Ampicillin-Sulbactam

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# Overview
Ampicillin-Sulbactam is an antibiotic that is FDA approved for the treatment of beta-lactamase producing strains of Staphylococcus aureus, Escherichia coli, Klebsiella spp. (including K. pneumoniae), Proteus mirabilis, Bacteroides fragilis, Enterobacter spp., and Acinetobacter calcoaceticus.   Common adverse reactions include diarrhea.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Ampicillin and sulbactam for injection is indicated for the treatment of infections due to susceptible strains of the designated microorganisms in the conditions listed below.
- Skin and Skin Structure Infections caused by beta-lactamase producing strains of Staphylococcus aureus, Escherichia coli, Klebsiella spp (including K. pneumoniae*), Proteus mirabilis, Bacteroides fragilis, Enterobacter spp.*, and Acinetobacter calcoaceticus.
- Intra-Abdominal Infections caused by beta-lactamase producing strains of Escherichia coli, Klebsiella spp. (including K. pneumoniae), Bacteroides spp. (including B. fragilis), and Enterobacter spp.
- Gynecological Infections caused by beta-lactamase producing strains of Escherichia coli, and Bacteroides spp. (including B. fragilis).
- Efficacy for this organism in this organ system was studied in fewer than 10 infections.
- While ampicillin and sulbactam for injection is indicated only for the conditions listed above, infections caused by ampicillin-susceptible organisms are also amenable to treatment with ampicillin and sulbactam for injection due to its ampicillin content. Therefore, mixed infections caused by ampicillin-susceptible organisms and beta-lactamase producing organisms susceptible to ampicillin and sulbactam for injection should not require the addition of another antibiotic.
- Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify the organisms causing infection and to determine their susceptibility to ampicillin and sulbactam for injection.
- Therapy may be instituted prior to obtaining the results from bacteriological and susceptibility studies, when there is reason to believe the infection may involve any of the beta-lactamase producing organisms listed above in the indicated organ systems. Once the results are known, therapy should be adjusted if appropriate.
- To reduce the development of drug-resistant bacteria and maintain effectiveness of ampicillin and sulbactam for injection and other antibacterial drugs, ampicillin and sulbactam for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
- Ampicillin and sulbactam for injection may be administered by either the IV or the IM routes.
- For IV administration, the dose can be given by slow intravenous injection over at least 10-15 minutes or can also be delivered, in greater dilutions with 50-100 mL of a compatible diluent as an intravenous infusion over 15-30 minutes.
- Ampicillin and sulbactam for injection may be administered by deep intramuscular injection.
- The recommended adult dosage of ampicillin and sulbactam for injection is 1.5 g (1 g ampicillin as the sodium salt plus 0.5 g sulbactam as the sodium salt) to 3 g (2 g ampicillin as the sodium salt plus 1 g sulbactam as the sodium salt) every six hours. This 1.5 to 3 g range represents the total of ampicillin content plus the sulbactam content of ampicillin and sulbactam for injection, and corresponds to a range of 1 g ampicillin/0.5 g sulbactam to 2 g ampicillin/1 g sulbactam. The total dose of sulbactam should not exceed 4 grams per day.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ampicillin sodium and sulbactam sodium in adult patients.

### NonGuideline-Supported Use
- Infection of skin AND/OR subcutaneous tissue
- Infectious disease of abdomen
- Pelvic inflammatory disease

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- The recommended daily dose of ampicillin and sulbactam for injection in pediatric patients is 300 mg per kg of body weight administered via intravenous infusion in equally divided doses every 6 hours.
- This 300 mg/kg/day dosage represents the total ampicillin content plus the sulbactam content of ampicillin and sulbactam for injection, and corresponds to 200 mg ampicillin/100 mg sulbactam per kg per day.
- The safety and efficacy of ampicillin and sulbactam for injection administered via intramuscular injection in pediatric patients have not been established. Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations, and the total dose of sulbactam should not exceed 4 grams per day. The course of intravenous therapy should not routinely exceed 14 days. In clinical trials, most children received a course of oral antimicrobials following initial treatment with intravenous ampicillin and sulbactam for injection.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ampicillin sodium and sulbactam sodium in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Ampicillin sodium and sulbactam sodium in pediatric patients.

# Contraindications
- The use of ampicillin and sulbactam for injection is contraindicated in individuals with a history of hypersensitivity reactions to any of the penicillins.

# Warnings
- SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE APT TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR HYPERSENSITIVITY REACTIONS TO MULTIPLE ALLERGENS.
- THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE THERAPY WITH A PENICILLIN, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, AND OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AMPICILLIN AND SULBACTAM FOR INJECTION SHOULD BE DISCONTINUED AND THE APPROPRIATE THERAPY INSTITUTED.
- SERIOUS ANAPHYLACTOID REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ampicillin and sulbactam for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment C. difficile, and surgical evaluation should be instituted as clinically indicated.

# Adverse Reactions

## Clinical Trials Experience
There is limited information regarding Ampicillin-Sulbactam Clinical Trials Experience in the drug label.

## Postmarketing Experience
- Ampicillin and sulbactam for injection is generally well tolerated. The following adverse reactions have been reported.
- Pain at IM injection site - 16%
- Pain at IV injection site - 3%
- Thrombophlebitis - 3%
- The most frequently reported adverse reactions were diarrhea in 3% of the patients and rash in less than 2% of the patients.
- Additional systemic reactions reported in less than 1% of the patients were: itching, nausea, vomiting, candidiasis, fatigue, malaise, headache, chest pain, flatulence, abdominal distension, glossitis, urine retention, dysuria, edema, facial swelling, erythema, chills, tightness in throat, substernal pain, epistaxis and mucosal bleeding.
- Available safety data for pediatric patients treated with ampicillin and sulbactam for injection demonstrate a similar adverse events profile to those observed in adult patients. Additionally, atypical lymphocytosis has been observed in one pediatric patient receiving ampicillin and sulbactam for injection.
- Adverse laboratory changes without regard to drug relationship that were reported during clinical trials were:
- Hepatic
- Increased AST (SGOT), ALT (SGPT), alkaline phosphatase, and LDH.
- Hematologic
- Decreased hemoglobin, hematocrit, RBC, WBC, neutrophils, lymphocytes, platelets and increased lymphocytes, monocytes, basophils, eosinophils, and platelets
- Blood Chemistry
- Decreased serum albumin and total proteins.
- Renal
- Increased BUN and creatinine.
- Urinalysis
- Presence of RBC's and hyaline casts in urine.
- The following adverse reactions have been reported with ampicillin-class antibiotics and can also occur with ampicillin and sulbactam for injection.
- Gastritis, stomatitis, black "hairy" tongue and enterocolitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment.
- Urticaria, erythema multiforme, and an occasional case of exfoliative dermatitis have been reported. These reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, the drug should be discontinued, unless the opinion of the physician dictates otherwise. Serious and occasional fatal hypersensitivity (anaphylactic) reactions can occur with a penicillin.
- Hematologic
- In addition to the adverse laboratory changes listed above for ampicillin and sulbactam for injection, agranulocytosis has been reported during therapy with penicillins. All of these reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Some individuals have developed positive direct Coombs Tests during treatment with ampicillin and sulbactam for injection, as with other beta-lactam antibiotics.

# Drug Interactions
There is limited information regarding Ampicillin-Sulbactam Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in mice, rats, and rabbits at doses up to ten (10) times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to ampicillin and sulbactam for injection. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ampicillin-Sulbactam in women who are pregnant.

### Labor and Delivery
- Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions, and duration of contractions. However, it is not known whether the use of ampicillin and sulbactam for injection in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.

### Nursing Mothers
- Low concentrations of ampicillin and sulbactam are excreted in the milk; therefore, caution should be exercised when ampicillin and sulbactam for injection is administered to a nursing woman.

### Pediatric Use
- The safety and effectiveness of ampicillin and sulbactam for injection have been established for pediatric patients one year of age and older for skin and skin structure infections as approved in adults. Use of ampicillin and sulbactam for injection in pediatric patients is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetic studies, a controlled clinical trial conducted in pediatric patients and post-marketing adverse events surveillance.

### Geriatic Use
There is no FDA guidance on the use of Ampicillin-Sulbactam in geriatric settings.

### Gender
There is no FDA guidance on the use of Ampicillin-Sulbactam with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Ampicillin-Sulbactam with respect to specific racial populations.

### Renal Impairment
- In patients with impairment of renal function the elimination kinetics of ampicillin and sulbactam are similarly affected, hence the ratio of one to the other will remain constant whatever the renal function. The dose of ampicillin and sulbactam for injection in such patients should be administered less frequently in accordance with the usual practice for ampicillin and according to the following recommendations:

### Hepatic Impairment
There is no FDA guidance on the use of Ampicillin-Sulbactam in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ampicillin-Sulbactam in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Ampicillin-Sulbactam in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral
- Intravenous

### Monitoring
There is limited information regarding Ampicillin-Sulbactam Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Ampicillin-Sulbactam and IV administrations.

# Overdosage
- Neurological adverse reactions, including convulsions, may occur with the attainment of high CSF levels of beta-lactams. Ampicillin may be removed from circulation by hemodialysis. The molecular weight, degree of protein binding and pharmacokinetics profile of sulbactam suggest that this compound may also be removed by hemodialysis.

# Pharmacology

## Mechanism of Action
- Ampicillin is similar to benzyl penicillin in its bactericidal action against susceptible organisms during the stage of active multiplication. It acts through the inhibition of cell wall mucopeptide biosynthesis. Ampicillin has a broad spectrum of bactericidal activity against many gram-positive and gram-negative aerobic and anaerobic bacteria. (Ampicillin is, however, degraded by beta-lactamases and therefore the spectrum of activity does not normally include organisms which produce these enzymes.)
- A wide range of beta-lactamases found in microorganisms resistant to penicillins and cephalosporins have been shown in biochemical studies with cell free bacterial systems to be irreversibly inhibited by sulbactam. Although sulbactam alone possesses little useful antibacterial activity except against the Neisseriaceae, whole organism studies have shown that sulbactam restores ampicillin activity against beta-lactamase producing strains. In particular, sulbactam has good inhibitory activity against the clinically important plasmid mediated beta-lactamases most frequently responsible for transferred drug resistance. Sulbactam has no effect on the activity of ampicillin against ampicillin susceptible strains.
- The presence of sulbactam in the ampicillin and sulbactam for injection formulation effectively extends the antibiotic spectrum of ampicillin to include many bacteria normally resistant to it and to other beta-lactam antibiotics. Thus, ampicillin and sulbactam for injection possesses the properties of a broad-spectrum antibiotic and a beta-lactamase inhibitor.
- While in vitro studies have demonstrated the susceptibility of most strains of the following organisms, clinical efficacy for infections other than those included in the indications section has not been documented.
- Staphylococcus aureus (beta-lactamase and non-beta-lactamase producing), Staphylococcus epidermidis (beta-lactamase and non-beta-lactamase producing), Staphylococcus saprophyticus (beta-lactamase and non-beta-lactamase producing), Streptococcus faecalis (Enterococcus), Streptococcus pneumoniae (formerly D. pneumoniae), Streptococcus pyogenes, Streptococcus viridans.
- Hemophilus influenzae (beta-lactamase and non-beta-lactamase producing), Moraxella (Branhamella) catarrhalis (beta-lactamase and non-beta-lactamase producing), Escherichia coli (beta-lactamase and non-beta-lactamase producing), Klebsiella species (all known strains are beta-lactamase producing), Proteus mirabilis (beta-lactamase and non-beta-lactamase producing), Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Morganella morganii, and Neisseria gonorrhoeae (beta-lactamase and non-beta-lactamase producing).
- Clostridium species, Peptococcus species, Peptostreptococcus species, Bacteroides species, including B. fragilis.
 These are not beta-lactamase producing strains and, therefore, are susceptible to ampicillin alone.
- For the Kirby-Bauer method of susceptibility testing, a 20 mcg (10 mcg ampicillin + 10 mcg sulbactam) diffusion disk should be used. The method is one outlined in the NCCLS publication M2-A4.1 With this procedure, a report from the laboratory of "Susceptible" indicates that the infecting organism is likely to respond to ampicillin and sulbactam for injection therapy and a report of "Resistant" indicates that the infecting organism is not likely to respond to therapy. An "Intermediate" susceptibility report suggests that the infecting organism would be susceptible to ampicillin and sulbactam for injection if a higher dosage is used or if the infection is confined to tissues or fluids (e.g., urine) in which high antibiotic levels are attained.
- Broth or agar dilution methods may be used to determine the minimal inhibitory concentration (MIC) value for susceptibility of bacterial isolates to ampicillin/sulbactam. The method used is one outlined in the NCCLS publication M7-A2.2 Tubes should be inoculated to contain 105 to 106 organisms/mL or plates "spotted" with 104 organisms.
- The recommended dilution method employs a constant ampicillin/sulbactam ratio of 2:1 in all tubes with increasing concentrations of ampicillin. MIC's are reported in terms of ampicillin concentration in the presence of sulbactam at a constant 2 parts ampicillin to 1 part sulbactam.

## Structure
- Ampicillin and Sulbactam for Injection, USP is an injectable antibacterial combination consisting of the semisynthetic antibiotic ampicillin sodium and the beta-lactamase inhibitor sulbactam sodium for intravenous and intramuscular administration.
- Ampicillin sodium is derived from the penicillin nucleus, 6-aminopenicillanic acid. Chemically, it is monosodium (2S, 5R, 6R)-6--3,3-dimethyl-7-oxo-4-thia-1-azabicycloheptane-2-carboxylate and has a molecular weight of 371.39. Its chemical formula is C16H18N3NaO4S. The structural formula is:
- Ampicillin and Sulbactam for Injection, USP, ampicillin sodium/sulbactam sodium parenteral combination, is available as a white to off-white dry powder for reconstitution. Ampicillin and Sulbactam for Injection, USP dry powder is freely soluble in aqueous diluents to yield pale yellow to yellow solutions containing ampicillin sodium and sulbactam sodium equivalent to 250 mg ampicillin per mL and 125 mg sulbactam per mL. The pH of the solutions is between 8 and 10.
- Dilute solutions (up to 30 mg ampicillin and 15 mg sulbactam per mL) are essentially colourless to pale yellow. The pH of dilute solutions remains the same.
- 1.5 g of Ampicillin and Sulbactam for Injection, USP (1 g ampicillin as the sodium salt plus 0.5 g sulbactam as the sodium salt) parenteral contains approximately 115 mg (5 mEq) of sodium.
- 3 g of Ampicillin and Sulbactam for Injection, USP (2 g ampicillin as the sodium salt plus 1 g sulbactam as the sodium salt) parenteral contains approximately 230 mg (10 mEq) of sodium.

## Pharmacodynamics
There is limited information regarding Ampicillin-Sulbactam Pharmacodynamics in the drug label.

## Pharmacokinetics
- Immediately after completion of a 15-minute intravenous infusion of ampicillin and sulbactam for injection, peak serum concentrations of ampicillin and sulbactam are attained. Ampicillin serum levels are similar to those produced by the administration of equivalent amounts of ampicillin alone. Peak ampicillin serum levels ranging from 109 to 150 mcg/mL are attained after administration of 2000 mg of ampicillin plus 1000 mg sulbactam and 40 to 71 mcg/mL after administration of 1000 mg ampicillin plus 500 mg sulbactam. The corresponding mean peak serum levels for sulbactam range from 48 to 88 mcg/mL and 21 to 40 mcg/mL, respectively. After an intramuscular injection of 1000 mg ampicillin plus 500 mg sulbactam, peak ampicillin serum levels ranging from 8 to 37 mcg/mL and peak sulbactam serum levels ranging from 6 to 24 mcg/mL are attained.
- The mean serum half-life of both drugs is approximately 1 hour in healthy volunteers.
- Approximately 75 to 85% of both ampicillin and sulbactam are excreted unchanged in the urine during the first 8 hours after administration of ampicillin and sulbactam for injection to individuals with normal renal function. Somewhat higher and more prolonged serum levels of ampicillin and sulbactam can be achieved with the concurrent administration of probenecid.
- In patients with impaired renal function the elimination kinetics of ampicillin and sulbactam are similarly affected, hence the ratio of one to the other will remain constant whatever the renal function. The dose of ampicillin and sulbactam for injection in such patients should be administered less frequently in accordance with the usual practice for ampicillin.
- Ampicillin has been found to be approximately 28% reversibly bound to human serum protein and sulbactam approximately 38% reversibly bound.
- The following average levels of ampicillin and sulbactam were measured in the tissues and fluids listed:
- Penetration of both ampicillin and sulbactam into cerebrospinal fluid in the presence of inflamed meninges has been demonstrated after IV administration of ampicillin and sulbactam for injection.
- The pharmacokinetics of ampicillin and sulbactam in pediatric patients receiving ampicillin and sulbactam for injection are similar to those observed in adults. Immediately after a 15-minute infusion of 50 to 75 mg ampicillin and sulbactam for injection/kg body weight, peak serum and plasma concentrations of 82 to 446 mcg ampicillin/mL and 44 to 203 mcg sulbactam/mL were obtained. Mean half-life values were approximately 1 hour.

## Nonclinical Toxicology
There is limited information regarding Ampicillin-Sulbactam Nonclinical Toxicology in the drug label.

# Clinical Studies
- Data from a controlled clinical trial conducted in pediatric patients provided evidence supporting the safety and efficacy of ampicillin and sulbactam for injection for the treatment of skin and skin structure infections.
- Of 99 pediatric patients evaluable for clinical efficacy, 60 patients received a regimen containing intravenous ampicillin and sulbactam for injection, and 39 patients received a regimen containing intravenous cefuroxime. This trial demonstrated similar outcomes (assessed at an appropriate interval after discontinuation of all antimicrobial therapy) for ampicillin and sulbactam for injection - and cefuroxime - treated patients:
- Most patients received a course of oral antimicrobials following initial treatment with intravenous administration of parenteral antimicrobials. The study protocol required that the following three criteria be met prior to transition from intravenous to oral antimicrobial therapy: 1) receipt of a minimum of 72 hours of intravenous therapy; 2) no documented fever for prior 24 hours; and 3) improvement or resolution of the signs and symptoms of infection.
- The choice of oral antimicrobial agent used in this trial was determined by susceptibility testing of the original pathogen, if isolated, to oral agents available. The course of oral antimicrobial therapy should not routinely exceed 14 days.

# How Supplied
- Ampicillin and Sulbactam for Injection, USP is supplied as a sterile off-white dry powder in glass vials. The following packages are available
- Vials containing 1.5 g (NDC 10019-634-01) equivalent of Ampicillin and Sulbactam for Injection, USP (1 g ampicillin as the sodium salt plus 0.5 g sulbactam as the sodium salt)
- Vials containing 3 g (NDC 10019-633-02) equivalent of Ampicillin and Sulbactam for Injection, USP (2 g ampicillin as the sodium salt plus 1 g sulbactam as the sodium salt)

## Storage
- Ampicillin and Sulbactam for Injection, USP sterile powder is to be stored at 20 to 25C

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Ampicillin-Sulbactam Patient Counseling Information in the drug label.

# Precautions with Alcohol
- Alcohol-Ampicillin sodium and sulbactam sodium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- AMPICILLIN AND SULBACTAM

# Look-Alike Drug Names
There is limited information regarding Ampicillin-Sulbactam Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price