Continuing Education Activity

Ampicillin is a medication used in the management and treatment of certain bacterial infections. It is in the penicillin class of medications. 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 the treatment of 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 to restrict 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 that 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 including Escherichia coli, Salmonella species, 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 the treatment of 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 therapy 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]

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, morphogenetic formation of cell wall peptidoglycan structure. Therefore, the inactivation of PBPs by bound antimicrobial has immediate arresting actions on their function.

• The second stage comprises the physiological effects caused by this receptor-ligand interaction. PBPs 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.[8]

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 7.4 or 14.8 ml, respectively, 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.

Half-life

• The half-life of ampicillin is 0.7 to 1.5 hours in adults with normal kidney function.

Dosing Modifications in Renal Impairment

• 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

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[9]

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]

Adverse Effects

Serious Adverse Drug Reactions

• The primary adverse effects of ampicillin include seizure, enterocolitis, agranulocytosis, hemolytic anemia, immune thrombocytopenia, and pseudomembranous colitis.[10]

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.[11][12]

Gastrointestinal Adverse Drug Reactions

• Stomatitis

• Pseudomembranous colitis

• Enterocolitis

• Black hairy tongue

• Mainly seen with oral dose administration).[13]

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 the 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 described, infrequently, with vanishing bile duct syndrome.[14]

Neurological Adverse Drug Reactions

• Headache

• Seizures[15]

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.[16]

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 treatment.[17][18]

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 a patient with a previous history of penicillin hypersensitivity and/or 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 indicated.[11]

Clostridium Difficile Infection 

• Antibacterial treatment alters the natural flora of the intestine leading to overgrowth of C. difficile. Clostridioides difficile associated diarrhea (CDAD) can occur with nearly all antibacterial agents 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. Therefore, CDAD is a consideration for all patients after antibacterial use who present with diarrhea. 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 and protein supplementation along with the antimicrobial regimen of C. difficile and surgical evaluation should be an option if indicated.[17]

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 the majority of the cases, the rash is maculopapular, generalized, and pruritic. Therefore, ampicillin administration is not a recommendation in these patients. Whether these patients are truly allergic to penicillin remains unknown.[19]

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.[20]

Monitoring

• When prescribing ampicillin for a long duration, monitor renal, hepatic, and hematologic functions periodically.

• Additionally, observe for signs of anaphylaxis during the first dose.[21]

Toxicity

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

• In overdose cases, discontinuation of the medication, symptomatic treatment, and supportive care is necessary.

• Previously, whole bowel irrigation has been reported to be effective in severe cases of oral overdoses.[22]

• In patients with decreased renal function, the ampicillin is removable via hemodialysis but not peritoneal dialysis.[23]

Enhancing Healthcare Team Outcomes

Ampicillin is a widely prescribed antimicrobial by clinicians 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. 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.[24]

Pharmacists should verify dosing and 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 and 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 hemodialysis. 

As outlined above, various healthcare providers, including clinicians(MDs, DOs, NPs, PAs), specialists, nurses, pharmacists, participate in a team-based approach to optimize patient care. Additionally, antimicrobial stewardship is necessary for reducing global drug resistance. Consequently, the interprofessional team should work in collaboration for antimicrobial stewardship and enhanced patient outcomes. [Level 5]