VA Class:AM111

AHFS Class:

• Aminopenicillins 8:12.16.08

Generic Name(s):

• Ampicillin Sodium and Sulbactam Sodium

• Ampicillin Sodium

• Sulbactam Sodium

Chemical Name:

• 4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, [2 S -[2α,5α,6β( S *)]]-6-[(Aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-, mixt. with (2 S - cis )-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid 4,4-dioxide

• [2 S -[2α,5α,6β( S *)]]-6-[(Aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid monosodium salt

• (2 S - cis )-3,3-Dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0) heptane-2-carboxylic acid 4,4-dioxide

Ampicillin sodium and sulbactam sodium (ampicillin/sulbactam) is a fixed combination of the sodium salts of ampicillin (an aminopenicillin antibiotic) and sulbactam (a β-lactam β-lactamase inhibitor);1,27,30,61 sulbactam synergistically expands ampicillin's spectrum of activity against many strains of β-lactamase-producing bacteria.30,61,65,69,122,131,134,137

The fixed combination of ampicillin sodium and sulbactam sodium (ampicillin/sulbactam) is used parenterally for the treatment of skin and skin structure,1,30,64,48,58,61,86,88,90 intra-abdominal,1,30,53,57,61,64,82 and gynecologic 1,30,50,61,64,74,75,91 infections caused by susceptible bacteria. The drug also has been used parenterally for the treatment of some other infections,30,35,58,64,59,78,87,114,144 including respiratory tract infections†30,57,61,64,77,81,84,88,89,113,305 caused by susceptible bacteria.

Ampicillin/sulbactam is used principally for the treatment of infections caused by, or suspected of being caused by, susceptible β-lactamase-producing strains of staphylococci, Enterobacteriaceae, and/or Bacteroides .1 Although ampicillin/sulbactam also may be effective in the treatment of infections caused by non-β-lactamase-producing bacteria susceptible to ampicillin alone, most clinicians state that an aminopenicillin used alone is preferred to the fixed combination drug for the treatment of these infections and that ampicillin/sulbactam should be reserved for use in the treatment of infections caused by, or suspected of being caused by, β-lactamase-producing bacteria when an aminopenicillin alone would be ineffective.101,130 Ampicillin/sulbactam may be particularly useful for empiric treatment of intra-abdominal or gynecologic infections likely to involve anaerobes (e.g., mixed aerobic-anaerobic infections) or for infections suspected of being caused by both ampicillin-resistant and ampicillin-susceptible bacteria.61,130 For most other infections caused by susceptible organisms, including Staphylococcus aureus or S. epidermidis †, Bacteroides , Klebsiella pneumoniae , Escherichia coli , Proteus vulgaris †, Providencia rettgeri †, Morganella morganii †, Eikenella corrodens , or Pasteurella multocida †, ampicillin/sulbactam generally is considered an alternative to other anti-infectives.101 When used for the treatment of infections caused by Enterobacteriaceae in severely ill patients, some clinicians recommend combined therapy with ampicillin/sulbactam and an aminoglycoside.101 Because ampicillin/sulbactam is not active against Pseudomonas , the drug should not be used alone in infections known or suspected of being caused by Ps. aeruginosa .64,65,89

Prior to initiation of therapy with ampicillin/sulbactam, appropriate specimens should be obtained for identification of the causative organism(s) and in vitro susceptibility tests.1 Ampicillin/sulbactam may be started pending results of susceptibility tests if the infection is believed to be caused by β-lactamase-producing bacteria susceptible to the drug, but should be discontinued and other appropriate anti-infective therapy substituted if the organism is found to be resistant to the drug.1 If the infection is found to be caused by non-β-lactamase-producing organisms susceptible to ampicillin, some clinicians suggest that therapy should be changed to an aminopenicillin alone, unless this is impractical.101

Skin and Skin Structure Infections

Ampicillin/sulbactam is used in adults and children 1 year of age or older for the treatment of a variety of skin and skin structure infections, including wound infections, cellulitis, ulcers, abscesses, and furunculosis,1,30,48,58,61,64,71,86,88,90 caused by susceptible β-lactamase-producing strains of Staphylococcus aureus ,1,58,71,88,90 E. coli ,1,58,71,88,90 Klebsiella (including K. pneumoniae ),1,71 P. mirabilis ,1,58,71,90 Bacteroides (including B. fragilis ),1 or Acinetobacter .1 The drug also has been effective when used for the treatment of skin and skin structure infections caused by other susceptible gram-positive bacteria, including S. epidermidis †,58,71,88,90 S. warneri †,58,90 or Enterococcus faecalis †,1,71,90 or other susceptible gram-negative bacteria, including susceptible strains of Citrobacter †,71 Enterobacter †,71 or Morganella morganii †.58,90

In controlled studies in adults with serious skin and skin structure infections, ampicillin/sulbactam was at least as effective as a regimen of clindamycin with or without an aminoglycoside.30,64 Ampicillin/sulbactam therapy generally results in clinical and bacteriologic cure rates of 86-100% in adults with skin and skin structure infections caused by susceptible bacteria.30,48,58,64,71,86,88,90 In a clinical trial in pediatric patients with skin and skin structure infections, initial treatment with IV ampicillin/sulbactam was as effective as IV cefuroxime (clinical success rate of 85 or 87%, respectively); most patients were switched to an oral regimen after initial IV treatment.1 Although ampicillin/sulbactam appears to be an effective regimen for the treatment of serious skin and skin structure infections, concomitant use of an anti-infective agent that is active against Pseudomonas (e.g., an aminoglycoside) may be necessary in some of these infections.30,64 In addition, less severe skin and skin structure infections (e.g., cellulitis, impetigo, erysipelas) usually can be treated with other antibacterials that have a narrower spectrum of activity (e.g., penicillinase-resistant penicillins, erythromycin, cephalosporins).64,101

Intra-abdominal and Gynecologic Infections

Ampicillin/sulbactam is used in adults for the treatment of a variety of intra-abdominal and gynecologic infections caused by susceptible E. coli , Klebsiella (including K. pneumoniae ), Bacteroides (including B. fragilis ), or Enterobacter .1,47,49,52,53,55,57,61,75,76,82,85 Most intra-abdominal and gynecologic infections are mixed aerobic-anaerobic infections,47,52,54,55,61,75,83,91 and efficacy of ampicillin/sulbactam in these polymicrobial infections is based on the drug's broad spectrum of activity against both gram-positive and gram-negative aerobic and anaerobic bacteria and on its distribution into most tissues and fluids.47,55,75,83,91 Depending on suspected organisms and severity of the infection, addition of an aminoglycoside may be considered.64,101

Intra-abdominal Infections

Ampicillin/sulbactam has been effective when used in adults as an adjunct to surgical measures (e.g., drainage) in the treatment of appendicitis, peritonitis, perforated appendix, diverticulitis, postoperative bowel infections, small bowel infarct, intra-abdominal or retroperitoneal abscess, cholecystitis, and secondary liver infections caused by susceptible bacteria.30,53,57,61,64,82

Use of ampicillin/sulbactam in adults with intra-abdominal infections has been associated with clinical and bacteriologic cure rates of 78-96%.30,53,64,82 In a few studies in adults, ampicillin/sulbactam appeared to be at least as effective as other regimens used in the adjunctive treatment of intra-abdominal infections (e.g., clindamycin or metronidazole and an aminoglycoside, cefoxitin with or without an aminoglycoside, imipenem and cilastatin sodium) and generally was associated with fewer adverse effects than these other regimens.30,53,82 However, in at least one study, ampicillin/sulbactam was less effective than a regimen of clindamycin and gentamicin in the treatment of patients with perforated or gangrenous appendicitis; most treatment failures in patients receiving ampicillin/sulbactam were the result of overgrowth with Pseudomonas .64 Some clinicians suggest that, although ampicillin/sulbactam alone may be as effective as multiple-drug regimens for the treatment of less severe intra-abdominal infections, an aminoglycoside probably should be used concomitantly with the drug for empiric therapy in more serious intra-abdominal infections, including hospital-acquired infections, pending results of in vitro susceptibility tests.64,101

Gynecologic Infections

Ampicillin/sulbactam is used in adults for the treatment of gynecologic infections including endometritis (after abortion or curettage), postpartum endomyometritis, posthysterectomy pelvic cellulitis, vaginal cuff abscess, salpingitis, tubo-ovarian abscess, pelvic peritonitis or abscess, surgical wound sepsis, uncomplicated acute pelvic inflammatory disease (PID), or complicated PID that may include pelvic peritonitis, tubo-ovarian abscesses, endometritis, or posthysterectomy pelvic cellulitis.49,50,52,54,55,56,61,64,74,75,76,83,91,344 The clinical and bacteriologic cure rates of ampicillin/sulbactam in the treatment of these gynecologic infections have been 83-100%.49,50,52,55,64,74,75,83,91

In several studies in patients with mixed aerobic-anaerobic gynecologic infections, ampicillin/sulbactam was as effective as cefoxitin or cefotetan or multiple-drug regimens such as clindamycin or metronidazole and an aminoglycoside in the treatment of these infections49,56,64,76,91 and generally was associated with fewer adverse effects.55 The fact that ampicillin/sulbactam generally is considered to be inactive against Mycoplasma and to have incomplete inhibitory activity against Chlamydia should be considered if the drug is used in the treatment of gynecologic infections,49,64,75,83,91 and concomitant tetracycline (e.g., doxycycline) or, alternatively, macrolide therapy probably should be included if there is a possibility that these organisms are involved in the gynecologic infection being treated.55,64,75,83,91

The US Centers for Disease Control and Prevention (CDC) states that a regimen of IV ampicillin/sulbactam with oral or IV doxycycline is an alternative parenteral regimen for the treatment of PID and provides good coverage against Chlamydia trachomatis , N. gonorrhoeae , and anaerobes for women with tuboovarian abscess.344 CDC states that the preferred parenteral regimens for the treatment of PID are a regimen of IV ceftriaxone with oral or IV doxycycline and oral or IV metronidazole or a regimen of IV cefotetan (or IV cefoxitin) with oral or IV doxycycline.344 For further information on the treatment of PID, see Uses: Pelvic Inflammatory Disease in the Cephalosporins General Statement 8:12.06.

Gonorrhea and Associated Infections

Ampicillin/sulbactam has been used for the treatment of uncomplicated gonorrhea, including infections caused by penicillinase-producing strains of Neisseria gonorrhoeae (PPNG) and nonpenicillinase-producing strains of the organism.30,47,61,80,94,95 However, CDC has not recommended use of penicillins for the treatment of gonococcal infections for over 30 years because of the widespread prevalence of PPNG resistant to penicillins.265,344 Ceftriaxone is the drug of choice for the treatment of gonococcal infections.344

Respiratory Tract Infections

Ampicillin/sulbactam has been used for the treatment of lower respiratory tract infections†, including pneumonia,57,61,77,84,88,89,113 bronchitis,57,61,84,88,89 acute exacerbations of chronic bronchitis,61,84,88 and bronchiectasis84,88 caused by susceptible staphylococci, streptococci, Haemophilus influenzae , H. parainfluenzae , Moraxella catarrhalis , E. coli , Klebsiella , or Proteus mirabilis .77,81,84,88,89 Ampicillin/sulbactam therapy is reported to have clinical and bacteriologic cure rates of 58-100% when used for the treatment of lower respiratory tract infections.64,47,61,81,84,88,89

Some clinicians suggest that ampicillin/sulbactam is an effective alternative for the treatment of lower respiratory tract infections known or suspected of being caused by ampicillin-resistant organisms, including community-acquired or nosocomial pneumonia, chronic obstructive pulmonary disease, and exacerbation of severe chronic bronchitis in hospitalized patients.64,77,81,84,89,101 Overgrowth with Ps. aeruginosa has been reported in some patients receiving ampicillin/sulbactam alone for the treatment of respiratory infections.89

The American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) recommend a regimen of ampicillin/sulbactam with a macrolide (azithromycin or clarithromycin) as one of several options for empiric treatment of nonsevere community-acquired pneumonia (CAP) in hospitalized adults who do not have risk factors for methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA) or Ps. aeruginosa .305

Ampicillin/sulbactam has been effective for the treatment of respiratory tract infections† (e.g., pneumonia, tracheobronchitis) or bacteremia caused by strains of Acinetobacter baumannii that were resistant to imipenem and cilastatin sodium as well as most other anti-infectives tested.93 However, other anti-infectives (e.g., imipenem and cilastatin sodium or meropenem with or without an aminoglycoside) are preferred in the treatment of infections caused by susceptible Acinetobacter .4,101

Ampicillin/sulbactam has been used in a limited number of adults and children for the treatment of various ear, nose, and throat infections† including tonsillitis, sinusitis, rhinitis, pharyngitis, acute epiglottitis,61,88,112 and acute and chronic otitis media caused by susceptible staphylococci, streptococci, Klebsiella , Proteus , M. catarrhalis , or H. influenzae .88,112 Although the drug generally was effective in the treatment of these infections,88,112 other anti-infectives are considered drugs of choice for these infections.4

Bone and Joint Infections

Ampicillin/sulbactam has been used for the treatment of bone and joint infections†, including osteomyelitis and/or septic arthritis, caused by susceptible β-lactamase-producing organisms.30,58,61,64,90,114

Endocarditis

Ampicillin/sulbactam has been used for the treatment of endocarditis†.61 Although other regimens are preferred, the American Heart Association (AHA) states that a regimen of ampicillin/sulbactam and an aminoglycoside can be considered as an alternative for the treatment of endocarditis involving native valves or prosthetic valves or other prosthetic material caused by β-lactamase-producing Enterococcus .450 AHA also states that ampicillin/sulbactam may be considered an option for the treatment of endocarditis cause by fastidious gram-negative bacilli of the HACEK group (i.e., Haemophilus , Aggregatibacter , Cardiobacterium hominis , Eikenella corrodens , Kingella ).450,452

Current guidelines from AHA should be consulted for information on management of endocarditis.450,452

Meningitis

Ampicillin/sulbactam has been used for the treatment of meningitis† caused by H. influenzae , N. meningitidis , or S. pneumoniae .35,59,61,78 In one study in infants and children, ampicillin sodium (400 mg/kg daily) and sulbactam sodium (50 mg/kg daily) was as effective as a regimen of IV chloramphenicol (100 mg/kg daily) and IV ampicillin (400 mg/kg daily) for the treatment of meningitis caused by H. influenzae , N. meningitidis , or S. pneumoniae .59 Although some clinicians suggest that ampicillin/sulbactam therapy may be an effective alternative to therapy with ampicillin and chloramphenicol in infants and children for the treatment of meningitis caused by H. influenzae , S. pneumoniae , or N. meningitidis and might be especially useful in areas where ampicillin- and chloramphenicol-resistant strains have been reported,59,87 other drugs are preferred for the treatment of CNS infections.61,101 Treatment failures have been reported when ampicillin/sulbactam was used in patients with meningitis caused by K. pneumoniae .35

Urinary Tract Infections

Ampicillin/sulbactam has been used for the treatment of uncomplicated urinary tract infections† caused by susceptible bacteria, including S. epidermidis , E. coli , K. pneumoniae , or P. mirabilis .30,61,113,144 Although the drug may be effective for these infections,144 treatment failures have been reported.101 Ampicillin/sulbactam is unlikely to be effective for the treatment of urinary tract infections caused by extended-spectrum β-lactamase-producing (ESBL) strains of E. coli , K. pneumoniae , and P. mirabilis .61

Perioperative Prophylaxis

Ampicillin/sulbactam has been used for perioperative prophylaxis† to reduce the incidence of infections in patients undergoing certain contaminated or potentially contaminated surgery† (e.g., GI or biliary tract surgery, vaginal or abdominal hysterectomy).30,51,60,61,64,96,97,98,99

Ampicillin/sulbactam is recommended as one of several options for perioperative prophylaxis in patients undergoing biliary tact surgery, colorectal surgery, gynecologic and obstetric procedures (e.g., vaginal, abdominal, or laparoscopic hysterectomy), head and neck surgery (involving incisions through oral or pharyngeal mucosa), non-cardiac thoracic surgery (e.g., lobectomy, pneumonectomy, lung resection, thoracotomy), or urologic procedures involving implanted prosthesis.96,97 Local susceptibility patterns of potential pathogens should be considered when selecting ampicillin/sulbactam for perioperative prophylaxis in procedures that involve exposure to bowel flora (e.g., E. coli ) that may be resistant to the drug.96,97

In adults undergoing biliary tract surgery, a single 3-g dose of ampicillin/sulbactam (2 g of ampicillin and 1 g of sulbactam) was as effective as a single dose of cefazolin (1 g)64 or cefoxitin (2 g)99 in preventing postoperative wound infection. A single 1.5-g dose of ampicillin/sulbactam (1 g of ampicillin and 0.5 g of sulbactam) has been used effectively for prophylaxis in various gynecologic procedures, including abdominal or vaginal hysterectomy.51 In a study in adults, ampicillin/sulbactam was as effective as cefoxitin for prevention of postoperative infections in patients undergoing colorectal or transurethral surgery.30 In a study in children 5-13 years of age undergoing appendectomy, a single dose of ampicillin/sulbactam (15 mg/kg of ampicillin and 7.5 mg/kg of sulbactam) given IV at the time of anesthesia was as effective as a single dose of metronidazole (7.5 mg/kg) and cefotaxime (25 mg/kg) in the prevention of postoperative sepsis; therapy with the drug was continued for 72 hours after surgery in patients with gangrenous or perforated appendixes at the time of surgery.60 Ampicillin/sulbactam also has been used with some success for perioperative prophylaxis in patients with head and neck cancer undergoing surgery.139,145 Although in one study ampicillin/sulbactam appeared to be as effective as a regimen of clindamycin and amikacin in such patients, patients who received ampicillin/sulbactam had a higher incidence of postoperative infection with anaerobes than patients who received the other regimen.139

Reconstitution and Administration

The fixed combination of ampicillin sodium and sulbactam sodium (ampicillin/sulbactam) is administered by IM or slow IV injection or by IV infusion.1 A combination of ampicillin and sulbactam also have been administered orally as a preparation containing the drugs covalently linked as a double ester in a single molecule (sultamicillin; CP-49,952), but an oral dosage form is not commercially available in the US.65,66,138,140

IM or IV solutions of ampicillin/sulbactam should be allowed to stand after dissolution to allow any foaming to dissipate in order to permit visual inspection for complete solubilization.1

IM Injection

For IM injection, vials labeled as containing 1.5 or 3 g of ampicillin/sulbactam should be reconstituted with 3.2 or 6.4 mL, respectively, of sterile water for injection or 0.5 or 2% lidocaine hydrochloride injection to provide a solution containing 375 mg of the fixed combination per mL (250 mg of ampicillin and 125 mg of sulbactam per mL).1 Reconstituting ampicillin/sulbactam with lidocaine hydrochloride can minimize the local pain associated with IM injection of the drug.47,64,65,92

IM injections of ampicillin/sulbactam should be made deeply into a large muscle mass within 1 hour after reconstitution.1

IV Injection or Infusion

For IV administration, vials labeled as containing 1.5 or 3 g of ampicillin/sulbactam should be reconstituted with sterile water for injection to yield solutions containing 375 mg of the drug per mL (250 mg of ampicillin and 125 mg of sulbactam per mL).1 An appropriate volume of reconstituted drug then should be diluted immediately with a compatible IV solution to yield solutions containing 3-45 mg of the drug per mL (2-30 mg of ampicillin and 1-15 mg of sulbactam per mL).1

IV injections of ampicillin/sulbactam should be given slowly over at least 10-15 minutes.1

IV infusions of ampicillin/sulbactam should be administered over 15-30 minutes.1

Dosage

Ampicillin/sulbactam is commercially available for parenteral administration as a sterile powder containing a 2:1 ratio of ampicillin to sulbactam.1 The ampicillin component is provided as ampicillin sodium and the sulbactam component is provided as sulbactam sodium; potency of each component is expressed in terms of the base.1

Dosage of ampicillin/sulbactam usually is expressed in terms of the total (sum) of the dosage of both components of the fixed combination (i.e., dosage of ampicillin plus dosage of sulbactam);1 pediatric dosage of ampicillin/sulbactam also has been expressed in terms of the ampicillin content.5

The manufacturer's dosage recommendations for adults are the same for IM and IV administration;1 however, higher serum concentrations usually are attained with IV administration of the drug,1,30,33,46,63,65,67 and this route generally is preferred, especially for severe infections.101,102

Adult Dosage

Intra-abdominal, Gynecologic, or Skin and Skin Structure Infections

The usual adult IM or IV dosage of ampicillin/sulbactam for the treatment of skin and skin structure, intra-abdominal, or gynecologic infections caused by susceptible organisms ranges from 1.5 g (1 of ampicillin and 0.5 g of sulbactam) to 3 g (2 g of ampicillin and 1 g of sulbactam) every 6 hours.1

The maximum adult dosage of sulbactam recommended by the manufacturer is 4 g (i.e., 8 g of ampicillin and 4 g of sulbactam in fixed combination) daily.1 While comparative efficacy of various dosages in the usual range have not been established,101 patients in many of early clinical studies received a maximum of 3 g (2 g of ampicillin and 1 g of sulbactam).30,48,49,53,58,65,89,90,91,101

Pelvic Inflammatory Disease

For the treatment of pelvic inflammatory disease (PID), CDC recommends that IV ampicillin/sulbactam be given in a dosage of 3 g (2 g of ampicillin and 1 g of sulbactam) every 6 hours in conjunction with doxycycline (100 mg orally or IV every 12 hours).344 The parenteral regimen may be discontinued 24-48 hours after there is clinical improvement and treatment switched to an oral regimen of doxycycline (100 mg twice daily) and metronidazole (500 mg twice daily) to complete 14 days of therapy.344

Respiratory Tract Infections

For empiric treatment of nonsevere community-acquired pneumonia† (CAP) in hospitalized adults without risk factors for MRSA or Ps. aeruginosa , ATS and IDSA recommend that ampicillin/sulbactam be given in a dosage of 1.5 g (1 of ampicillin and 0.5 g of sulbactam) to 3 g (2 g of ampicillin and 1 g of sulbactam) every 6 hours in conjunction with azithromycin (500 mg daily) or clarithromycin (500 mg twice daily).305

Endocarditis

If IV ampicillin/sulbactam is used as an alternative for the treatment of endocarditis† cause by β-lactamase-producing Enterococcus , AHA recommends a dosage of 3 g (2 g of ampicillin and 1 g of sulbactam) every 6 hours given in conjunction with an aminoglycoside.450

Perioperative Prophylaxis

For perioperative prophylaxis†, a dosage of 3 g (2 g of ampicillin and 1 g of sulbactam) given within 60 minutes prior to initial incision is recommended.96,97

Although additional intraoperative doses may be given every 2 hours during prolonged procedures,96,97 postoperative doses generally are not recommended.96,97

Pediatric Dosage

The manufacturer states that pediatric patients who weigh 40 kg or more may receive the usual adult dosage of ampicillin/sulbactam.1

The American Academy of Pediatrics (AAP) suggests that pediatric patients beyond the neonatal period† may receive a dosage of 100-200 mg/kg of ampicillin daily (as ampicillin/sulbactam) in 4 divided doses for the treatment of severe infections.5 A dosage of 200-400 mg/kg of ampicillin daily (as ampicillin/sulbactam) in 4 divided doses is recommended for meningitis or severe infections caused by resistant S. pneumoniae .5

For the treatment of skin and skin structure infections in pediatric patients 1 year of age or older, the manufacturer recommends a dosage of 300 mg/kg daily (200 mg of ampicillin and 100 mg of sulbactam) given by IV infusion in equally divided doses every 6 hours.1 The manufacturer recommends that the duration of IV ampicillin/sulbactam therapy in pediatric patients not exceed 14 days; in clinical studies, most children received an oral anti-infective after an initial regimen of IV ampicillin/sulbactam.1

Pelvic Inflammatory Disease

For the treatment of PID in adolescents, CDC recommends that IV ampicillin/sulbactam be given in a dosage of 3 g (2 g of ampicillin and 1 g of sulbactam) every 6 hours in conjunction with doxycycline (100 mg orally or IV every 12 hours).344 The parenteral regimen may be discontinued 24-48 hours after there is clinical improvement and treatment switched to an oral regimen of doxycycline (100 mg twice daily) and metronidazole (500 mg twice daily) to complete 14 days of therapy.344

Perioperative Prophylaxis

For perioperative prophylaxis†, pediatric patients may receive 50 mg/kg of ampicillin (as ampicillin/sulbactam) within 60 minutes prior to initial incision.97

Although additional intraoperative doses may be given every 2 hours during prolonged procedures,96,97 postoperative doses generally are not recommended.96,97

Dosage in Renal Impairment

Because the pharmacokinetics of both ampicillin and sulbactam are affected to the same degree in patients with renal impairment, the recommended 2:1 ratio of the drugs remains the same regardless of the degree of renal impairment.1

The manufacturer recommends that patients with renal impairment receive the usually recommended doses of ampicillin/sulbactam, but doses should be given less frequently than usual and the dosing intervals should be based on the patient's creatinine clearance.1 The manufacturer recommends that patients with creatinine clearances of 30 mL/minute per 1.73 m² or greater receive 1.5 g (1 g of ampicillin and 0.5 g of sulbactam) to 3 g (2 g of ampicillin and 1 g of sulbactam) of the drug every 6-8 hours and that patients with creatinine clearances of 15-29 or 5-14 mL/minute per 1.73 m² receive these doses every 12 or 24 hours, respectively.1

Because ampicillin and sulbactam are removed by hemodialysis, some clinicians suggest that patients undergoing hemodialysis receive 1.5 g (1 g of ampicillin and 0.5 g of sulbactam) to 3 g (2 g of ampicillin and 1 g of sulbactam) once every 24 hours and that the dose preferably should be given immediately after dialysis.34,72

The fixed combination of ampicillin sodium and sulbactam sodium (ampicillin/sulbactam) generally is well tolerated.1,30,47,49,57,58,61,74,88 The frequency and severity of adverse effects reported with the commercially available fixed-combination preparation for parenteral administration generally are similar to those reported with parenteral ampicillin alone.57,58,88,92 With the exception of local reactions at the IM injection site,1 adverse effects generally have been reported in 10% or less of patients receiving parenteral ampicillin/sulbactam,30,47,88 and have been severe enough to require discontinuance of the drug in less than 1% of patients.30,88,92 The most frequent adverse effects of parenteral ampicillin/sulbactam are pain at the IM or IV injection site,30,57,77,88,92 diarrhea,1,30 and rash.1

Parenteral sulbactam sodium alone is associated with few adverse effects, principally pain at the injection site and diarrhea.30,65

For information on adverse effects reported with ampicillin and other aminopenicillins as well as the usual precautions and contraindications associated with these drugs, see Cautions in the Aminopenicillins General Statement 8:12.16.08.

Dermatologic and Sensitivity Reactions

Rash1,30,74,88 has been reported in less than 2% of patients receiving parenteral ampicillin/sulbactam.1,30 Urticaria,1,74 pruritus,30,88 dry skin,30 and erythema1,30 also have been reported with the drug. Severe skin reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, acute generalized exanthematous pustulosis (AGEP), erythema multiforme, and exfoliative dermatitis, have been reported in patients receiving ampicillin/sulbactam or ampicillin.1

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving penicillin therapy.1 (See Cautions: Precautions and Contraindications.) Systemic allergic reactions have been reported during parenteral ampicillin/sulbactam therapy and required discontinuance of the drug.55,71

Hepatotoxicity

Ampicillin/sulbactam has been associated with hepatic dysfunction, including hepatitis and cholestatic jaundice.1 Although hepatotoxicity usually is reversible, deaths have been reported.1

Transient increases in serum concentrations of AST (SGOT) and/or ALT (SGPT),1,30,47,49,53,71,74 alkaline phosphatase,1 LDH,1,30,53,71 creatine kinase (CK, creatine phosphokinase, CPK),30,74 bilirubin,1,53 and γ-glutamyltransferase (γ-glutamyltranspeptidase, GT, GGTP) have been reported in up to 11% of patients receiving parenteral ampicillin/sulbactam.1,30,47

GI Effects

Diarrhea,1,30,47,50,53,58 nausea,1,30,50,58,88 and vomiting1,50,88 have been reported in up to 4% of patients receiving parenteral ampicillin/sulbactam.1,30,47,50 Flatulence,1,30 abdominal discomfort or distension,1,30 rectal bleeding,30 and glossitis1,30 have been reported in less than 1% of patients receiving the drug parenterally. Gastritis,1 stomatitis,1 and black or hairy tongue1 have been reported in patients receiving ampicillin/sulbactam or ampicillin.

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly known as Clostridium difficile ).1,302 C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with parenteral ampicillin/sulbactam.1 C. difficile produces toxins A and B which contribute to development of CDAD;1,302 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1 (See Cautions: Precautions and Contraindications.)

Local Reactions

The most frequent adverse effect of parenteral ampicillin/sulbactam is pain at the injection site.1,30,47,88 Pain at the injection site has been reported in 3-16% of patients receiving the drug IM1,30,47,88 and in up to 3% of patients receiving the drug IV.1,30 Pain following IM administration of ampicillin/sulbactam may be minimized or avoided if 0.5 or 2% lidocaine hydrochloride is used as the diluent when preparing IM injections of the drug.92,47,65 Phlebitis,1,30,50 thrombophlebitis,1,30 and inflammation at the injection site also have been reported in up to 3% of patients receiving the drug IV.1,30

Other Adverse Effects

Decreased concentrations of serum albumin and total protein have been reported.1 Increased BUN1 and serum creatinine concentrations,1 presence of red blood cells and hyaline casts in urine,1 urine retention,1,30 dysuria,1,30 and hematuria1 have been reported in less than 1% of patients receiving the drug.1

Decreased hemoglobin concentration,1,74 hematocrit,1,74 and erythrocyte,1,74 leukocyte,1 neutrophil,1 lymphocyte,1 and platelet1 counts and increased lymphocyte,1 monocyte,1 basophil,1 eosinophil,1,30,49,74,88 and platelet1 counts have been reported in patients receiving parenteral ampicillin/sulbactam. Although some of these hematologic changes may represent hypersensitivity reactions, many have not been attributed directly to the drug.1

Other adverse effects that have been reported in less than 1% of patients receiving parenteral ampicillin/sulbactam include headache,1,30 fatigue,1,30 malaise,1,30,88 confusion,30 dizziness,74,88 changes in smell or taste perception,30 chest pain or tightness,30 edema,1,30 facial swelling,1,30 chills,1 throat tightness,1 substernal pain,1 epistaxis,1,30 and mucosal bleeding.1

Reversible glycogenosis has been reported in animals receiving sulbactam.1 Diffuse hepatocellular glycogen deposits associated with increases in liver enzymes and hepatomegaly have occurred in rats and dogs that received high doses of sulbactam for prolonged periods of time.30,65 These adverse effects in animals were dose and time dependent and are not expected to occur in humans with the usually recommended ampicillin/sulbactam dosages and corresponding plasma concentrations of the drug attained during the relatively short periods of therapy.1,30,65 Similar glycogen deposits have not been reported in humans receiving ampicillin/sulbactam, although patients with preexisting liver dysfunction, diabetes mellitus, hypoglycemia, or glycogen storage disease were excluded from most early clinical studies of the drug.65 In subsequent studies in patients with type I or II diabetes mellitus, sulbactam given at the usually recommended dosages did not appear to affect glucose mobilization or regulation.30,65

Precautions and Contraindications

Ampicillin/sulbactam is contraindicated in individuals with a history of serious hypersensitivity reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) to ampicillin, sulbactam, or other beta-lactam antibacterials (e.g., penicillins, cephalosporins).1

Ampicillin/sulbactam also is contraindicated in individuals with a history of cholestatic jaundice/hepatic dysfunction associated with the drug.1

Ampicillin/sulbactam shares the toxic potentials of the penicillins, including the risk of hypersensitivity reactions, and the usual precautions of penicillin therapy should be observed.1 Prior to initiation of therapy with ampicillin/sulbactam, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens.1 (See Cautions: Hypersensitivity Reactions, in the Natural Penicillins General Statement 8:12.16.04.) If an allergic reaction occurs, ampicillin/sulbactam should be discontinued and appropriate therapy instituted.1

Because a high percentage of patients with infectious mononucleosis have developed rash during therapy with aminopenicillins (see Cautions: Ampicillin Rash, in the Aminopenicillins General Statement 8:12.16.08), the manufacturer states that ampicillin/sulbactam should not be used in patients mononucleosis.1

Because hepatotoxicity has been associated with ampicillin/sulbactam, hepatic function should be monitored at regular intervals if the drug is used in patients with hepatic impairment.1

As with use of other anti-infectives, use of ampicillin/sulbactam may result in overgrowth of nonsusceptible organisms, especially Pseudomonas or Candida .1 If superinfection occurs, the drug should be discontinued and appropriate therapy initiated.1

Because CDAD has been reported with nearly all anti-infectives, including ampicillin/sulbactam, it should be considered in the differential diagnosis of patients who develop diarrhea during or after ampicillin/sulbactam therapy.1 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1 If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued as soon as possible.302 Patients should be managed with appropriate anti-infective therapy directed against C. difficile (e.g., fidaxomicin, vancomycin, metronidazole), supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.1,302 Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued; however, it is important to contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1

To reduce development of drug-resistant bacteria and maintain effectiveness of ampicillin/sulbactam and other antibacterials, ampicillin/sulbactam should be used only for the treatment of infections proven or strongly suspected to be caused by susceptible bacteria.1 Prescribing ampicillin/sulbactam in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.1

Patients should be advised that antibacterials (including ampicillin/sulbactam) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with ampicillin/sulbactam or other antibacterials in the future.1

When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.1 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.1

Information on test methods and quality control standards for in vitro susceptibility testing of antibacterials and specific interpretive criteria for such testing recognized by FDA is available at [Web].1,303 For most antibacterials, including ampicillin/sulbactam, FDA recognizes the standards published by the Clinical and Laboratory Standards Institute (CLSI).303,304 (See In Vitro Susceptibility Testing under Spectrum.)

For a more complete discussion of these and other precautions associated with the use of ampicillin, see Cautions: Precautions and Contraindications, in the Aminopenicillins General Statement 8:12.16.08.

Pediatric Precautions

Safety and efficacy of IV ampicillin/sulbactam have been established for the treatment of skin and skin structure infections in children 1 year of age or older.1 Use of the drug for this use 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.1

Safety and efficacy of IV ampicillin/sulbactam for the treatment of intra-abdominal infections or any other indication in pediatric patients have not been established.1

Safety and efficacy of IM administration of ampicillin/sulbactam have not been established for any indication in pediatric patients.1

Various combinations of ampicillin and sulbactam (e.g., 1.3:1, 2:1, 3:1, 4:1, 7:1, and 8:1 ratios of ampicillin to sulbactam) have been administered IM or IV to neonates and children 1 month to 17 years of age without unusual adverse effects.35,40,47,59,60,87,112,113,114 The most frequent adverse effects of parenteral ampicillin/sulbactam in children are transient increases in serum liver enzyme concentrations, diarrhea, and rash.59,87,112,113,114

Geriatric Precautions

Although serum half-lives of ampicillin and sulbactam are slightly longer in geriatric adults than in younger adults,31 dosage of ampicillin/sulbactam does not need to be modified in geriatric patients with renal function normal for their age.66 In geriatric adults with renal impairment, doses and/or frequency of administration of ampicillin/sulbactam should be modified in response to the degree of renal impairment.1

Mutagenicity and Carcinogenicity

Studies have not been performed to date to evaluate the mutagenic or carcinogenic potential of ampicillin/sulbactam.1

Pregnancy, Fertility, and Lactation

Pregnancy

There are no adequate or controlled studies using ampicillin/sulbactam in pregnant women.1 Reproduction studies in mice, rats, and rabbits using ampicillin and sulbactam doses up to 10 times the usual human dose have not revealed evidence of impaired fertility or harm to the fetus due to ampicillin/sulbactam.1 Because animal reproduction studies are not always predictive of human response, ampicillin/sulbactam should be used during pregnancy only when clearly needed.1

Although the clinical importance is unclear, administration of ampicillin alone to pregnant women has resulted in a transient decrease in plasma concentrations of total conjugated estriol, estriol glucuronide, conjugated estrone, and estradiol; this effect also may occur following administration of ampicillin/sulbactam.1 IV administration of ampicillin to guinea pigs has resulted in decreased uterine tone and decreased frequency, height, and duration of uterine contractions.1 It is not known whether use of ampicillin/sulbactam in humans during labor or delivery could have any immediate or delayed adverse effects on the fetus, prolong the duration of labor, or increase the likelihood of forceps delivery, other obstetrical intervention, or resuscitation of the neonate.1

Lactation

Because ampicillin and sulbactam are distributed into milk in low concentrations, ampicillin/sulbactam should be used with caution in nursing women.1

For further information on these and other drug interactions reported with aminopenicillins, see Drug Interactions in the Aminopenicillins General Statement 8:12.16.08. In addition, while not all drug interactions reported with other penicillins have been reported with aminopenicillins, the possibility that they could occur with these drugs should be considered.101

Aminoglycosides

The antibacterial activity of aminoglycosides and penicillins may be additive or synergistic in vitro against some organisms.11,116,282,450 In vitro and animal studies indicate that a synergistic bactericidal effect can occur against some strains of enterococci when ampicillin is used in conjunction with amikacin, gentamicin, streptomycin, or tobramycin.11,116,282,450

Ampicillin is potentially physically and/or chemically incompatible with aminoglycosides in vitro.70,300 In one in vitro study, sulbactam concentrations of 25 mcg/mL had no appreciable affect on aminoglycosides in serum at 37°C;70 however, at concentrations of 75 mcg/mL, sulbactam inactivated tobramycin (but not other aminoglycosides tested) and, at concentrations of 200 mcg/mL or greater (with or without ampicillin), sulbactam inactivated amikacin, gentamicin, and tobramycin.70 Some clinicians suggest that in vivo inactivation of aminoglycosides by sulbactam is unlikely to occur since sulbactam concentrations of 25 mcg/mL usually are not achieved clinically.70

Allopurinol

An increased incidence of rash reportedly occurs in patients with hyperuricemia who are receiving allopurinol and concomitant ampicillin compared with those receiving either drug alone.1,14,19,30 It is unclear whether this increased incidence of rash is caused by concomitant use of the drug or the hyperuricemia present in these patients.1,14,30 The manufacturer states that there are no data to date on concomitant use of allopurinol with ampicillin/sulbactam.1

Methotrexate

Concomitant use of methotrexate and penicillins may reduce the renal clearance of methotrexate, resulting in increased serum concentrations of methotrexate and increased hematologic and GI toxicity.109 Patients should be carefully monitored if methotrexate and penicillins are used concomitantly.109

Probenecid

Oral probenecid administered shortly before or concomitantly with the fixed combination of ampicillin sodium and sulbactam sodium (ampicillin/sulbactam) competitively inhibits renal tubular secretion of both ampicillin and sulbactam and produces higher and prolonged serum concentrations of the drugs.1,30,33,65 The serum half-life of sulbactam may be increased by 18-45% by concomitant probenecid.33,92

Laboratory Test Interferences

For more complete information on these and other laboratory test interferences reported with penicillins, see Laboratory Test Interferences in the Natural Penicillins General Statement 8:12.16.04. Although not all laboratory test interferences reported with other penicillins have been reported with ampicillin, the possibility that these interferences could occur with any of the aminopenicillins should be considered.

Ampicillin can interfere with urinary glucose determinations using cupric sulfate (e.g., Benedict's solution, Clinitest^®), but does not affect glucose oxidase methods (e.g., Clinistix^®, Tes-Tape^®).1

Acute Toxicity

Overdosage of ampicillin/sulbactam would be expected to produce manifestations that principally are extensions of the adverse reactions reported with the drug.101 The fact that high CSF concentrations of β-lactam antibiotics may cause neurologic effects, including seizures, should be considered.1 Because ampicillin and sulbactam are both removed from the circulation by hemodialysis,1,34 these procedures may enhance elimination of the drug from the body if overdosage occurs in patients with impaired renal function; these procedures probably are unnecessary in patients with normal renal function.101

Mechanism of Action

The fixed combination of ampicillin sodium and sulbactam sodium (ampicillin/sulbactam) usually is bactericidal in action.1,61,119,131,132,137 Concurrent administration of sulbactam does not alter the mechanism of action of ampicillin.30,65,92,119 However, because sulbactam has a high affinity for and binds to certain β-lactamases that generally inactivate ampicillin by hydrolyzing the β-lactam ring, concurrent administration of the drug with ampicillin results in a synergistic bactericidal effect which expands the spectrum of activity of ampicillin against many strains of β-lactamase-producing bacteria that are resistant to ampicillin alone.1,30,65,69,117,119,131,134,137,143 For information on the mechanism of action of ampicillin, see Mechanism of Action in the Natural Penicillins General Statement 8:12.16.04 and in the Aminopenicillins General Statement 8:12.16.08.

Sulbactam is a β-lactam β-lactamase inhibitor that is active against a wide range of bacterial β-lactamases and acts as an irreversible inhibitor.27,61,65,66,92,115,117,119,134,137,143 The drug is considered a “suicide inhibitor”27,65,92,134,143 because the interaction between sulbactam and target β-lactamases causes both the drug and the enzyme to be incapable of further action.27,65,92,134,143 Sulbactam inhibition of β-lactamases is concentration and time dependent.65,134,143 At low sulbactam concentrations, a first-order reaction occurs and at high concentrations a zero-order reaction occurs.65 Results of in vitro studies indicate that ampicillin to sulbactam ratios of 2:1, 1:1, or 1:2 result in optimal β-lactamase inhibition and antibacterial activity.30,65,119,132

Sulbactam inactivates both plasmid- and chromosome-mediated β-lactamases.27,30,92,119,133,134,143 In vitro studies indicate that sulbactam generally inhibits staphylococcal β-lactamases30,64,65,92,137 and β-lactamases classified as Richmond-Sykes types II, III (TEM type, HSV-1), IV, V (PSE and OXA types), and VI.30,64,65,92,119,133 The drug generally does not inhibit inducible, chromosomally mediated cephalosporinases classified as Richmond-Sykes type I,30,64,65,92,115,119,129,133 which may be produced by Pseudomonas aeruginosa , Citrobacter , Enterobacter , and Serratia .64,65

In addition to its affinity for bacterial β-lactamases, sulbactam has an affinity for and binds to some bacterial penicillin-binding proteins (PBPs).30,61,64,65,134 PBPs are the target enzymes of β-lactam antibiotics and this binding may be the mechanism of sulbactam's intrinsic antibacterial activity against some organisms.30,61,64,65,134 It also may contribute to the synergistic bactericidal effect that occurs between sulbactam and ampicillin or other β-lactam anti-infectives.65,134 Sulbactam has a strong affinity for PBP 1a of Proteus mirabilis and Escherichia coli and PBP 2 of Acinetobacter .30,65,134 The drug has a lesser affinity for PBPs of Staphylococcus aureus , PBP 1a of E. coli , and PBP 2 of E. coli o P. mirabilis .30,134

The minimum bactericidal concentration (MBC) of ampicillin/sulbactam for ampicillin-resistant strains of S. aureus , Haemophilus influenzae , and Bacteroides fragilis generally is only 1-2 times higher than the minimum inhibitory concentration (MIC);30,119,137,141 however, the MBC may be 8 times higher than the MIC for some strains.141

Unlike clavulanic acid, sulbactam generally does not induce production of type I chromosomally mediated cephalosporinases in Pseudomonas 119,135 or Enterobacteriaceae, including Citrobacter ,129,135 Enterobacter ,115,118,129,135 Morganella ,118,129,135 and Serratia marcescens .129,135

Spectrum

The fixed combination of ampicillin sodium and sulbactam sodium (ampicillin/sulbactam) has a wide spectrum of activity and is active in vitro against many gram-positive and -negative aerobic and anaerobic bacteria.30,61,65,92,119,132 Ampicillin/sulbactam is active in vitro against organisms susceptible to ampicillin alone.1,30,65,119,132 In addition, because sulbactam can inhibit certain β-lactamases that generally inactivate ampicillin, ampicillin/sulbactam is active in vitro against many β-lactamase-producing organisms that are resistant to ampicillin alone,1,27,30,61,65,69,117,119,130,131,132,137 including ampicillin-resistant strains of staphylococci, Haemophilus , Neisseria , and Bacteroides .30,61,119,132

Sulbactam alone has some intrinsic antibacterial activity against certain organisms.1,27,30,64,61,65,69,119,132,134,137,143 In vitro, sulbactam concentrations of 0.1-4 mcg/mL inhibit many strains of Neisseria meningitidis , nonpenicillinase- and penicillinase-producing N. gonorrhoeae , non-β-lactamase-producing Moraxella catarrhalis ,143 and some strains of Acinetobacter .64,65,69,92,119,132,137,143 In addition, sulbactam concentrations of 8-16 mcg/mL inhibit some strains of Bacteroides and Legionella in vitro.119 However, sulbactam concentrations of 25 mcg/mL or greater generally are required for in vitro inhibition of other gram-positive or -negative bacteria, and the drug is not therapeutically useful alone.69,132

In Vitro Susceptibility Testing

When in vitro susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI), clinical isolates identified as susceptible are inhibited by drug concentrations usually achievable when the recommended dosage is used for the site of infection, resulting in likely clinical efficacy.304 Clinical isolates identified as intermediate have MICs or zone diameters that approach usually attainable blood and tissue concentrations and/or for which response rates may be lower than response rates for isolates identified as susceptible.304 The intermediate category also includes a buffer zone for inherent variability in test methods that should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.304 If results of in vitro susceptibility testing indicate that a clinical isolate is resistant , the strain is not inhibited by drug concentrations generally achievable with usual dosage schedules and/or MICs or zone diameters fall in the range where specific microbial resistance mechanisms are likely and clinical efficacy of the drug against the isolate has not been reliably demonstrated in clinical studies.304

Strains of staphylococci resistant to penicillinase-resistant penicillins also should be considered resistant to ampicillin/sulbactam, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.304 In addition, CLSI currently recommends that non-β-lactamase-producing strains of H. influenzae that are resistant to ampicillin (BLNAR H. influenzae ) be considered resistant to ampicillin/sulbactam despite the fact that results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.304

CLSI states that, for streptococci and non-β-lactamase-producing enterococci, results of in vitro susceptibility tests using ampicillin can be used to predict susceptibility to ampicillin/sulbactam.304 However, to determine susceptibility of staphylococci and gram-negative enteric bacteria to ampicillin/sulbactam, CLSI recommends that disk-diffusion and dilution susceptibility tests be performed using appropriate combinations of ampicillin sodium and sulbactam sodium.304 For information on interpretive criteria specified for ampicillin, see Spectrum: In Vitro Susceptibility Testing in the Aminopenicillins General Statement 8:12.16.08.

To test in vitro susceptibility to ampicillin/sulbactam, a 1:1 ratio of ampicillin to sulbactam generally is used for disk-diffusion procedures and a 2:1 ratio of the drugs is used for agar or broth dilution procedures.304

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to ampicillin/sulbactam, a disk containing 20 mcg of the drug (10 mcg of ampicillin and 10 mcg of sulbactam) is used.304

When disk-diffusion susceptibility testing is performed according to CLSI standardized procedures using CLSI interpretive criteria, Staphylococcus , Enterobacterales, and Acinetobacter with growth inhibition zones of 15 mm or greater are susceptible to ampicillin/sulbactam, those with zones of 12-14 mm have intermediate susceptibility, and those with zones of 11 mm or less are resistant to the drug.304

When disk-diffusion susceptibility testing is performed according to CLSI standardized procedures, Haemophilus with growth inhibition zones of 20 mm or greater are considered susceptible to ampicillin/sulbactam and those with zones of 19 mm or less are considered resistant to the drug.304

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to CLSI standardized procedures using CLSI interpretive criteria, Staphylococcus , Enterobacterales, and Acinetobacter with MICs of 8 mcg/mL or less of ampicillin in the presence of sulbactam at a constant 2:1 ratio are susceptible to ampicillin/sulbactam, those with MICs of 16 mcg/mL of ampicillin have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater of ampicillin are resistant to the drug.304

When susceptibility of Haemophilus is tested according to CLSI standardized procedures, Haemophilus with MICs of 2 mcg/mL or less of ampicillin in the presence of sulbactam at a constant 2:1 ratio are susceptible to ampicillin/sulbactam and those with MICs of 4 mcg/mL or greater of ampicillin in the presence of sulbactam at a constant 2:1 ratio are resistant to the drug.304

Gram-positive Aerobic Bacteria

Gram-positive Aerobic Cocci

Ampicillin/sulbactam is active in vitro against many gram-positive aerobic cocci including Streptococcus pneumoniae ,1,61,65,119,123 S. pyogenes (group A β-hemolytic streptococci),1,61,65,119 S. agalactiae (group B streptococci),119 viridans streptococci,1,61 and penicillinase-producing and nonpenicillinase-producing strains of Staphylococcus aureus ,1,30,64,61,65,91,119,131,132,143 S. epidermidis ,1,30,64,65,91,119,132 S. saprophyticus ,1 and S. warneri .58 The drug is active in vitro against some strains of Enterococcus faecalis .1,61,91,119 Ampicillin/sulbactam is active in vitro against most strains of penicillinase-producing staphylococci that are resistant to ampicillin alone.30,64,65,119,131,132,143 Although ampicillin/sulbactam may be active in vitro against some strains of staphylococci resistant to penicillinase-resistant penicillins including methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA) and methicillin-resistant S. epidermidis ,30,61,65,119,125,131,132,137,143 in vitro activity against these organisms does not necessarily correlate with in vivo activity and the manufacturer, CLSI, and most clinicians state that strains of staphylococci resistant to penicillinase-resistant penicillins (e.g., nafcillin, oxacillin) should be considered resistant to ampicillin/sulbactam.1,5,304

In in vitro studies using dilutions containing a 2:1 ratio of ampicillin to sulbactam, the MIC₉₀ (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of ampicillin/sulbactam for penicillinase-producing and nonpenicillinase-producing strains of S. aureus and S. epidermidis is 0.12-8 mcg/mL of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs.30,64,91,119,132 The MIC₉₀ of ampicillin/sulbactam for group A β- hemolytic streptococci,119 group B streptococci,119 S. pneumoniae ,119,123 and E. faecalis 91,119 is 0.03-1 mcg/mL of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs. Although some strains of E. faecium are inhibited in vitro by 0.5-8 mcg/mL of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs, many strains of the organism require concentrations of 16 mcg/mL or greater for in vitro inhibition and are considered resistant to the drug.150 (See Resistance.)

Gram-positive Aerobic Bacilli

Ampicillin/sulbactam is active in vitro against Listeria monocytogenes .92 The drug reportedly is inactive against Nocardia asteroides .65

Gram-negative Aerobic Bacteria

Neisseria

Ampicillin/sulbactam is active in vitro against most strains of Neisseria meningitidis 92,119 and penicillinase-producing and nonpenicillinase-producing N. gonorrhoeae .1,94,119,132

In in vitro studies using dilutions containing a 2:1 ratio of ampicillin to sulbactam, the MIC₉₀ of ampicillin/sulbactam for N. meningitidis is 0.12-2 mcg/mL or less of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs.92,119 The MIC₉₀ of the drug for PPNG is 4 mcg/mL of ampicillin in the presence of 2 mcg/mL of sulbactam.94,132

Haemophilus

Ampicillin/sulbactam is active in vitro against most β-lactamase-producing and non-β-lactamase-producing strains of Haemophilus influenzae 1,30,61,64,119,123,127,132,143 and H. ducreyi .65,143 Although some strains of non-β-lactamase-producing H. influenzae that are resistant to ampicillin (BLNAR H. influenzae ) may be susceptible to ampicillin/sulbactam in vitro, CLSI currently recommends that these strains be considered resistant to the drug.304

The MIC₉₀ of ampicillin/sulbactam reported for non-β-lactamase-producing strains of H. influenzae is 0.25-0.5 mcg/mL and the MIC₉₀ of the drug for β-lactamase producing strains is 0.78-2 mcg/mL of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs.30,64,119,123,127,132

Moraxella catarrhalis

Ampicillin/sulbactam is active in vitro against both β-lactamase-producing and non-β-lactamase-producing strains of Moraxella catarrhalis .1,61,64,123,132 The MIC₉₀ of the drug reported for these organisms is 0.015-0.8 mcg/mL of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs.64,123,132

Enterobacteriaceae

Ampicillin/sulbactam is active in vitro against Enterobacteriaceae that are susceptible to ampicillin alone (e.g., some strains of Escherichia coli , Proteus mirabilis , Salmonella , Shigella ).1,61,64,119,132 In addition, ampicillin/sulbactam is active in vitro against many β-lactamase-producing Enterobacteriaceae that are resistant to ampicillin alone, including many strains of β-lactamase-producing Citrobacter ,119,132 Klebsiella ,1,64,91,119,132 Morganella morganii ,1,119 Proteus ,1,91,119,132 Providencia ,1,119 and Yersinia enterocolitica 143 and some strains of β-lactamase-producing E. coli .1,64,91,119,132 Although ampicillin/sulbactam is active in vitro against some strains of Enterobacter cloacae , E. aerogenes , and E. agglomerans ,53,64,91,92,119 many strains of Enterobacter as well as most strains of Serratia are resistant to the drug.53,64,91,92,119,132 (See Resistance.)

In in vitro studies using dilutions containing a 2:1 ratio of ampicillin to sulbactam, the MIC₉₀ of ampicillin/sulbactam for E. coli , including multiple-drug resistant strains, generally is 4-16 mcg/mL of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs.91,92,119,132 However, the MIC₉₀ for E. coli occasionally has been reported as 16-32 mcg/mL.30 The MIC₉₀ of the drug for Klebsiella ,30,91,119,132 including K. pneumoniae and K. oxytoca ,30,132 and for Citrobacter 119 and Proteus 30,91,119,132 is 1-16 mcg/mL of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs. Serratia marcescens usually has an MIC₉₀ of 16-32 mcg/mL or greater of ampicillin in the presence of sulbactam at a constant 2:1 ratio and generally is considered resistant to the drug.64,92,119,132

Other Gram-negative Aerobic Bacteria

Ampicillin/sulbactam is active in vitro against some strains of Acinetobacter .61,92,93,119,132 The MIC₉₀ of the drug reported for Acinetobacter baumannii ( A. calcoaceticus subsp. anitratus ), A. lwoffi ( A. calcoaceticus subsp. lwoffi ), and A. haemolyticus is 1-8 mcg/mL of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs.93,119

Ampicillin/sulbactam generally is inactive against Pseudomonas , including Ps. aeruginosa .61,92,119

Some strains of Burkholderia pseudomallei and B. cepacia may be inhibited in vitro by the drug.121,128

In one study, the MIC₉₀ of ampicillin/sulbactam reported for Legionella , including L. pneumophila , was 2 mcg/mL of ampicillin in the presence of 1 mcg/mL of sulbactam.119

Ampicillin/sulbactam has some in vitro activity against Campylobacter fetus subsp. jejuni .124

Anaerobic Bacteria

Ampicillin/sulbactam is active in vitro against both gram-positive and -negative anaerobic bacteria and is active against some anaerobes that are resistant to many other anti-infectives, including other β-lactam antibiotics, metronidazole, and clindamycin.55,65,130,132

Ampicillin/sulbactam is active in vitro against gram-positive anaerobic bacteria including Actinomyces ,30,136 Bifidobacterium ,30,136 Clostridium ,1,30,61,64,65,91,122,136 Eubacterium ,30,136 Lactobacillus ,30,91,136 Peptococcus ,1,61,136 Peptostreptococcus ,1,61,64,136 and Propionibacterium .91 The MIC₉₀ of ampicillin/sulbactam reported for Clostridium (including C. clostridioforme , C. innocuum , C. perfringens , C. ramosum , C. subterminale , and C. tertium ) is 0.5-8 mcg/mL of ampicillin in the presence of sulbactam in a constant 2:1 ratio of the drugs.64,91,122,136 Most other susceptible gram-positive anaerobes are inhibited in vitro by ampicillin/sulbactam concentrations of 0.25-2 mcg/mL of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs.30,64,91,122,136

Ampicillin/sulbactam is active in vitro against gram-negative anaerobic bacteria including most strains of Bacteroides , Porphyromonas , Prevotella ,1,30,61,64,55,65,91,119,120,122,130,132,136 and Fusobacterium .30,55,64,65,92,136 The MIC₉₀ of the drug reported for most Bacteroides in the B. fragilis group (e.g., B. fragilis , B. caccae , B. distasonis , B. ovatus , B. thetaiotamicron , B. uniformis , B. vulgatus ) is 1.6-16 mcg/mL of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs.30,55,64,91,92,119,120,122,130,132,136 The MIC₉₀ of the drug reported for B. capillosus 55,91,136 and B. ureolyticus 136 is 0.25-4 mcg/mL of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs. Ampicillin/sulbactam concentrations of 32 mcg/mL of ampicillin in the presence of 16 mcg/mL of sulbactam may be required for in vitro inhibition of B. gracilis , and this organism generally is considered resistant to the drug.122

The MIC₉₀ of ampicillin/sulbactam for Porphyromonas asaccharolyticus ( B. asaccharolytica ),64,136 Prevotella bivius ( B. bivia ),55,91,136 P. disiens ( B. disiens ),55,136 P. intermedius ( B. intermedia ),64,136 P. loescheii ( B. loescheii ), P. melaninogenicus ( B. melaninogenica ),64,136 and P. oralis ( B. oralis )136 is 0.25-4 mcg/mL of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs.

Fusobacterium , including F. nucleatum , generally is inhibited in vitro by concentrations of 0.1-8 mcg/mL of ampicillin in the presence of sulbactam at a constant 2:1 ratio of the drugs;30,55,64,122,136 however, some strains of F. necrophorum may be resistant to ampicillin/sulbactam.55,122,136

Chlamydia and Mycoplasma

Ampicillin/sulbactam generally is considered inactive against Mycoplasma and Chlamydia , including C. trachomatis .101 Like most other penicillins (e.g., amoxicillin, penicillin G), ampicillin reportedly has an incomplete inhibitory effect against Chlamydia and may be bacteriostatic but not bactericidal against these organism.61,101,146,147,148

Resistance

Gram-negative aerobic bacilli that produce Richmond-Sykes type I chromosomally mediated β-lactamases (e.g., Pseudomonas aeruginosa , Citrobacter , Enterobacter , Serratia ) generally are resistant to the fixed combination of ampicillin sodium and sulbactam sodium (ampicillin/sulbactam) because sulbactam does not inhibit most type I β-lactamases.

Some strains of Klebsiella ,53,117 Escherichia coli ,53,117,143 and Acinetobacter 117 and rare strains of Neisseria gonorrhoeae 117 are resistant to ampicillin/sulbactam. Rarely, strains of Bacteroides fragilis resistant to ampicillin/sulbactam have been reported.126

Results of in vitro studies using ampicillin-resistant strains of Staphylococcus aureus , Haemophilus influenzae , and B. fragilis indicate that serial passage of these strains in the presence of ampicillin/sulbactam or continuous culture in the presence of subinhibitory concentrations of the drug does not result in resistance to ampicillin/sulbactam.30,132,137

Enterococcus faecium generally is resistant to ampicillin/sulbactam.150 Resistance to aminopenicillins in some enterococci (e.g., E. faecalis , E. faecium ) can result from β-lactamase production149,150,151 or from decreased binding to and/or increased production of penicillin-binding proteins with a low affinity for the drugs (e.g., PBP 5 or 6).149,150,151 Enterococci that exhibit ampicillin resistance secondary to β-lactamase production may be susceptible in vitro when the aminopenicillin is combined with a β-lactamase inhibitor (e.g., clavulanic acid, sulbactam).151 Strains that exhibit ampicillin resistance secondary to alterations in PBPs remain resistant when the drug is combined with a -lactamase inhibitor such as sulbactam or clavulanic acid,150,151 and some evidence suggests that such strains occasionally may emerge secondary to high-dose drug exposure.150 In addition, enterococci resistant to multiple drugs (e.g., vancomycin, teicoplanin, aminoglycosides, ampicillin, penicillin G, imipenem, tetracyclines, synergistic combinations of β-lactam anti-infectives) have been reported with increasing frequency.149,150,151

Pharmacokinetics

Cross-over studies using fixed combinations of ampicillin sodium and sulbactam sodium, ampicillin sodium alone, and sulbactam sodium alone indicate that concomitant administration of sulbactam sodium does not appreciably affect the pharmacokinetics of either drug.1,30,33,46,63,65 Dosage of the fixed combination of ampicillin sodium and sulbactam sodium (ampicillin/sulbactam) generally is expressed in terms of the total of the ampicillin and sulbactam content of the fixed combination.1

The pharmacokinetics of ampicillin and sulbactam following parenteral administration are similar1,30,33,36,46,63,65,66,67 and reportedly are best described by an open, 2-compartment model.1,30,33,36,46,65,66 For additional information on absorption, distribution, and elimination of ampicillin, see Pharmacokinetics in the Aminopenicillins General Statement 8:12.16.08 and in Ampicillin 8:12.16.08.

Absorption

Sulbactam sodium is not absorbed appreciably from the GI tract and must be given parenterally.30,33,65,66 Although sulbactam is orally bioavailable following administration of an oral formulation containing ampicillin and sulbactam covalently linked as a double ester in a single molecule (sultamicillin; CP-49,952), this oral dosage formulation is not commercially available in the US.30,63,65,66,138,140,142

Peak serum concentrations of ampicillin and sulbactam are attained immediately following completion of a 15-minute IV infusion of ampicillin/sulbactam.1,63 In adults with normal renal function, peak serum concentrations of ampicillin are 40-71 mcg/mL following administration of a 1.5-g dose of ampicillin/sulbactam (1 g of ampicillin and 0.5 g of sulbactam) or 109-150 mcg/mL following a 3-g dose of the drug (2 g of ampicillin and 1 g of sulbactam);1,30,33,65 peak serum concentrations of sulbactam following these doses are 21-40 or 48-88 mcg/mL, respectively.1,30,33,65

Following IM injection of ampicillin/sulbactam, both drugs are rapidly and almost completely absorbed.30,33,46,65,67 Peak serum concentrations of ampicillin and sulbactam generally are attained within 30-40 and 30-52 minutes, respectively.30,65,67 In healthy adults with normal renal function, IM injection of 1.5 g of ampicillin/sulbactam (1 g of ampicillin and 0.5 g of sulbactam) results in peak serum concentrations of ampicillin of 8-37 mcg/mL and of sulbactam of 6-24 mcg/mL.1,30,67

Peak serum concentrations and areas under the concentration-time curve (AUCs) of ampicillin and sulbactam are slightly higher in geriatric patients than in younger adults; this presumably occurs because of reduced renal clearance in the elderly.31 In a study in healthy geriatric adults 65-85 years of age, a single 3-g dose of ampicillin/sulbactam (2 g of ampicillin and 1 g of sulbactam) given IV over 30 minutes resulted in peak serum concentrations of ampicillin and sulbactam that averaged 112.4 and 59.1 mcg/mL, respectively; the same dose administered to healthy adults 20-64 years of age resulted in peak serum concentrations of 82.4-99.8 and 42.5-52.2 mcg/mL, respectively.31

In a study in neonates who received ampicillin/sulbactam in a 1:1 ratio (50 mg/kg of each drug) given by rapid IV injection every 12 hours, plasma concentrations of ampicillin at 3, 8, and 12 hours after a dose averaged 86.8, 77.3, and 56.8 mcg/mL, respectively, and those of sulbactam at the same intervals averaged 110.2, 72.8, and 38.4 mcg/mL, respectively.40

There is no evidence that sulbactam accumulates in serum following IM or IV administration of 0.5-g doses every 6 hours for 3 days in adults with normal renal function.30,33,46,65

In a few patients with chronic renal failure undergoing continuous ambulatory peritoneal dialysis, intraperitoneal administration of a single 3-g dose of ampicillin/sulbactam (2 g of ampicillin and 1 g of sulbactam) instilled over 6 hours resulted in peak plasma concentrations of ampicillin and sulbactam of 87.5 and 27.8 mcg/mL, respectively.111

Distribution

Following IM or IV administration of ampicillin/sulbactam, both ampicillin and sulbactam are well distributed into fluids and tissues.1,30,33,65 Ampicillin and sulbactam distribute into peritoneal fluid,1,30,43,44,60,65 blister fluid,1,30,36,65,68 tissue fluid,1 sputum,30 middle ear effusion,65 intestinal mucosa,1,30,45,65 bronchial wall,42 alveolar lining fluid,42 sternum,41 pericardium,41 myocardium,41 endocardium,41 prostate,30,65 gallbladder,30,39,65 bile,30,39,65 myometrium,30,65,73 salpinges,30,65,73 ovaries,30,65,73 and appendix.1,60,65 Concentrations of the drugs in most of these tissues and fluids generally are 53-100% of concurrent serum concentrations.33,42,43,65

In adults with normal renal function, the apparent volume of distribution at steady state of ampicillin is 0.28-0.33 L/kg and that of sulbactam is 0.24-0.4 L/kg.65 The apparent volume of distribution of sulbactam at steady state in infants and children is 0.31-0.38 L/kg.32

Both ampicillin and sulbactam are distributed into CSF in low concentrations following IV or IM administration in adults and children.1,30,35,37,38,59,65 CSF concentrations of the drugs generally are higher in patients with inflamed meninges than in those with uninflamed meninges.35,37,38,59,65 In a study in adults receiving 0.8- to 2-g doses of ampicillin IV every 4 hours and 1-g doses of sulbactam IV every 6 hours, ampicillin concentrations in CSF ranged from less than 0.3 to 9.6 mcg/mL in those with mild meningeal inflammation and 1.4-23.8 mcg/mL in those with marked inflammation; sulbactam CSF concentrations in these patients ranged from less than 0.5 to 4.7 mcg/mL and from 1-10.7 mcg/mL, respectively.37

In patients undergoing cholecystectomy who received a single 1.5-g IV dose of ampicillin/sulbactam (1 g of ampicillin and 0.5 g of sulbactam), concentrations of ampicillin 0.25-1.5 hours after the dose averaged 15.9 mcg/mL in gallbladder bile, 7.7 mcg/g in gallbladder, and 20.2 mcg/mL in serum; concentrations of sulbactam in these samples averaged 4.3 mcg/mL, 6.3 mcg/g, and 19.9 mcg/mL, respectively.39

Ampicillin is approximately 15-28% bound to serum proteins and sulbactam is approximately 38% bound to serum proteins.1,33,65

Ampicillin and sulbactam both readily cross the placenta30,65 and concentrations in umbilical cord blood may be similar to serum concentrations.65 Ampicillin and sulbactam are distributed into milk in low concentrations.1,30,65,108 In lactating women who received 500-mg or 1-g doses of sulbactam by IV infusion over 20 minutes every 6 hours, concentrations of the drug in milk averaged 0.52 mcg/mL in samples obtained at random intervals between the first and thirteenth doses.108

Elimination

Serum concentrations of ampicillin and sulbactam both decline in a biphasic manner and half-lives of the drugs are similar.30,36,65 In healthy adults with normal renal function, both ampicillin and sulbactam have a distribution half-life (t_½α) of about 15 minutes and an elimination half-life (t_½β) of about 1 hour.33,65,67 In some studies, the t_½β of ampicillin ranged from 0.8-1.3 hours and that of sulbactam ranged from 0.97-1.4 hours.1,36,46,65,67 The t_½β of ampicillin and sulbactam are slightly longer in geriatric adults than in younger adults.31 In a study in healthy geriatric adults 65-85 years of age with renal function normal for their age, the elimination half-life of ampicillin averaged 1.4 hours and that of sulbactam averaged 1.6 hours.31

In infants and children younger than 12 years of age, sulbactam has a t_½β of 0.92-1.9 hours.32,33 In neonates, the half-lives of ampicillin and sulbactam vary inversely with a as renal tubular function matures, the drugs are cleared more rapidly.33,40,65,66

The major route of elimination of both sulbactam and ampicillin is glomerular filtration and tubular secretion.30,33,34,46,65 Only small amounts of the drugs are eliminated in feces and bile.33,45 Following IM or IV administration of ampicillin/sulbactam in adults with normal renal function, approximately 75-92% of the dose of ampicillin and the dose of sulbactam is excreted unchanged in urine within 8 hours.1,65,67

Serum concentrations of both ampicillin and sulbactam are higher and the half-lives of the drugs prolonged in patients with renal impairment.1,30,33,34,65 The elimination kinetics of both drugs appear to be affected to the same degree by impaired renal function.1,33,34,65,66 In one study, the half-lives of ampicillin and sulbactam averaged 1.6 and 1.6 hours, respectively, in adults with creatinine clearances of 30-60 mL/minute and 3.4 and 3.7 hours, respectively, in those with clearances of 7-30 mL/minute.34 In adults with creatinine clearances less than 7 mL/minute, the t_½β of ampicillin and sulbactam averaged 17.4 and 13.4 hours, respectively.34

Oral probenecid administered shortly before or with ampicillin/sulbactam competitively inhibits renal tubular secretion of both ampicillin and sulbactam and produces higher and prolonged serum concentrations of the drugs.1,30,33,46,65 (See Drug Interactions: Probenecid.)

Cystic fibrosis patients may eliminate sulbactam at faster rates than healthy individuals.32,65 In a study in children with cystic fibrosis, plasma clearance and apparent volume of distribution of sulbactam were about 1.5-2 times higher, peak plasma sulbactam concentrations were about 50% lower, and t_½β of the drug slightly shorter in these children than in children without cystic fibrosis.32

In healthy adults with normal renal function, renal clearance of ampicillin is 203-319 mL/minute and that of sulbactam is 169-204 mL/minute.33,36,65,67

Ampicillin and sulbactam are both removed by hemodialysis.1,34 The amount of the drugs removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate). In a few patients undergoing chronic dialysis, a 4-hour period of hemodialysis removed into the dialysate about 35% of the ampicillin dose and 45% of the sulbactam dose when a single 3-g dose of ampicillin/sulbactam (2 g of ampicillin and 1 g of sulbactam) was given 2 hours prior to dialysis.34

Chemistry and Stability

Chemistry

Ampicillin sodium and sulbactam sodium (ampicillin/sulbactam) is a fixed combination of the sodium salts of ampicillin and sulbactam.1,27,61 Ampicillin is an aminopenicillin.61,92 (See Ampicillin 8:12.16.08.) Sulbactam, a β-lactam β-lactamase inhibitor, is a synthetic penicillinate sulfone containing a β-lactam ring and derived from 6-aminopenicillanic acid.1,27,30,61,65,69,118 Although sulbactam has minimal antibacterial activity when used alone, the combined use of sulbactam sodium and certain penicillins or cephalosporins (e.g., amoxicillin, ampicillin, cefazolin, ceftizoxime, ceftriaxone, penicillin G) results in a synergistic effect that expands the spectrum of activity of the penicillin or cephalosporin against many strains of β-lactamase-producing bacteria.30,61,65,69,92,122,131,134,137

The fixed combination of ampicillin sodium and sulbactam sodium (ampicillin/sulbactam) is commercially available as a sterile powder for parenteral use containing a 2:1 ratio of ampicillin to sulbactam.1 Potency of the fixed combination is expressed in terms of the total ampicillin content plus the total sulbactam content.1

Ampicillin/sulbactam for parenteral use occurs as a white to off-white powder that is freely soluble in aqueous diluents.1 Each 1.5 g of ampicillin/sulbactam (1 g of ampicillin and 0.5 g of sulbactam) contains approximately 5 mEq (115 mg) of sodium; 3 g of the drug (2 g of ampicillin and 1 g of sulbactam) contains approximately 10 mEq (230 mg) of sodium.1 Following reconstitution, ampicillin/sulbactam solutions containing 375 mg/mL (250 mg of ampicillin and 125 mg of sulbactam per mL) occur as pale yellow to yellow solutions and have a pH of 8-10.1 Dilute solutions of the drug containing up to 30 mg of ampicillin and 15 mg of sulbactam are essentially colorless to pale yellow and have a pH of 8-10.1

Stability

Commercially available ampicillin/sulbactam sterile powder should be stored at 20-25°C.1

The stability of ampicillin sodium in solution is concentration dependent, decreasing as the concentration of the drug increases.300 Ampicillin sodium appears to be especially susceptible to inactivation in solutions containing dextrose, which appears to have a catalytic effect on hydrolysis of the drug.300 Sulbactam sodium is much more stable in aqueous solution than ampicillin sodium,65,110 but when combined with ampicillin sodium, sulbactam sodium does not substantially improve nor adversely affect the stability of the aminopenicillin.65,110 Therefore, the stability of ampicillin/sulbactam solutions is similar to that of ampicillin sodium solutions.65,110

Following reconstitution with sterile water for injection or 0.5 or 2% lidocaine hydrochloride injection, ampicillin/sulbactam solutions for IM injection containing 375 mg/mL (250 mg of ampicillin and 125 mg of sulbactam per mL) are stable for at least 1 hour,110 and the manufacturer recommends that such solutions be used within 1 hour after reconstitution.1

Following reconstitution with sterile water for injection or 0.9% sodium chloride injection, ampicillin/sulbactam solutions for IV administration containing 45 mg/mL (30 mg of ampicillin and 15 mg of sulbactam per mL) are stable for 8 hours at 25°C or 48 hours at 4°C,1 and solutions containing 30 mg/mL (20 mg of ampicillin and 10 mg of sulbactam per mL) are stable for 72 hours at 4°C.1,110 The manufacturer states that solutions for IV administration containing 45 mg/mL (30 mg of ampicillin and 15 mg of sulbactam per mL) in lactated Ringer's injection or (1/6) M sodium lactate injection are stable for 24 or 8 hours, respectively, when refrigerated at 4°C and for 8 hours at 25°C,1 although some investigators have reported more prolonged stability.110 Likewise, the manufacturer states that solutions in 5% dextrose injection containing 30 mg/mL (20 mg of ampicillin and 10 mg of sulbactam per mL) are stable for 2 hours at 25°C or 4 hours when refrigerated at 4°C and those containing 3 mg/mL (2 mg of ampicillin and 1 mg of sulbactam per mL) are stable for 4 hours at 25°C,1 despite some data suggesting more prolonged stability.110 The manufacturer also states that solutions of the combination in 5% dextrose with 0.45% sodium chloride injection containing 3 mg/mL are stable for 4 hours at 25°C and those containing 15 mg/mL (10 mg of ampicillin and 5 mg of sulbactam per mL) are stable for 4 hours at 4°C,1 although some investigators also have reported more prolonged stability with such solutions.110 Similarly, while some data indicate more prolonged stability than that recommended by the manufacturer,110 the manufacturer states that solutions diluted in 10% invert sugar and containing 3 mg/mL (2 mg of ampicillin and 1 mg of sulbactam per mL) are stable for 4 hours at 25°C and those containing 30 mg/mL (20 mg of ampicillin and 10 mg of sulbactam per mL) are stable for 3 hours when refrigerated.1

Ampicillin/sulbactam is potentially physically and/or chemically incompatible with some drugs, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature).70,301 Specialized references should be consulted for specific compatibility information.301 Because of the potential for incompatibility, ampicillin/sulbactam and aminoglycosides should not be admixed.1 .

Additional Information

For further information on chemistry and stability, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, and laboratory test interferences of ampicillin, see the Aminopenicillins General Statement 8:12.16.08 and see Ampicillin 8:12.16.08.

Only references cited for selected revisions after 1984 are available electronically.

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