Description: Unasyn® is a parenteral antibiotic that combines ampicillin with sulbactam, a beta-lactamase inhibitor. Unasyn® is similar to the oral agent Augmentin®. Sulbactam alone has weak antibacterial activity. In combination with sulbactam, ampicillin's spectrum is broadened to include many beta-lactamase-producing organisms. Unasyn® is used mainly to treat infections such as moderate to severe intra-abdominal infections, gynecologic infections, and skin and soft-tissue infection caused by susceptible organisms. It is not indicated for meningitis. Unasyn® was approved by the FDA in December 1986 and will come off patent in 1999. Mechanism of Action: Beta-lactam antibiotics such as ampicillin are mainly bactericidal. Like other penicillins, ampicillin inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. Penicillin-binding proteins vary among different bacterial species. Thus, the intrinisic activity of ampicillin, as well as the other penicillins, against a particular organism depends on their ability to gain access to and bind with the necessary PBP. Like all beta-lactam antibiotics, ampicillin's ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor. Sulbactam is an irreversible inhibitor of the beta-lactamases. Like clavulanic acid, sulbactam inhibits the activity of beta-lactamase Richmond types II, III, IV, V, and VI but not chromosomally mediated type I. Sulbactam has little useful antibacterial activity if used alone. Sulbactam does not alter the actions of ampicillin or the sensitivity of organisms to ampicillin if they are sensitive to ampicillin alone. Unasyn® has an expanded gram-positive spectrum that includes the penicillinase- and nonpenicillinase-producing staphylococci and streptococci. Inhibitory concentrations of ampicillin against methicillin-resistant staphylococci are lower with the addition of sulbactam; however, this organism is still somewhat resistant to Unasyn®. The drug's gram-negative spectrum includes N. gonorrhoeae, N. meningitidis, Moraxella (Branhamella) catarrhalis, H. influenzae, and many enteric bacilli including E. coli, Klebsiella pneumoniae, Proteus mirabilis, Morganella morganii, Salmonella, and Shigella. Pseudomonas and Serratia are resistant. Anaerobes are extremely susceptible to Unasyn®. Peptococcus and Peptostreptococcus species, Clostridium perfringes, Clostridium tetani, and Bacteroides fragilis are usually sensitive to Unasyn®. Clinicians are advised to consult specific organism susceptibility data prior to prescribing Unasyn®. Pharmacokinetics: Unasyn® is administered parenterally. The pharmacokinetics of ampicillin and sulbactam are similar between pediatric patients and adults. Peak serum levels of both ampicillin and sulbactam occur within 1 hour following an IM dose and immediately after IV infusion. Protein binding is approximately 15—25% for ampicillin and 38% for sulbactam. Both drugs are distributed into lungs; liver; gallbladder; prostate; middle ear effusions; bronchial secretions; maxillary sinus secretions; urine; and pleural, peritoneal, and synovial fluids. Therapeutic levels are attained within the CSF in the presence of inflammation; however, Unasyn® is not indicated for meningitis. The drug does cross the placenta. Approximately 15—25% of both drugs are metabolized. The drug and its metabolites are excreted into the urine primarily via tubular secretion and glomerular filtration. A small percentage of Unasyn® is excreted in breast milk. In patients with normal renal function, the elimination half-life of both ampicillin and sulbactam is 1—1.5 hours. The elimination half-life increases as renal function declines—up to 10—24 hours in patients with end-stage renal disease. Dosages need to be adjusted accordingly.

Indications...Dosage The following organisms are generally considered susceptible to ampicillin-sulbactam in vitro: Actinomyces sp.; Bacillus anthracis; Bacteroides funduliformis; Bifidobacterium sp.; Bordetella pertussis; Borrelia burgdorferi; Brucella sp.; Calymmatobacterium granulomatis; Clostridium perfringens; Clostridium sp.; Clostridium tetani; Corynebacterium diphtheriae; Corynebacterium xerosis; Eikenella corrodens; Enterococcus faecalis; Erysipelothrix rhusiopathiae; Escherichia coli; Eubacterium sp.; Gardnerella vaginalis; Haemophilus influenzae (beta-lactamase negative); Helicobacter pylori; Lactobacillus sp.; Leptospira sp.; Listeria monocytogenes; Moraxella catarrhalis; Neisseria gonorrhoeae; Neisseria meningitidis; Pasteurella multocida; Peptococcus sp.; Peptostreptococcus sp.; Propionibacterium sp.; Proteus mirabilis; Salmonella sp.; Salmonella typhi; Shigella sp.; Streptococcus agalactiae (group B streptococci); Streptococcus dysgalactiae; Streptococcus pneumoniae; Streptococcus pyogenes (group A beta-hemolytic streptococci); Treponema pallidum; Viridans streptococci; Haemophilus influenzae (beta-lactamase positive); Staphylococcus aureus (MSSA); Staphylococcus epidermidis; Bacteroides sp.; Haemophilus ducreyi; Acinetobacter sp.; Klebsiella pneumoniae; Porphyromonas sp.; Prevotella sp.; Fusobacterium sp.; Bacteroides fragilis. For the treatment of moderate to severe infections caused by susceptible organisms including intraabdominal infections (e.g. peritonitis, appendicitis, diverticulitis), intraabdominal abscess, gynecologic infections (e.g. endometritis, pelvic cellulitis), lower respiratory tract infections† (e.g. bronchitis†, bronchiectasis†, pneumonia†), urinary tract infection (UTI)†, bone and joint infections† (e.g. osteomyelitis†, infectious arthritis†): Parenteral dosage: Adults and adolescents: 1.5—3 g (as Unasyn®) IV/IM every 6 hours. Maximum daily dose is limited to 4 g of sulbactam sodium. Children weighing >= 40 kg†: 1.5—3 g (as Unasyn®) IV every 6 hours. Maximum daily dose is limited to 4 g of sulbactam sodium. The IM route is not recommended in children Children weighing < 40 kg†: The recommended dosage is 150—300 mg/kg/day IV of Unasyn® (i.e., 100—200 mg/kg/day ampicillin and 50—100 mg/kg/day sulbactam) in equally divided doses every 6 hours. The IM route is not recommended in children. •for the treatment of pelvic inflammatory disease (PID): Intravenous dosage: Adults and adolescents: As an alternative to first-line regimens, the CDC recommends 3 g (as Unasyn®) IV every 6 hours in combination with doxycycline IV or PO. Parenteral therapy may be discontinued 24 hours after a patient improves clinically; treatment should be continued with oral doxycycline or clindamycin to complete a total of 14 days of therapy.[1632] •for the treatment of uncomplicated gonorrhea† caused by Neisseria gonorrhoeae: Parenteral dosage: Adults: 1.5—3 g (as Unasyn®) IM as a single dose given alone or in conjunction with 1 g PO probenecid. For the treatment of skin and skin structure infections (e.g. cellulitis, diabetic foot ulcer): Parenteral dosage: Adults: 1.5—3 g (as Unasyn®) IV/IM every 6 hours. Maximum daily dose is limited to 4 g of sulbactam sodium. Children weighing >= 40 kg: 1.5—3 g (as Unasyn®) IV every 6 hours. Maximum daily dose is limited to 4 g of sulbactam sodium. The IM route is not recommended in children Children >= 1 year of age and weighing < 40 kg: The recommended dosage is 300 mg/kg/day IV of Unasyn® (i.e., 200 mg/kg/day ampicillin and 100 mg/kg/day sulbactam) in equally divided doses every 6 hours. The IM route is not recommended in children Patients with renal impairment: CrCl > 30 ml/min: no dosage adjustment needed. CrCl 15—30 ml/min: give 1.5—3 g IV or IM and extend dosing interval to every 12 hrs. CrCl 5—15 ml/min: give 1.5—3 g IV or IM and extend dosing interval to every 24 hrs. Intermittent Hemodialysis: Ampicillin and sulbactam are significantly removed during a standard hemodialysis session. Some clinicians recommend that patients undergoing hemodialysis receive 1.5—3 g (as Unasyn®) IV or IM every 24 hours, with the dose scheduled to be given immediately after dialysis. †non-FDA-approved indication

Administration Parenteral Administration •Ampicillin; sulbactam is administered intravenously or intramuscularly. •Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. •Unasyn® 1.5 grams corresponds to 1 gram of ampicillin plus 0.5 grams of sulbactam and Unasyn® 3 grams corresponds to 2 grams of ampicillin plus 1 gram of sulbactam. Intramuscular injection: •Use only freshly prepared solutions and administer within 1 hour after preparing. •Vials: reconstitute 1.5 or 3 g with 3.2 or 6.4 ml, respectively, of sterile water for injection, or 0.5% or 2% lidocaine HCl to give a solution containing 250 mg of ampicillin and 125 mg of sulbactam per ml. •Inject deeply into a large muscle (i.e., upper outer quadrant of the gluteus maximus or lateral part of the thigh). Aspirate prior to injection to avoid injection into a blood vessel. Intermittent IV injection or infusion: •Piggyback bottles and vials: reconstitute 1.5 or 3 g with 3.2 or 6.4 ml, respectively, with a compatible IV solution to give a solution containing 250 mg of ampicillin and 125 mg of sulbactam per ml. Withdraw volume containing appropriate dose and dilute to a concentration ranging 3—45 mg Unasyn® per ml (2—30 mg of ampicillin and 1—15 mg of sulbactam per ml). •ADD-Vantage® vials: for IV infusion only. Reconstitute with NS only using the appropriate ADD-Vantage® diluent containers. •IV injection: inject slowly over at least 10—15 minutes to avoid the possibility of seizures. •IV infusion: infuse slowly over 15—30 minutes.

Contraindications Ampicillin-sulbactam should be used with caution in patients with renal disease or renal impairment since the drug is eliminated via renal mechanisms. Penicillins can cause a variety of hypersensitivity reactions ranging from mild rash to fatal anaphylaxis. Patients who have experienced severe penicillin hypersensitivity should not receive ampicillin-sulbactam. Ampicillin-sulbactam should be used cautiously in all patients with penicillin hypersensitivity, cephalosporin hypersensitivity, and imipenem hypersensitivity. These patients are more susceptible to hypersensitivity reactions during therapy with ampicillin-sulbactam. Patients with allergies or allergic conditions including asthma, eczema, hives, or hay fever may have a greater risk for hypersensitivity reactions to penicillins. Ampicillin-sulbactam is relatively contraindicated in patients with viral disease or lymphatic leukemia, because these patients may be more likely to develop a drug rash. Patients with viral infection such as CMV, viral respiratory infections, and especially mononucleosis have a high incidence of reported rashes. Antibiotic therapy can result in superinfection or suprainfection with nonsusceptible organisms. Overgrowth of Candida can occur with penicillin therapy. Penicillins should be used with caution in patients with a history of GI disease, especially colitis, because the adverse GI effects associated with penicillin therapy can exacerbate the condition. Also, patients who develop diarrhea while taking or soon after taking penicillins should be considered for differential diagnosis of antibiotic-associated pseudomembranous colitis. Penicillins are excreted in breast milk. Penicillins may cause diarrhea, candidiasis, and skin rash in breast-feeding infants. The potential risk to the infant should be considered versus the potential benefit in the mother. A false-positive reaction for glucose in the urine has been observed in patients receiving penicillins and using Benedict's solution, Fehling's solution, and Clinitest® tablets. However, this reaction has not been observed with Tes-tape® (glucose Enzymatic Test Strip, USP, Lilly).

Interactions Probenecid inhibits renal tubular secretion of both ampicillin and sulbactam, leading to higher serum levels. In general, this interaction is not harmful. Although concomitant use of Unasyn® with the aminoglycosides can be synergistic against enterococci and group B streptococci, the drugs cannot be given or mixed together because they are chemically and physically incompatible and become inactivated when mixed. Ampicillin in large doses inhibits renal tubular secretion of methotrexate, thereby causing higher, prolonged serum levels of methotrexate. Use of ampicillin with allopurinol can increase the incidence of drug-related skin rash. Ampicillin can decrease the efficacy of oral contraceptives that contain estrogen due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. Breakthrough bleeding or contraceptive failure may occur. The incidence of the interaction of anti-infective agents with OCs is unpredictable; cases of antibiotic-associated contraceptive failure have been reported, but are not well-documented. Patients should be made aware of this potential interaction. The use of an alternative method of contraception may be recommended during use of antibiotics, especially ampicillin or amoxicillin. Depending on the length of antibiotic therapy, an additional contraceptive method may be needed for at least one OC cycle after the antibiotic is finished. Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as ampicillin. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.

Adverse Reactions Hypersensitivity reactions are common adverse reactions during penicillin therapy. These reactions can range from rashes to anaphylaxis. Hypersensitivity-related rashes include maculopapular rash, urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome, and bullous rash These rashes occur more frequently with the aminopenicillins than with the other penicillins. This may be due to more avid tissue-binding of ampicillin, which acts as a hapten in this case. The incidence of rash secondary to ampicillin seems to be higher in patients with viral illnesses, such as mononucleosis, or in patients with lymphatic leukemia. Interstitial nephritis, a hypersensitivity reaction, with renal tubular necrosis and nephrotic syndrome has been reported. Nausea/vomiting, anorexia, diarrhea, gastritis, and abdominal pain are commonly reported gastrointestinal side effects during ampicillin therapy. Diarrhea appears to occur more frequently with ampicillin than with the other aminopenicillins. Pseudomembranous colitis can occur during use of or following discontinuance of ampicillin-sulbactam, but this effect is rare. Seizures have been reported when large doses of penicillins were administered to patients with renal impairment.[545] Appropriate dosage adjustments should be observed in these patients. Hematologic effects seen with aminopenicillins include eosinophilia and hemolysis and are associated with hypersensitivity reactions. Other reactions seen include as anemia, thrombocytopenia, neutropenia, agranulocytosis, and leukopenia. These adverse hematologic effects are generally reversible after discontinuation of the aminopenicillin. Platelet dysfunction, prolonged bleeding time, and prolongation of APTT have been reported in patients receiving amoxicillin and ampicillin. Atypical lymphocytosis was reported in one pediatric patient receiving ampicillin; sulbactam. Other reported side effects of ampicillin-sulbactam include headache, dizziness, and elevated hepatic enzymes.

Ampicillin; Sulbactam Unasyn®

1632. Centers for Disease Control and Prevention. 1998 Guidelines for treatment of sexually transmitted diseases. Morbid Mortal Weekly Rep 1998;47(no. RR-1):1—116.