillin was developed to overcome the issue of drug resistance and extend the antimicrobial coverage of penicillins. It is also resistant to acid so it can be administered orally. This activity outlines the indications, action, and contraindications for ampicillin as a valuable agent in treating certain bacterial infections like those from E. coli, S. aureus, S. pneumoniae, H. influenzae, etc. In addition, this activity will highlight the mechanism of action, adverse event profile, off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions pertinent for interprofessional team members in treating patients with infections caused by susceptible bacteria.

Objectives:

• Identify the indications for the use of ampicillin.
• Describe the mechanism of action of ampicillin.
• Review the adverse effects associated with the use of ampicillin.
• Outline the role of interprofessional coordination in restricting unwarranted use of ampicillin and other antimicrobials.

Indications

Penicillins had been very effective against S. aureus; in the past, however, Staphylococcus aureus has become capable of exhibiting resistance against them by producing a penicillin hydrolyzing enzyme – penicillinase. After that, ampicillin was developed to overcome this issue and extend the antimicrobial coverage of penicillins. It is also resistant to acid so it can be administered orally.[1]

Ampicillin has effective minimum inhibitory concentration for most of medically important organisms in infectious disease like Escherichia coli: MIC = 4 mg/L, Staphylococcus aureus: MIC = 0.6-1 mg/L, Streptococcus pneumoniae: MIC = 0.03-0.06 mg/L, Hemophilus influenzae: MIC = 0.25 mg/L.[1] To reduce the development of drug-resistant bacteria and maintain the effectiveness of ampicillin should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.

FDA-approved Indications

• Respiratory tract infection: caused by: Streptococcus pneumoniae, penicillinase, and non-penicillinase-producing Staphylococcus aureus, group A beta-hemolytic Streptococci, Hemophilus influenzae.

• Bacterial meningitis: caused by Gram-negative bacteria: Neisseria meningitis, Escherichia coli, Gram-positive bacteria: Listeria monocytogenes, Group B Streptococci. Adding aminoglycosides increases its effectiveness against gram-negative bacteria.[2]

• Septicemia and endocarditis: caused by Gram-positive bacteria, including penicillin-susceptible Staphylococcus species, Streptococcus species, and Enterococcus species. Gram-negative bacteria include Escherichia coli, Salmonella species, and Proteus mirabilis. Endocarditis caused by enterococci usually responds to intravenous ampicillin. Adding aminoglycosides with ampicillin may increase its effectiveness when treating endocarditis caused by streptococci.[3]

• Genitourinary infections: caused by sensitive strains of Escherichia coli and Proteus mirabilis. The CDC no longer recommends ampicillin as a first-line agent in treating gonorrhea.[4]

• Gastrointestinal infections: caused by Salmonella typhi, Shigella species, and other Salmonella species, and usually improve with oral or intravenous therapy. Culture must be obtained for susceptibility and antimicrobial sensitivity; however, the clinician may start empiric treatment before receiving the results.[5] 

Off-label Clinical Uses

• Neonatal group B Streptococcal infection prophylaxis: Administered as an alternative to intramuscular penicillin.[6]

• Prophylaxis in surgery: Ampicillin is a routinely selected agent in orthopedic surgeries, especially prosthetic implants and dental surgeries.[7]

• Chorioamnionitis: Ampicillin, in combination with gentamicin, is used to treat chorioamnionitis.[8]

• Carbapenem-resistant Acinetobacter baumannii (CRAB): According to IDSA 2022 guidelines, ampicillin/sulbactam is the preferred agent for the infection caused by carbapenem-resistant Acinetobacter baumannii(CRAB).[9]

Mechanism of Action

Ampicillin is a beta-lactam antibiotic and is classified as aminopenicillins.

• The mode of action of beta-lactam antimicrobials 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 (PBPs). These proteins perform vital roles in cell cycle-related; formation of cell wall peptidoglycan structure. Therefore, the inactivation of PBPs by bound antimicrobials immediately affects their function.

• The second stage comprises the physiological effects caused by this receptor-ligand interaction. PBPs are involved in the cell wall's late stages of peptidoglycan synthesis. Because peptidoglycan maintains the integrity of the cell wall, which resides in a hypotonic environment, its disruption causes lysis and cell death.[10]

• It is important to recognize that ampicillin is primarily bactericidal against susceptible bacteria due to its inhibition of cell wall synthesis.

• Mechanism of resistance: Penicillinase (a β-lactamase) cleaves the beta-lactam ring and results in resistance to ampicillin. Hence ampicillin is usually combined with β-lactamase inhibitors like sulbactam.[11]

Pharmacokinetics

Absorption: Ampicillin injection diffuses readily in body tissues and fluids. 

Distribution:  Ampicillin shows low plasma protein binding(20%)) compared to 60 to 90% for other penicillins. Enhanced penetration through the blood-brain barrier and adequate CSF concentration is achieved due to inflammation in meningitis.[12]

Metabolism: Ampicillin is excreted largely unchanged in the urine, and its excretion can be delayed by concurrent administration of probenecid. 

Excretion: The half-life of ampicillin is 0.7 to 1.5 hours in adults with normal kidney function. According to a recent study, the pharmacokinetics of ampicillin vary significantly in late preterm and term neonates; clinicians should be cautious when administering ampicillin to preterm neonates.[13]

Administration

Ampicillin administration can be oral, intramuscular, or intravenous. Parenteral administration is preferable for severe or moderately severe infections. The oral route should not be the initial therapy in life-threatening conditions but can follow after parenteral therapy.

Oral Administration

• When administered orally, it should be on an empty stomach with 1 or 2 full glasses of water to increase absorption.

Intravenous Administration

• For intravenous administration, ampicillin may be administered as an IV bolus. Reconstitution of vials containing 125, 250, or 500 mg of the drug with 5 ml sterile water is recommended.

• Vials containing 1 or 2 g should be reconstituted at 7.4 or 14.8 ml of bacteriostatic or sterile water.

Intramuscular Administration

• If administering ampicillin intramuscularly, the injection should be into a large muscle mass. Reconstitute with bacteriostatic or sterile water to create solutions containing 125 or 250 mg/ml.

Rate of Administration

• Formulations reconstituted from 125, 250, or 500 mg vials must be given over 3 to 5 minutes by intravenous injection.

• Formulations reconstituted from 1 or 2 g vials must be given over 10 to 15 minutes by intravenous injection.

GI Tract Infection

• Bodyweight less than 40 kg: IV/IM 50 mg/kg/day every 6 to 8 hours

• Bodyweight more than 40 kg: IV/IM 500 mg every 6 hours

GU Tract Infection

• Bodyweight less than 40 kg: IV/IM 50 mg/kg/day every 6 to 8 hours

• Bodyweight more than 40 kg: IV/IM 500 mg every 6 hours

Respiratory Tract Infection

• Bodyweight less than 40 kg: IV/IM 250 to 500 mg/kg/day every 6 to 8 hours

• Bodyweight more than 40 kg: IV/IM 25 to 50 mg/kg/day every 6 hours

Urinary Tract infection 

• Caused by ampicillin susceptible enterococcus

• IV/IM 1 to 2 g every 4 to 6 hrs

Bacterial Meningitis/Septicemia

• IV 150 to 200 mg/kg/day every every 6 to 8 hours

Listeria Species

• IV 2 g every 4 hours[14]

Endocarditis Prophylaxis (off-label)

• In the respiratory tract, oral or dental procedure: IM, IV: 50 mg/kg as a single dose 30 to 60 minutes before the procedure.

• In gastrointestinal or genitourinary procedure: Only for patients at risk for endocarditis: IV/IM 2g 30 minutes before the procedure, followed by 1 g, 6 hours later with an aminoglycoside.

Endocarditis (off-label)

• Endocarditis caused by Listeria species

• IV/IM 200 mg/kg/day every 6 hours for 4 to 6 weeks 

Gonorrhea (not CDC recommended)

• IV 3.5 g administered once with 1 g probenecid

Streptococcus agalactiae (off-label)

• Maternal prophylaxis to prevent newborn infection

• IV first dose 2 g followed by 1 g every 4 hours till delivery[6]

Use in Specific Patient Populations

Patients with Hepatic Impairment: No dose adjustment has been provided in the manufacturer's labeling.

Patients with Renal Impairment: The dosing frequency should be adjusted based on patient CrCl.

• CrCl <10 mL/min: Administer every 12 to 24 hours
• CrCl 10-50 mL/min: Administer every 6 to 12 hours 
• CrCl >50 mL/min: Administer every 6 hours.

Pregnancy Considerations: Ampicillin is widely used during pregnancy(Former FDA category B). ACOG guidelines recommend that pregnant mothers with preterm PROM(premature rupture of membranes) should be treated with intravenous ampicillin and erythromycin, followed by oral antibiotics to decrease neonatal complications.[15] In addition, listeriosis during pregnancy has been associated with vertical transmission in newborns and higher mortality, for which ampicillin is often used with other antibiotics.[16] 

Breastfeeding Considerations: Clinical data suggest that administration of ampicillin during lactation produces low levels in milk that are not anticipated to cause adverse effects in breastfed infants. However, alteration of the infant's gastrointestinal flora has been reported; consequently, when ampicillin is used during lactation, monitor for diarrhea and thrush.[17]

Adverse Effects

Serious Adverse Drug Reactions

• The primary adverse effects of ampicillin include seizure, enterocolitis, agranulocytosis, hemolytic anemia, immune thrombocytopenia, and pseudomembranous colitis.[18]

Local Adverse Reactions

• Pain at IM/IV injection site 

• Thrombophlebitis 

Hypersensitivity Reactions

• Rashes and urticaria occur frequently.

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

• Anaphylaxis is the most severe complication experienced and is usually associated with the parenteral form. Anaphylaxis is life-threatening and requires rapid treatment.[19][20]

Gastrointestinal Adverse Drug Reactions

• Stomatitis

• Pseudomembranous colitis

• Enterocolitis

• Black hairy tongue

• Mainly seen with oral dose administration).[21]

Hepatotoxicity

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

• Isolated instances of idiosyncratic liver injury have been reported in persons receiving ampicillin. The serum enzyme pattern is a hepatocellular pattern with marked elevations in ALT and AST, minimal elevations in alkaline phosphatase, and rapid recovery after withdrawal.

• In addition, cholestatic forms of hepatic injury with marked alkaline phosphatase elevations have also been infrequently described with vanishing bile duct syndrome.[22]

Nephrotoxicity

• Case reports of ampicillin-sulbactam-induced nephrotoxicity and AKI have been reported, mainly when used in combination with vancomycin.[23]

Neurological Adverse Drug Reactions

• Headache

• Seizures[24]

Hematological Adverse Drug Reactions

• Reports exist of anemia, thrombocytopenic purpura, thrombocytopenia, eosinophilia, agranulocytosis, and leukopenia during ampicillin therapy.

• These reactions are reversible on discontinuation of therapy, the etiology being a hypersensitive phenomenon.[25]

Opportunistic Infections

• During therapy, superinfection with some bacteria or mycotic organisms is possible.

• Opportunistic infection warrants discontinuation of therapy and substitution of appropriate treatment.[26][27]

Drug-Drug Interactions

• Stevens-Johnson syndrome (SJS) has been reported due to the concomitant use of ampicillin and allopurinol.[28]

Contraindications

Infection by penicillinase-producing organisms

• Ampicillin is contraindicated in the treatment of infections caused by penicillinase-producing organisms. The rationale behind it is penicillinase (beta-lactamase) will inactivate ampicillin.

Hypersensitivity

• Severe and life-threatening anaphylactoid reactions can occur with penicillin therapy. Although anaphylaxis more commonly occurs following parenteral therapy, it can also present after oral administration. It is more likely in patients with a previous history of penicillin hypersensitivity and reaction to multiple allergens. Before initiating therapy, the clinician should carefully inquire about hypersensitivity reactions to cephalosporins, allergens, or penicillin.

• If a hypersensitivity reaction occurs, the clinician should discontinue ampicillin therapy and initiate alternative antimicrobial therapy. Anaphylactoid reactions require immediate emergency treatment with oxygen, epinephrine, steroids, and airway management, including intubation(if clinically indicated).[19]

Clostridium Difficile Infection 

• Antibacterial treatment alters the intestine's natural flora, leading to the overgrowth of C. difficile. Clostridioides difficile-associated diarrhea (CDAD) can occur with 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, CDAD is a consideration for all patients who present with diarrhea after antibacterial use. Since it is reported to occur 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 cessation of therapy. Adequate fluid and electrolyte management, protein supplementation, and the antimicrobial regimen of C. difficile and surgical evaluation should be an option if indicated.[26]

Concomitant Infectious Mononucleosis Infection

• A high proportion (43%) of patients with infectious mononucleosis started on ampicillin can develop a rash. Ideally, the rash appears 7 to 10 days following the initiation of ampicillin therapy and remains for a few days to one week after discontinuation of the drug. In most cases, the rash is maculopapular, generalized, and pruritic. Therefore, ampicillin administration is not a recommendation for these patients. Whether these patients are truly allergic to penicillin remains unknown.[29]

Absence of Strong Indication

• Ampicillin administration without a specific indication or proof of a bacterial infection or a prophylactic indication is not likely to benefit the patient. Instead, it increases the risk of the growth of drug-resistant bacteria.[30]

Monitoring

• When prescribing ampicillin for a long duration, monitor renal and hepatic function. 

• Additionally, monitor for signs and symptoms of anaphylaxis during the first dose.[31]

• Providers should carefully monitor the parenteral solution for particulate matter and discoloration and discard it if needed.[32]

Toxicity

• Neurological adverse reactions, including convulsions, may occur due to high CSF concentrations of ampicillin.

• Management of overdose requires medication discontinuation, symptomatic treatment, and supportive care.

• Previously, whole bowel irrigation has been reported to be effective in severe cases of oral overdoses.[33]

• In patients with decreased renal function, ampicillin is removable via hemodialysis but not peritoneal dialysis.[34]

• In case of anaphylaxis, epinephrine should be administered without delay. According to AAFP, after administering epinephrine, clinicians should administer adjunctive treatment, including corticosteroids, antihistamines, and beta2 agonists. Referral to an allergist/immunologist should be considered.[35]

Enhancing Healthcare Team Outcomes

Ampicillin is a widely prescribed antimicrobial by clinicians and other healthcare professionals working collaboratively as an interprofessional team. While the antimicrobial is effective, clinicians should not empirically prescribe for all infections as the resistance to this agent is increasing globally. Antimicrobial stewardship is a coordinated program that promotes the appropriate use of antimicrobials. According to CDC, core elements of outpatient antimicrobial stewardship are commitment, action for policy and practice, tracking and reporting, education, and expertise.[36]

Nephrology consultation is essential for hemodialysis. 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. 

As outlined above, various healthcare providers, including clinicians (MDs, DOs, NPs, PAs), specialists, nurses, and pharmacists, participate in an interprofessional team-based approach to optimize patient care. Additionally, antimicrobial stewardship is necessary for reducing global drug resistance. An observational study of eight years involving twenty-three antibiotics, including ampicillin, demonstrated that rates of Clostridioides difficile infection (CDI) could be reduced using interprofessional antimicrobial stewardship between clinicians, pharmacists, infection control nurses, and other healthcare professionals.[37] [Level 3]