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Unasyn (Ampicillin Sodium / Sulbactam Sodium) - Description and Clinical Pharmacology

 
 



UNASYN®
(ampicillin sodium/sulbactam sodium)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of UNASYN® and other antibacterial drugs, UNASYN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

UNASYN is an injectable antibacterial combination consisting of the semisynthetic antibiotic ampicillin sodium and the beta-lactamase inhibitor sulbactam sodium for intravenous and intramuscular administration.

Ampicillin sodium is derived from the penicillin nucleus, 6-aminopenicillanic acid. Chemically, it is monosodium (2S, 5R, 6R)-6-[(R)-2-amino-2-phenylacetamido]-3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate and has a molecular weight of 371.39. Its chemical formula is C16H18N3NaO4S. The structural formula is:

Sulbactam sodium is a derivative of the basic penicillin nucleus. Chemically, sulbactam sodium is sodium penicillinate sulfone; sodium (2S, 5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate 4,4-dioxide. Its chemical formula is C8H10NNaO5S with a molecular weight of 255.22. The structural formula is:

UNASYN, ampicillin sodium/sulbactam sodium parenteral combination, is available as a white to off-white dry powder for reconstitution. UNASYN dry powder is freely soluble in aqueous diluents to yield pale yellow to yellow solutions containing ampicillin sodium and sulbactam sodium equivalent to 250 mg ampicillin per mL and 125 mg sulbactam per mL. The pH of the solutions is between 8.0 and 10.0.

Dilute solutions (up to 30 mg ampicillin and 15 mg sulbactam per mL) are essentially colorless to pale yellow. The pH of dilute solutions remains the same.

1.5 g of UNASYN (1 g ampicillin as the sodium salt plus 0.5 g sulbactam as the sodium salt) parenteral contains approximately 115 mg (5 mEq) of sodium.

3 g of UNASYN (2 g ampicillin as the sodium salt plus 1 g sulbactam as the sodium salt) parenteral contains approximately 230 mg (10 mEq) of sodium.

CLINICAL PHARMACOLOGY

General

Immediately after completion of a 15-minute intravenous infusion of UNASYN, peak serum concentrations of ampicillin and sulbactam are attained. Ampicillin serum levels are similar to those produced by the administration of equivalent amounts of ampicillin alone. Peak ampicillin serum levels ranging from 109 to 150 mcg/mL are attained after administration of 2000 mg of ampicillin plus 1000 mg sulbactam and 40 to 71 mcg/mL after administration of 1000 mg ampicillin plus 500 mg sulbactam. The corresponding mean peak serum levels for sulbactam range from 48 to 88 mcg/mL and 21 to 40 mcg/mL, respectively. After an intramuscular injection of 1000 mg ampicillin plus 500 mg sulbactam, peak ampicillin serum levels ranging from 8 to 37 mcg/mL and peak sulbactam serum levels ranging from 6 to 24 mcg/mL are attained.

The mean serum half-life of both drugs is approximately 1 hour in healthy volunteers.

Approximately 75 to 85% of both ampicillin and sulbactam are excreted unchanged in the urine during the first 8 hours after administration of UNASYN to individuals with normal renal function. Somewhat higher and more prolonged serum levels of ampicillin and sulbactam can be achieved with the concurrent administration of probenecid.

In patients with impaired renal function the elimination kinetics of ampicillin and sulbactam are similarly affected, hence the ratio of one to the other will remain constant whatever the renal function. The dose of UNASYN in such patients should be administered less frequently in accordance with the usual practice for ampicillin (see DOSAGE and ADMINISTRATION).

Ampicillin has been found to be approximately 28% reversibly bound to human serum protein and sulbactam approximately 38% reversibly bound.

The following average levels of ampicillin and sulbactam were measured in the tissues and fluids listed:

TABLE A Concentration of UNASYN in Various Body Tissues and Fluids
Fluid or TissueDose
(grams)
Ampicillin/Sulbactam
Concentration
(mcg/mL or mcg/g)
Ampicillin/Sulbactam
Peritoneal Fluid0.5/0.5 IV7/14
Blister Fluid (Cantharides)0.5/0.5 IV8/20
Tissue Fluid1/0.5 IV8/4
Intestinal Mucosa0.5/0.5 IV11/18
Appendix2/1 IV3/40

Penetration of both ampicillin and sulbactam into cerebrospinal fluid in the presence of inflamed meninges has been demonstrated after IV administration of UNASYN.

The pharmacokinetics of ampicillin and sulbactam in pediatric patients receiving UNASYN are similar to those observed in adults. Immediately after a 15-minute infusion of 50 to 75 mg UNASYN/kg body weight, peak serum and plasma concentrations of 82 to 446 mcg ampicillin/mL and 44 to 203 mcg sulbactam/mL were obtained. Mean half-life values were approximately 1 hour.

MICROBIOLOGY

Ampicillin is similar to benzyl penicillin in its bactericidal action against susceptible organisms during the stage of active multiplication. It acts through the inhibition of cell wall mucopeptide biosynthesis. Ampicillin has a broad spectrum of bactericidal activity against many gram-positive and gram-negative aerobic and anaerobic bacteria. (Ampicillin is, however, degraded by beta-lactamases and therefore the spectrum of activity does not normally include organisms which produce these enzymes.)

A wide range of beta-lactamases found in microorganisms resistant to penicillins and cephalosporins have been shown in biochemical studies with cell free bacterial systems to be irreversibly inhibited by sulbactam. Although sulbactam alone possesses little useful antibacterial activity except against the Neisseriaceae, whole organism studies have shown that sulbactam restores ampicillin activity against beta-lactamase producing strains. In particular, sulbactam has good inhibitory activity against the clinically important plasmid mediated beta-lactamases most frequently responsible for transferred drug resistance. Sulbactam has no effect on the activity of ampicillin against ampicillin susceptible strains.

The presence of sulbactam in the UNASYN formulation effectively extends the antibiotic spectrum of ampicillin to include many bacteria normally resistant to it and to other beta-lactam antibiotics. Thus, UNASYN possesses the properties of a broad-spectrum antibiotic and a beta-lactamase inhibitor.

While in vitro studies have demonstrated the susceptibility of most strains of the following organisms, clinical efficacy for infections other than those included in the indications section has not been documented.

Gram-Positive Bacteria: Staphylococcus aureus (beta-lactamase and non-beta-lactamase producing), Staphylococcus epidermidis (beta-lactamase and non-beta-lactamase producing), Staphylococcus saprophyticus (beta-lactamase and non-beta-lactamase producing), Streptococcus faecalis 1 (Enterococcus), Streptococcus pneumoniae (formerly D. pneumoniae), Streptococcus pyogenes , Streptococcus viridans .

Gram-Negative Bacteria: Hemophilus influenzae (beta-lactamase and non-beta-lactamase producing), Moraxella (Branhamella) catarrhalis (beta-lactamase and non-beta-lactamase producing), Escherichia coli (beta-lactamase and non-beta-lactamase producing), Klebsiella  species (all known strains are beta-lactamase producing), Proteus mirabilis (beta-lactamase and non-beta-lactamase producing), Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Morganella morganii, and Neisseria gonorrhoeae (beta-lactamase and non-beta-lactamase producing).

Anaerobes: Clostridium species, Peptococcus species, Peptostreptococcus species, Bacteroides species, including B. fragilis.

Susceptibility Testing

Diffusion Technique

For the Kirby-Bauer method of susceptibility testing, a 20 mcg (10 mcg ampicillin + 10 mcg sulbactam) diffusion disk should be used. The method is one outlined in the NCCLS publication M2-A4.1 With this procedure, a report from the laboratory of "Susceptible" indicates that the infecting organism is likely to respond to UNASYN therapy and a report of "Resistant" indicates that the infecting organism is not likely to respond to therapy. An "Intermediate" susceptibility report suggests that the infecting organism would be susceptible to UNASYN if a higher dosage is used or if the infection is confined to tissues or fluids (e.g., urine) in which high antibiotic levels are attained.

Dilution Techniques

Broth or agar dilution methods may be used to determine the minimal inhibitory concentration (MIC) value for susceptibility of bacterial isolates to ampicillin/ sulbactam. The method used is one outlined in the NCCLS publication M7-A2.2 Tubes should be inoculated to contain 105 to 106 organisms/mL or plates "spotted" with 104 organisms.

The recommended dilution method employs a constant ampicillin/sulbactam ratio of 2:1 in all tubes with increasing concentrations of ampicillin. MIC's are reported in terms of ampicillin concentration in the presence of sulbactam at a constant 2 parts ampicillin to 1 part sulbactam.

Recommended ampicillin/sulbactam, Susceptibility RangesThe non-beta-lactamase producing organisms which are normally susceptible to ampicillin, such as Streptococci, will have similar zone sizes as for ampicillin disks., Staphylococci resistant to methicillin, oxacillin, or nafcillin must be considered resistant to UNASYN.,The quality control cultures should have the following assigned daily ranges for ampicillin/sulbactam:
DisksMode MIC
(mcg/mL ampicillin/
mcg/mL sulbactam)
E. coli (ATCC 25922)20–24 mm2/1
S. aureus (ATCC 25923)29–37 mm0.12/0.06
E. coli (ATCC 35218)13–19 mm8/4
1 These are not beta-lactamase producing strains and, therefore, are susceptible to ampicillin alone.

ResistantIntermediateSusceptible
Gram(-) and Staphylococcus
  Bauer/Kirby≤11 mm12–13 mm≥14 mm
  Zone Sizes
  MIC (mcg of ampicillin/mL)≥3216≤ 8
Hemophilus influenzae
  Bauer/Kirby≤19≥20
  Zone Sizes
  MIC (mcg of ampicillin/mL)≥ 4≤ 2

CLINICAL STUDIES

Skin and Skin Structure Infections in Pediatric Patients

Data from a controlled clinical trial conducted in pediatric patients provided evidence supporting the safety and efficacy of UNASYN for the treatment of skin and skin structure infections. Of 99 pediatric patients evaluable for clinical efficacy, 60 patients received a regimen containing intravenous UNASYN, and 39 patients received a regimen containing intravenous cefuroxime. This trial demonstrated similar outcomes (assessed at an appropriate interval after discontinuation of all antimicrobial therapy) for UNASYN- and cefuroxime-treated patients:

Thera p eutic Re g imen
Clinical Success
Clinical Failure
UNASYN51/60 (85%)9/60 (15%)
Cefuroxime34/39 (87%)5/39 (13%)

Most patients received a course of oral antimicrobials following initial treatment with intravenous administration of parenteral antimicrobials. The study protocol required that the following three criteria be met prior to transition from intravenous to oral antimicrobial therapy: 1) receipt of a minimum of 72 hours of intravenous therapy; 2) no documented fever for prior 24 hours; and 3) improvement or resolution of the signs and symptoms of infection.

The choice of oral antimicrobial agent used in this trial was determined by susceptibility testing of the original pathogen, if isolated, to oral agents available. The course of oral antimicrobial therapy should not routinely exceed 14 days.

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