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 the treatment of certain bacterial infections like those from E. coli, S. aureus, S. pneumoniae, H. influenzae, etc. This activity will highlight the mechanism of action, adverse event profile, off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions pertinent for members of the interprofessional team 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, S. aureus has become capable of exhibiting resistance against them by producing a penicillin hydrolyzing enzyme – penicillinase. After that, subsequent efforts to overcome this issue and extend the antimicrobial coverage of penicillins, ampicillin was developed. 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 E. coli: MIC = 4 mg/L, S. aureus: MIC = 0.6-1 mg/L, Streptococcus pneumoniae: MIC = 0.03-0.06 mg/L, H. influenzae: MIC = 0.25 mg/L.[1]

Ampicillin is FDA approved for the treatment of the infections caused by specific bacteria listed as follows:

Respiratory tract infection

Caused by: Streptococcus pneumoniae, penicillinase, and non-penicillinase producing Staphylococcus aureus, group A beta-hemolytic Streptococci, Hemophilus influenzae.

Bacterial meningitis[2]

Caused by: Gram-negative bacteria: Neisseria meningitidis, Escherichia coli, and, Gram-positive bacteria: Listeria monocytogenes, Group B Streptococci. Adding aminoglycosides increases its effectiveness against gram-negative bacteria

Septicemia and Endocarditis[3]

Caused by: Gram-positive bacteria, including penicillin-susceptible Staphylococcus spp., Streptococcus spp., and Enterococcus spp.

Gram-negative bacteria including Escherichia coli, Salmonella spp., 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.

Genitourinary infections[4]

Caused by sensitive strains of Escherichia coli and Proteus mirabilis.

Gastrointestinal infections[5]

Caused by Salmonella typhi, Shigella spp., and other Salmonella spp., and usually improve with oral or intravenous therapy. Culture must be obtained for susceptibility, and antimicrobial sensitivity; however, empiric therapy may be started before receiving the results.

Prophylaxis in surgery[6]

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

Neonatal Group B Streptococcal infection prophylaxis[6]

Can be administered as an alternative to intramuscular penicillin

Dosing

• Endocarditis prophylaxis (Off Label):

In the respiratory tract, oral or dental procedure: IV or IV 50 mg/kg per 30 to 60 minutes

In gastrointestinal or genitourinary procedure:

Only for patients at risk for endocarditis:

High risk: 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 sp.: IV/IM 200 mg/kg/day every 6 hours for 4 to 6 weeks 

• GI tract infections

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 infections:

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

• Bacterial meningitis/ septicemia:

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

• Gonorrhea (Not CDC recommended)

IV 3.5 g administered once with 1 g probenecid

• Urinary tract infection caused by ampicillin susceptible enterococcus

IV/IM 1 to 2 g every 4 to 6 hrs

• Listeria sp.

IV 2 g every 4 hours

• S. agalactiae (off-label)

Maternal prophylaxis to prevent newborn infection:

IV first dose 2 g followed by 1 g every 4 hours till delivery

Mechanism of Action

The mode of action of beta-lactam antimicrobials 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 (PBPs). These proteins perform vital roles in cell cycle-related, morphogenetic formation of cell wall peptidoglycan structure. 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 bacteriostatic or 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.

Adverse Effects

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

Common adverse effects appear below, in detail[9][10][11]:

Gastrointestinal

• Stomatitis, glossitis, black 'hairy' tongue, nausea, vomiting, pseudomembranous colitis, enterocolitis, and diarrhea. (Mainly seen with oral dose administration).

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.

Liver

• A moderate elevation of serum glutamic oxaloacetic transaminase (SGOT) 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 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

• 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.

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 treatment.

Contraindications

Infection by penicillinase-producing organisms

Ampicillin is contraindicated in the treatment of infections caused by penicillinase-producing organisms. Penicillinase (beta-lactamase) will inactivate ampicillin.

Hypersensitivity [10]

Serious 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, a careful inquiry should be made relating to 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.

Clostridioides difficile infection [9]

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 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. CDAD is a consideration for all patients after antibacterial use who present with diarrhea. Since it is reported to occur 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 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.

Concomitant infectious mononucleosis infection [12]

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.

Absence of a strong indication

Ampicillin administration without a strong indication of or proof of a bacterial infection or a prophylactic indication is not likely to result in a benefit to the patient and instead increases the risk of growth of drug-resistant bacteria.

Monitoring

When administering a prolonged therapy, monitor renal, hepatic, and hematologic functions periodically. Additionally, watch 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. Whole bowel irrigation has been proven to be effective in severe cases of oral overdoses.[13]

Enhancing Healthcare Team Outcomes

Ampicillin is often prescribed by many clinicians, including the nurse practitioner. However, we have entered an era of drug resistance, and it is crucial for all healthcare workers not empirically to prescribe ampicillin for every type of infection. The clinician will decide to treat with ampicillin but can consult with a pharmacist, particularly one with board certification in infectious disease. Pharmacists can review the antibiogram and verify dosing and duration. Nursing can counsel the patient on how to take the medication, answer any questions, and monitor patient adherence and therapeutic effectiveness, reporting any concerns to the prescriber. There should be an interprofessional effort to minimize and limit the use of antimicrobials to only those with bacterial infections that will benefit from the course of therapy and avoid use in nonbacterial illnesses. [Level 5]