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Ampicillin

Author: Suhel A. Sabunwala Author: Preeti Patel Editor: Ashish R. Patel Updated: 6/18/2026 9:47:33 AM

Indications

The activity of ampicillin is nearly identical to that of penicillin G, except that ampicillin has higher activity against enterococci. Because ampicillin is susceptible to β-lactamases, it can be used only in infections caused by non–β-lactamase-producing organisms, such as Haemophilus influenzae, H parainfluenzae, Escherichia coli, Shigella spp., and Salmonella spp. Ampicillin should be used for infections caused by bacterial species that intrinsically produce β-lactamase, such as Enterobacter cloacae, Serratia marcescens, Acinetobacter baumannii, Pseudomonas aeruginosa, and Proteus vulgaris. Ampicillin is an acceptable alternative antibiotic for infections caused by Neisseria meningitidis, Erysipelothrix rhusiopathiae, and Pasteurella multocida.[1][2]

FDA-Approved Indications

  • Bloodstream infection: Pathogen-directed therapy based on culture and susceptibility results. Ampicillin should be used only when susceptibility has been established. For Listeria bloodstream infection, ampicillin may need to be combined with gentamicin.[3][4]
  • Endocarditis: Pathogen-directed therapy based on culture and susceptibility results. Ampicillin should be used only for susceptible organisms. For native or prosthetic valve endocarditis caused by ampicillin-susceptible Enterococcus, ampicillin should be combined with ceftriaxone or gentamicin.[5][6][7]
  • Intra-abdominal infections: Intra-abdominal infections, such as appendicitis, cholecystitis, cholangitis, diverticulitis, bowel perforation, and colitis, may warrant ampicillin use in combination with sulbactam in hemodynamically stable patients or after adequate source control, based on culture and susceptibility results. Empiric ampicillin use in complicated intra-abdominal infections should be avoided.[8]
  • Bacterial meningitis: Ampicillin is often initiated empirically in combination with other antimicrobials for community-acquired infection in immunocompetent patients older than 50 years and in immunocompromised patients. Therapy is then continued based on culture and susceptibility results for infections caused by Listeria and Enterococcus.[9]
  • Urinary tract infections: Ampicillin can be used for complicated pyelonephritis, renal abscess, and uncomplicated cystitis caused by ampicillin-susceptible Enterococcus.[10][11]

Off-Label Uses

  • Anthrax: For systemic infection, including meningitis, combine ampicillin with another appropriate antimicrobial agent.[12]
  • Bone and joint infections: Ampicillin may be used for bone and joint infections, including discitis and prosthetic joint infections, when culture and susceptibility results support its use. Ampicillin should be used only for susceptible organisms.[13][14]
  • Chorioamnionitis and tubo-ovarian abscess: Ampicillin is used in combination with gentamicin.[15][16]
  • Peritoneal dialysis catheter-related peritonitis: Intraperitoneal (IP) administration is preferred; however, IP ampicillin is not recommended for treating enterococcal peritonitis.[17] 
  • Endocarditis prophylaxis: Ampicillin may be used for endocarditis prophylaxis in patients undergoing dental procedures.[18] 
  • Carbapenem-resistant Acinetobacter baumannii infections: The Infectious Diseases Society of America (IDSA) recommends an antibiotic regimen that includes a sulbactam-containing agent for carbapenem-resistant A baumannii infections. The preferred regimen is sulbactam-durlobactam in combination with a carbapenem, such as imipenem-cilastatin or meropenem. If sulbactam-durlobactam is unavailable, an alternative regimen is high-dose ampicillin-sulbactam combined with at least 1 additional agent, such as polymyxin B, minocycline (preferred over tigecycline), or cefiderocol.[19]

Mechanism of Action

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Mechanism of Action

Penicillin is a β-lactam antibiotic, and its antibacterial activity stems from inhibition of bacterial cell wall synthesis. Both gram-positive and gram-negative bacteria have cell walls composed of peptidoglycans that protect against osmotic changes.[20] The basic subunit of peptidoglycan is a disaccharide composed of N-acetylglucosamine and N-acetylmuramic acid linked to a pentapeptide side chain. Penicillin inhibits the enzymes required for peptidoglycan cross-linking. Consequently, bacterial cell wall assembly is disrupted, resulting in a loss of structural integrity.

Penicillin-sensitive reactions are catalyzed by proteins known as penicillin-binding proteins (PBPs).[21] PBPs are inhibited by β-lactam antibiotics through covalent binding to an active-site serine residue. The antibacterial activity of β-lactam antibiotics is mediated by their binding to high-molecular-weight PBPs. β-Lactamases are enzymes that hydrolyze the β-lactam ring, thereby inactivating the drug.

Pharmacokinetics

When administered orally, ampicillin is only partially absorbed (30%-55%), and food decreases its absorption.[22][23] Ampicillin is 20% protein bound, primarily to albumin.[24] Only the unbound drug exerts antibacterial activity. About 21% of the dose is metabolized, and 26% to 43% of the drug is excreted unchanged in the urine. The serum half-life is 1.0 to 1.3 hours in patients with normal renal function (creatinine clearance [CrCl] >90 mL/min). In patients with renal failure (CrCl <10 mL/min), the half-life is prolonged to 8 to 20 hours. Ampicillin is also secreted into the urine by the renal tubular cells. Probenecid inhibits this secretion and may prolong the drug's half-life.[25]

Ampicillin is well distributed to most tissues, including the lungs, liver, kidneys, muscles, and placenta.[26] Bone concentrations are variable.[27] Distribution to the eye, brain, cerebrospinal fluid (CSF), and prostate is limited in the absence of inflammation.[26] CSF concentrations range from 13% to 14% of serum concentrations when meninges are inflamed.

Ampicillin is actively secreted unchanged into the bile, resulting in biliary concentrations at least 10-fold higher than serum concentrations.[28]

Administration

Ampicillin can be administered orally, intramuscularly, or intravenously. Oral therapy is often used as step-down therapy after intravenous (IV) ampicillin; however, it is generally not preferred because of its low bioavailability (39%-54%).[29]

Oral Administration

  • When administered orally, ampicillin should be taken on an empty stomach (30 minutes before or 2 hours after meals) with 1 to 2 full glasses of water to enhance absorption.

Intravenous Administration

  • For IV administration, ampicillin may be administered as an IV push. Reconstitution of vials containing 125, 250, or 500 mg of ampicillin with 5 mL of sterile water is recommended.
  • Vials containing 1 or 2 g should be reconstituted with 7.4 or 14.8 mL of bacteriostatic or sterile water, respectively.
  • For intermittent IV infusions, the concentration should not exceed 30 mg/mL. For ease of outpatient administration, the total daily dose may be administered as a continuous 24-hour infusion.[30]

Intramuscular Administration

  • If administered intramuscularly, ampicillin should be injected into a large muscle mass. Reconstitute with bacteriostatic or sterile water to prepare solutions containing 125 or 250 mg/mL. Solutions for intramuscular (IM) injection should be used within 1 hour of preparation.

Intraperitoneal Administration

  • Ampicillin may be administered intraperitoneally either intermittently (1 exchange with dwell time >6 hours) or continuously with each exchange. 

Rate of Administration

  • Formulations reconstituted from 125-, 250-, or 500-mg vials should be administered by IV injection over 3 to 5 minutes.
  • Formulations reconstituted from 1- or 2-g vials should be administered by IV injection over 10 to 15 minutes.

Dosage

  • Ampicillin is typically dosed at 2 g every 4 to 6 hours. Dosage should be adjusted according to renal function, with progressive dose reductions as CrCl decreases below 50 mL/min (1-2 g every 6-8 hours), 30 mL/min (1-2 g every 8-12 hours), and 15 mL/min (1-2 g every 12-24 hours).

Duration

  • Bacteremia: Duration should be pathogen-directed. In uncomplicated cases with rapid clearance of bacteremia, treatment is typically administered for 5 to 7 days. In complicated infections, such as central nervous system infections or nondrainable abscesses, therapy is generally extended to 7 to 14 days. For Listeria infections, a treatment duration of 14 to 21 days is recommended.[4]
  • Intra-abdominal infection: Treatment is generally continued for 4 to 5 days following adequate source control. 
  • Endocarditis: Duration is pathogen-directed and typically ranges from 4 to 6 weeks.
  • Bone and joint infections: Treatment is generally administered for 4 to 6 weeks.
  • Urinary tract infections: Ampicillin is generally not recommended as a first-line agent. When used for uncomplicated urinary tract infections, the typical treatment duration is 5 to 7 days.

Specific Patient Populations

Pregnancy considerations: Ampicillin is widely used during pregnancy (formerly US Food and Drug Administration [FDA] pregnancy category B). The American College of Obstetricians and Gynecologists (ACOG) recommends treating patients with preterm premature rupture of membranes with IV ampicillin and erythromycin, followed by oral antibiotics, to reduce neonatal complications.[31] In addition, listeriosis during pregnancy is associated with vertical transmission and increased neonatal mortality. Ampicillin is often used in combination with other antibiotics for treatment.[32]

Breastfeeding considerations: Clinical data suggest that administering ampicillin during lactation results in low milk levels that are not expected to cause adverse effects in breastfed infants. However, alterations in the infant's gastrointestinal flora have been reported. Therefore, infants exposed to ampicillin through breast milk should be monitored for diarrhea and thrush.[33]

Adverse Effects

Hypersensitivity Reactions

These reactions are mediated by penicilloyl derivatives, which are produced by opening the β-lactam ring and sensitizing immunoglobulin E antibodies. These reactions may present as rash, exfoliative dermatitis, or anaphylaxis.[34] Other allergic responses include serum sickness, characterized by fever, urticaria, joint pain, and edema; however, this reaction is very uncommon (<0.01%).[35] Serum sickness and Stevens-Johnson syndrome are thought to occur through immunoglobulin M activation and binding to the drug and its derivatives.

Hematologic Effects

Ampicillin can cause neutropenia when high doses are administered over a prolonged period.[36] Ampicillin may rarely cause hemolytic anemia or thrombocytopenia.[37][38]

Nephrotoxicity

Ampicillin may rarely cause interstitial nephritis, which may present with rash, proteinuria, and hematuria.[39] Interstitial nephritis may initially present with an increase in serum creatinine and can progress to anuria and renal failure. These findings typically resolve after discontinuation of the offending agent.

Central Nervous System Toxicity

Myoclonic seizures are more common with high-dose IV penicillin but may rarely occur with IV ampicillin as well.[40]

Gastrointestinal Intolerance

Nausea, vomiting, dysgeusia, and diarrhea have been reported with ampicillin use.[41]

Hepatotoxicity

Ampicillin may rarely cause elevations in alkaline phosphatase and aspartate aminotransferase levels.[42]

Clostridioides difficile Infection

Although the risk of C difficile infection is lower than that associated with many other antimicrobials,[43] prolonged ampicillin therapy can alter the normal gut microbiota, resulting in colonization by antimicrobial-resistant organisms and an increased risk of C difficile infection.

Contraindications

Infection by Penicillinase-Producing Organisms

  • Ampicillin is contraindicated in the treatment of infections caused by penicillinase-producing organisms because penicillinase (β-lactamase) inactivates 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. These reactions are more likely to occur in patients with a history of penicillin hypersensitivity and multiple allergic reactions. Before initiating therapy, clinicians should carefully inquire about prior hypersensitivity reactions to penicillins, cephalosporins, and other allergens.
  • If a hypersensitivity reaction occurs, clinicians should discontinue ampicillin therapy and initiate alternative antimicrobial treatment. Anaphylactoid reactions require immediate emergency treatment with oxygen, epinephrine, steroids, and airway management, including intubation (if clinically indicated).[44]
  • Case reports have described Kounis syndrome with cardiogenic shock following administration of ampicillin-sulbactam. Affected patients may not develop cutaneous manifestations but can develop severe hypotension and inferolateral myocardial ischemia. Epinephrine should be avoided in such cases.[45]

Clostridioides difficile Infection 

  • Antibacterial treatment alters the intestinal flora, leading to overgrowth of C difficile. C 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 are associated with increased morbidity and mortality because they may be refractory to the recommended antimicrobial therapy and may require colectomy. Therefore, CDAD should be considered in all patients who present with diarrhea after antibacterial therapy. Because CDAD has been reported more than 2 months after antibacterial exposure, a careful medication history should be obtained.
  • If CDAD is confirmed, ongoing systemic antimicrobial therapy should be discontinued or minimized whenever possible. Adequate fluid and electrolyte management, protein supplementation, and the antimicrobial regimen for C difficile, such as oral vancomycin or fidaxomicin, should be initiated promptly. If fulminant colitis with toxic megacolon is present, surgical consultation should be obtained to assess the need for colectomy.[46]

Concomitant Infectious Mononucleosis Infection

  • Approximately 43% of patients with infectious mononucleosis who receive ampicillin develop a rash. The rash typically appears 7 to 10 days after initiation of ampicillin therapy and persists for several days to 1 week after discontinuation of the drug. In most cases, the rash is maculopapular, generalized, and pruritic. Antibiotic use, including Ampicillin, should be avoided in patients with infectious mononucleosis when suspicion for superimposed bacterial pharyngitis is low.[47]

Nephropathy

  • Renal dysfunction and nephropathy have been reported with Ampicillin.[48]
Pause and Reflect

A 72-year-old man with chronic kidney disease presents with fever, flank pain, and pyuria. Urine culture grows Enterococcus faecalis, which is susceptible to ampicillin. What factors should be considered when determining the clinical utility and dosing of ampicillin?

Teaching Points

  • Ampicillin is active against susceptible Enterococcus species and can be used for complicated pyelonephritis or renal abscess caused by ampicillin-susceptible Enterococcus.
  • Because ampicillin is inactivated by β-lactamases, it should not be used against β-lactamase–producing organisms unless combined with an appropriate β-lactamase inhibitor.
  • Renal function must be assessed because ampicillin is primarily eliminated by the kidneys and requires dosage adjustment in patients with renal impairment.
  • Ampicillin inhibits bacterial cell wall synthesis by binding PBPs and blocking peptidoglycan cross-linking.

Monitoring

  • When ampicillin is prescribed for a prolonged period, renal and hepatic function should be monitored periodically.[49]  
  • Additionally, patients should be monitored for signs and symptoms of anaphylaxis following the first dose.[50] 
  • Therapeutic drug monitoring of ampicillin using ultrafiltration to measure the non–protein-bound, pharmacologically active fraction may help optimize dosing and reduce toxicity.[51] 
  • Clinicians should carefully inspect the parenteral solution for particulate matter and discoloration and discard the solution if either is present.[52]

Toxicity

  • Neurological adverse reactions, including convulsions, may occur due to high CSF concentrations of ampicillin.
  • Management of overdose includes discontinuation of ampicillin, symptomatic treatment, and supportive care.
  • Whole-bowel irrigation has been reported to be effective in severe cases of oral ampicillin overdose.[53]
  • In patients with impaired renal function, ampicillin can be removed by hemodialysis but not by peritoneal dialysis.[54]
  • In cases of anaphylaxis, epinephrine should be administered immediately. According to the American Academy of Family Physicians (AAFP), adjunctive therapy, including corticosteroids, antihistamines, and β2-agonists, may be administered after epinephrine. Referral to an allergist/immunologist should be considered.[55]
  • Ampicillin-induced liver injury is usually reversible. The injury typically resolves after discontinuation of ampicillin; however, normalization of liver enzyme levels and hepatic function may take several weeks to months. Treatment is supportive.[56]
  • Ampicillin can also cause severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Treatment includes discontinuation of the drug and supportive care. In severe cases, adjunctive therapies, such as corticosteroids, cyclosporine, and intravenous immunoglobulin (IVIG), may be required.[57]

Enhancing Healthcare Team Outcomes

Ampicillin is one of the most commonly prescribed antibiotics. It is a first-line antibiotic for certain serious infections, including endocarditis caused by Enterococcus species and meningitis caused by Listeria monocytogenes. When combined with sulbactam, it is often used to treat intra-abdominal infections. Although ampicillin remains an important therapeutic agent, clinicians must be aware of increasing antimicrobial resistance. When resistance is suspected or documented, alternative antimicrobial therapy should be considered, as treatment failure may lead to serious clinical consequences.

Clinicians must also remain vigilant for potential adverse reactions associated with ampicillin. Because ampicillin is a penicillin-derived antibiotic, allergic reactions and cross-reactivity with other β-lactam antibiotics may occur. Hypersensitivity reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis are potentially life-threatening adverse events. Clinicians should exercise caution when prescribing ampicillin for the first time and monitor patients for at least 30 minutes after administering the drug to rule out any allergic reaction. Emergency equipment and medications, including epinephrine and airway management supplies, should be readily available to manage severe hypersensitivity reactions.

Ampicillin dosing may vary according to age, renal function, and indications. Serious infections, such as endocarditis, osteomyelitis, and meningitis, may require maximal dosing; however, dosage adjustment may be necessary in patients with renal impairment and in older adults. Both underdosing and overdosing of ampicillin can result in adverse outcomes. Clinicians should collaborate closely with pharmacists to optimize dosing.

Antibiotic resistance continues to increase, and every effort should be made to use the shortest effective duration of therapy and to avoid unnecessary empiric antibiotic use when an alternative diagnosis is evident. Deaths attributable to antimicrobial resistance increased by more than 80% among adults aged 70 or older between 1990 and 2021.[58] Antimicrobial stewardship is a coordinated, interprofessional, team-based approach to optimizing antibiotic use. This approach promotes high-quality, cost-effective care while reducing the risk of antimicrobial resistance and C difficile infection. Although C difficile infection is less commonly associated with ampicillin than with some other antimicrobial agents, clinicians should maintain a low threshold for evaluating patients for C difficile infection, particularly during prolonged therapy.

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