Piperacillin/Tazobactam (ZOSYN)

}iperacillin/tazobactam (ZOSYN, Lederle Laboratories , Pearl River, NY) is the most recently approved combination of a [3-1actam antimicrobial agent with an inhibitor of bacterial [3-1actamases. In vitro and clinical studies have demonstrated efficacy in polymicrobial infections such as obstetric, gynecologic, and soft-tissue infections. Piperacillin/ tazobactam appears to be an appropriate drug for the empiric treatment of gynecologic infections because of its broad spectrum, good penetration of tissues, and minimal side-effect profile. Multiple studies have demonstrated that piperacillin/tazo-bactam, compared with "gold standard" treatment regimens, is an equally effective and safe alternative. It may also prove to be more cost effective, based on early reports of broad microbiologic coverage and high cure rates.

cacy in polymicrobial infections such as obstetric, gynecologic, and soft-tissue infections. Piperacillin/ tazobactam appears to be an appropriate drug for the empiric treatment of gynecologic infections because of its broad spectrum, good penetration of tissues, and minimal side-effect profile. Multiple studies have demonstrated that piperacillin/tazobactam, compared with "gold standard" treatment regimens, is an equally effective and safe alternative. It may also prove to be more cost effective, based on early reports of broad microbiologic coverage and high cure rates.
Tazobactam sodium is a triazolymethyl penicillanic-acid sulfone derivative. The triazole ring facilitates the binding of tazobactam to [3-1actamases. The chemical name is sodium (2S, 3S, 5R)-3me hyl-7-oxo-3-1H,2,3-triazol-1-ylme hyl)-4-h a-1-azabicyclo- [ [3-1actam inhibitors. 13-1actam inhibitors have the ability to bind irreversibly to 13-1actamase enzymes, thereby increasing the antimicrobial activity of several [3lactam antibiotics. Although tazobactam has little intrinsic antimicrobial activity, it binds covalently to a clinically important number of plasmids and chromosomally mediated [3-1actamases. It has enhanced piperacillin's bactericidal activity. Tazobactam provides an added advantage over other [3-lactam inhibitors in that it exhibits minimal induction of class-l, chromosomally mediated 13-1actamase enzymes. [4][5][6] PHARMACOKINETICS The pharmacokinetics of piperacillin and tazobactam are similar. Tazobactam and piperacillin are highly water soluble. They bind very weakly to plasma proteins (20-30%) after intravenous (IV) administration. As both agents leave the intravascular space quickly, distribution is complete within 30 rain after administration, Piperacillin and tazobactam are widely distributed in tissues and therapeutic levels are achieved in skin, muscle, intestinal mucosa, appendix tissue, and fatty tissue. The peak concentrations of piperacillin and tazobactam in muscle, skin, and gastrointestinal mucosa occur within 1-2 h after infusion.
Piperacillin plasma concentrations, following the infusion of piperacillin/tazobactam, are similar to those attained when equivalent doses of piperacillin are administered alone. The mean peak plasma concentrations are approximately 134, 242, and 298 Ixg/ml for 2.25-, 3.375-, and 4.5-g doses, respectively. The corresponding mean peak plasma concentrations of tazobactam are 15.24 and 34 Ixg/ml, respectively. The total clearance decreases slightly with an increase in dose. The plasma half-life of piperacillin and of tazobactam ranges from 0.7 to 1.2 h.
The amount of inhibitor that can be delivered to the site of infection is an important determinant of the efficacy of a drug combination. The standard dose of piperacillin/tazobactam is 3.375 g (3 g of piperacillin and 0.375 g of tazobactam) administered q 6 h. After the dosing of 3 g of piperacillin and 0.375 g of tazobactam over 5 min, the maximum concentration (Cmax) (rag/l) is 336 with an area under the curve (AUC) of 230; Cl,v is 219; and 51.7% is excreted in the urine. Multiple dosing has not been shown to affect the pharmacokinetics. Currently, pharmacokinetic studies are addressing if the doses of 3.375 g q 6 h and 4.5 g q 8 h are bioequivalent.
An q-8-h dosing of piperacillin/tazobactam is believed to be possible based on several earlier studies on piperacillin pharmacokinetics in normal patients.
Piperacillin is metabolized to a minimally active desthyl metabolite that insignificantly contributes to the overall elimination of piperacillin. Tazobactam is metabolized to an essentially inactive metabolite (M 1).z The elimination pathways of both piperacillin and tazobactam include ultrafiltration (kidney); paracellular elimination; and renal, hepatic, and gastrointestinal secretions. Both compounds are believed to be eliminated renally by tubular secretion and glomercular filtration; therefore, renal failure compromises its elimination. It has been suggested that the dosing interval be extended to 8 h in patients with creatinine clearances (Ccr) that range between 20 and 40 ml/min and to 10 h with Ccr of <20 ml/min, The concomitant administration of probenecid and piperacillin/tazobactam significantly prolongs the 13 half-life (tl/zbota) for tazobactam and significantly decreases the piperacillin mean CLR. 1 The authors of this study suggested that these changes CUL VER AND MARTENS likely offered no therapeutic advantage or warranted dosage modifications if probenecid is used concurrently.

SAFETY PROFILE
Overall, piperacillin/tazobactam has a safety profile similar to those of other 13-1actam/13-1actamase inhibitor combinations. The adverse reactions, which are generally not severe, rarely interfere with the continuation of therapy.
Only 3.2% of 2,261 patients studied worldwide had adverse effects that warranted the termination of therapy. The most common adverse experiences related to treatment were allergic skin reactions (1.3%) and gastrointestinal disturbances (0.9%), most often diarrhea. Clinical comparative studies have documented a higher incidence of diarrhea with piperacillin/tazobactam treatment than with other combination antibiotic therapies. 1 The most common laboratory abnormalities have been related to hepatic function: a 1.1% increase in total bilirubin levels and a 5.6% increase in alanine aminotransferase levels. The incidence of elevations increased with concurrent aminoglycoside administration. Piperacillin/tazobactam has been classified as a pregnancy-risk category-B drug.

SPECTRUM OF ANTIMICROBIAL ACTIVITYEMPIRIC AND SELECTED
Two large comparative studies were performed to evaluate piperacillin/tazobactam's in vitro antimicrobial activity, lz'13 These studies demonstrated that piperacillin/tazobactam has an excellent empiric spectrum. This combination is highly active against gram-positive bacteria, including strains that produce [3-1actamase, and inhibits a wide spectrum of both fastidious and non-fastidious gram-negative bacilli, including Pseudomonas aeruginosa. Piperacillin/tazobactam also inhibits a broader spectrum of anaerobes than does ampicillin/sulbactam or ticarcillin/clavulanate. A large comparative study tested the antimicrobial activity of piperacillin combined with tazobactam at a fixed concentration of 4 Ixg/ml and a ratio of 8:1. A total of 5,029 clinical isolates of gramnegative and gram-positive aerobic pathogens and 447 fastidious organisms including anaerobes from 5 medical centers were included. z The study results were as follows: >95;% inhibition of Enterobacteriaceae; 93.5% inhibition for non-enteric gram-nega-   A national survey of the in vitro spectrum of piperacillin/tazobactam at 236 medical centers also demonstrated its wide antimicrobial activity. 13 Piperacillin/tazobactam and imipenem displayed the widest antimicrobial spectra, inhibiting >90% of all isolates tested. Piperacillin/tazobactam, similar to other combination regimens comprising the penicillin group, does not cover methicillin-resistant staphylococci, strains of enterococci that are resistant to both 13lactams and chromosomally mediated 13-1actamases. 14 Pseudomonas spp. should be covered with higher doses of piperacillin/tazobactam (4/0.5 g q 6 h or 3/0.75 g q 4 h) plus an aminoglycoside.
In summary, in vitro studies have demonstrated the broad antimicrobial activity and clinical efficacy of piperacillin/tazobactam. CLINICAL APPLICATIONS Currently, the Food and Drug Administration (FDA) has approved piperacillin/tazobactam for the treatment of intraabdominal infections, skin and skin-structure infections, postpartum endometritis or pelvic inflammatory disease (PID), and community-and hospital-acquired pneumonia.
The majority of pelvic infections are polymicrobial in nature, with mixed aerobic, facultative, and anaerobic bacteria involved. The medical literature supports empiric treatment regimens with adequate coverage comparable to a single-agent cephalosporin or extended-spectrum penicillins with high rates of cure. In previous studies, piperacillin alone has been shown to be as efficacious as standard regimens in the treatment of pelvic infections. 8'19 In a randomized study by Sweet et al., z piperacillin and tazobactam, 3.375 g q 6 h (N 196) was compared with clindamycin, 900 mg, and gentamicin, 2.5-5.0 mg/kg/d q 8 h (N 103) in hospitalized women with pelvic infections. A total of 87% of the infections were either endometritis or PID. The combination of piperacillin/tazobactam produced favorable clinical responses in 85% of the patients vs. 87% of the gentamicin/clindamycin-treated group. These differences were not clinically significant. The bacteriologic responses were comparable in the 2 groups: 78% and 82%, respectively. Some Streptococcus spp. were the only organisms isolated that were resistant to piperacillin/tazobactam. The investigators concluded that the combination of COST Although the costs for the acquisition and administration of antibiotics vary by institution, the relative costs are usually comparable. The costs for acquisition plus a $5.00/dose charge for IV preparation and administration for various antibiotic regimens commonly utilized for the treatment of obstetric and gynecologic infections at our hospital are given in Table 2. Therefore, piperacillin/tazobactam appears to be comparable to other [3-1actamase inhibitor combinations and much less expensive than imipenem-cilastatin. Although single-agent cephalosporins and clindamycin/gentamicin are less expensive, their enterococcal coverage is lacking. While the significance of enterococcal coverage is still under debate, the recent increase in vancomycin-resistant enterococci is of great concern, indicating that enterococcal coverage may become a factor in the selection of empiric antibiotics in the future.

CONCLUSIONS
Piperacillin/tazobactam is an appropriate regimen for the treatment of gynecologic infections. This regimen covers a broad spectrum of pathogens, thereby providing empiric coverage (