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

 
 



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

DESCRIPTION

Ampicillin and Sulbactam for Injection, USP is a sterile 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:

Ampicillin and Sulbactam for Injection, USP parenteral combination, is available as a white to yellowish dry powder for reconstitution. Ampicillin and Sulbactam for Injection, USP dry powder is freely soluble in aqueous diluents to yield pale yellow to yellow solutions containing ampicillin sodium and sulbactam sodium equivalent to 250 mg ampicillin per mL and 125 mg sulbactam per mL. The pH of the solutions is between 8 and 10.

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

Each 1.5 gram vial contains 1.5 g Ampicillin and Sulbactam for Injection, USP (equivalent to 1 g ampicillin as the sodium salt plus 0.5 g sulbactam as the sodium salt).

Each 3 gram vial contains 3 g Ampicillin and Sulbactam for Injection, USP (equivalent to 2 g ampicillin as the sodium salt plus 1 g sulbactam as the sodium salt).

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 Ampicillin and Sulbactam for Injection formulation effectively extends the antibiotic spectrum of ampicillin to include many bacteria normally resistant to it and to other beta-lactam antibiotics. Thus, Ampicillin and Sulbactam 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 AND USAGE 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 (Enterococcus), Streptococcus pneumoniae (formerly D. pneumoniae), Streptococcus pyogenes , Streptococcus viridans .

Gram-Negative Bacteria: Haemophilus 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.

These are not beta-lactamase producing strains and, therefore, are susceptible to ampicillin alone.

Susceptibility Testing

Diffusion Technique

For the disk diffusion method of susceptibility testing, a 20 mcg (10 mcg ampicillin + 10 mcg sulbactam) disk should be used. The standardized procedure1 ,2 requires the use of a standardized inoculum concentration. With this procedure, a report from the laboratory of “Susceptible” indicates that the infecting organism is likely to respond to Ampicillin and Sulbactam therapy and a report of “Resistant” indicates that the infecting organism is not likely to respond to therapy.

An “Intermediate” susceptibility report suggests that the infecting organism would be susceptible to Ampicillin and Sulbactam 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, agar, microdilution or equivalent methods may be used to determine the minimal inhibitory concentration (MIC) value for susceptibility of bacterial isolates using standardized methods, inoculums and concentrations of ampicillin/sulbactam.1 ,3,4

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.

TABLE 2. Recommended Ampicillin/Sulbactam, Disk Diffusion and MIC Susceptibility Ranges 1 , 2 , 3 (Zone diameter in mm)
Organisms Inhibition zone diameter (mm) MIC (mcg/mL of ampicillin)
Resistant Intermediate Susceptible Resistant Intermediate Susceptible

Enterobacteriaceae , Acinetobacter calcoaceticus , Staphylococcus spp.

≤11

12-14

≥15

≥32

16

≤8

Haemophilus influenzae

≤19

--

≥20

≥4

--

≤2

1 The non-beta-lactamase producing organisms which are normally susceptible to ampicillin, such as Streptococci, will have similar zone sizes as for ampicillin disks.
2 Staphylococci resistant to methicillin, oxacillin, or nafcillin must be considered resistant to ampicillin/sulbactam.
3 The quality control cultures should have the following assigned daily ranges for ampicillin/sulbactam (see Table 3):

TABLE 3. Quality Control Ranges for Ampicillin/Sulbactam Disk Diffusion and MIC Determinations

Disk Diffusion

MIC

(Zone diameter in mm)

(mcg/mL ampicillin/

mcg/mL sulbactam)

E. coli

(ATCC 25922)

19-24

2/1–8/4

S. aureus

(ATCC 25923)

29–37

Not applicable

E. coli

(ATCC 35218)

13–19

8/4–32/16

H. influenza

(ATCC 49247)

14–22

2/1-8/4

CLINICAL PHARMACOLOGY

General

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

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

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

In patients with impaired renal function the elimination kinetics of ampicillin and sulbactam are similarly affected, hence the ratio of one to the other will remain constant whatever the renal function. The dose of Ampicillin and Sulbactam for Injection in such patients should be administered less frequently in accordance with the usual practice for ampicillin (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 1. Concentration of Ampicillin and Sulbactam for Injection in Various Body Tissues and Fluids
Fluid or Tissue Dose
(grams)
Ampicillin/ Sulbactam
Concentration
(mcg/mL or mcg/g)
Ampicillin/ Sulbactam

Peritoneal Fluid

0.5/0.5 IV

7/14

Blister Fluid (Cantharides)

0.5/0.5 IV

8/20

Tissue Fluid

1/0.5 IV

8/4

Intestinal Mucosa

0.5/0.5 IV

11/18

Appendix

2/1 IV

3/40

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

The pharmacokinetics of ampicillin and sulbactam in pediatric patients receiving Ampicillin and Sulbactam are similar to those observed in adults. Immediately after a 15-minute infusion of 50 to 75 mg Ampicillin and Sulbactam/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.

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 Ampicillin and Sulbactam for Injection for the treatment of skin and skin structure infections. Of 99 pediatric patients evaluable for clinical efficacy, 60 patients received a regimen containing intravenous Ampicillin and Sulbactam, and 39 patients received a regimen containing intravenous cefuroxime. This trial demonstrated similar outcomes (assessed at an appropriate interval after discontinuation of all antimicrobial therapy) for Ampicillin and Sulbactam- and cefuroxime-treated patients:

TABLE 4.
Therapeutic Regimen Clinical Success Clinical Failure

Ampicillin and Sulbactam

51/60 (85%)

9/60 (15%)

Cefuroxime

34/39 (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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