Combination Of Tazobactam Research Articles

Etiological Factors of Infections in Diabetic Foot Syndrome – Attempt to Define Optimal Empirical Therapy

Diabetic foot syndrome (DFS) represents one of the most frequent reasons for lower limb amputation in developed countries. In most cases, it is associated with bacterial infection, requiring optimal antibiotic therapy. The aim of this study was to identify the most frequent pathogens responsible for infections associated with DFS, establish the optimal protocol of empirical therapy, and ascertain the clinical variables that may determine the choice of the appropriate antibacterial agent. The analysis included hospital records of patients treated at the Department between 2008 and 2010. A total of 102 individuals were identified; their material was cultured and tested for antibiotic susceptibility. A total of 199 bacterial strains were isolated. There was a predominance of Gram-positive bacteria, particularly Staphylococcus aureus, Staphylococcus coagulase-negative strains, and Enterococcus faecalis. Of note was the high percentage of E. faecalis infection (16.08%). One can speculate on the potential etiological factors in the case of some bacteria, e.g. patients infected with S. aureus were characterized by higher monocytosis and lymphocytosis as compared to other patients. Analysis of drug susceptibility revealed that ciprofloxacin has the highest (but still only 44%) efficacy of all agents tested as monotherapy, and a combination of piperacillin and tazobactam or amoxicillin and clavulanate with aminoglycosides is particularly beneficial. Staphylococcus spp. predominates amongst the etiological factors of DFS infection; however, the rate of E. faecalis infection is alarmingly high. Monotherapy enables effective treatment in a minority of cases; therefore, at least two-drug protocols should be implemented from the very beginning of the therapy.

Isolation and molecular characterization of New Delhi metallo-beta-lactamase-1 producing superbug in Bangladesh

New Delhi metallo-beta-lactamse-1 (NDM-1) producing superbugs create a global public health problem because of their resistance to most antibiotics. This study was conducted to determine the presence of MBL producers, including NDM-1 producers, in Bangladesh, along with the antimicrobial resistance patterns of these organisms. Thirty-five isolates resistant to imipenem by disk diffusion technique were investigated for MBL production. Minimum inhibitory concentration (MIC) of imipenem was determined by agar dilution method. MBL producers were phenotypically detected by double disk synergy test and combined disk assay. Gene encoding blaIMP-1, blaIMP-2, blaVIM-1, blaVIM-2, blaNDM-1 and class 1 integron was identified by PCR. Thirty-one (88.57%) MBL producers were detected by PCR, 24 (68.57%) by double disk synergy test, and 30 (85.71%) by combined disk assay. Eight (22.86%) were positive for blaNDM-1, 13 (37.15%) for blaVIM-1, 21 (60.00%) for blaVIM-2, 18 (51.43%) for blaIMP-1, and 9 (25.71%) for blaIMP-2. More than one blaMBL was present in 23 (65.71%) of the isolates. MIC of imipenem of MBL producers ranged from ≥256 µg/ml to ≤8 µg/ml. All the NDM-1 producing isolates carried class 1 integron. NDM-1 producers were 100% resistant to amoxicillin, cephradine, cefuroxime, ceftazidime, cefotaxime, ceftriaxone, aztreonam, gentamicin and piperacillin, 87.5% to amikacin, 75% to ciprofloxacin, and 62.5% to co-trimoxazole and the combination of tazobactam and piperacillin. All were sensitive to colistin. The results of this study provide insight into the presence of blaMBL, including blaNDM-1, in Bangladesh. Urgent epidemiological monitoring of MBL producers in Bangladesh may combat their rapid dissemination.

Stasis Dermatitis as a Complication of Recurrent Levofloxacin-Associated Bilateral Leg Edema

Several drugs have been associated with the development of peripheral edema. Leg edema can result in dermatitis of the lower extremities. We describe levofloxacin-induced peripheral leg edema, which progressed to stasis dermatitis. A 76-year-old man with a history of esophageal adenocarcinoma was administered intravenous vancomycin and a combination of piperacillin and tazobactam by injection for treatment of aspiration pneumonia. Prior to discharge, the patient's antibiotic therapy was switched to oral levofloxacin. The patient developed drug-associated bilateral peripheral leg edema and stasis dermatitis. Both the dermatitis and leg edema resolved after withdrawal of levofloxacin and administration of topical corticosteroid therapy. The patient had a similar reaction to levofloxacin one year prior, which had subsided with discontinuation of the drug. Several medications have been documented to cause leg edema and secondary stasis dermatitis. The timing, recurrence, and resolution of edema and stasis dermatitis with respect to the administration and termination of levofloxacin suggest that the leg edema and stasis dermatitis occurred secondary to levofloxacin administration. Levofloxacin can be added to the list of drugs associated with the development of peripheral leg edema. Stasis dermatitis proceeded by lower extremity edema can be added to the list of adverse events associated with levofloxacin.

Improving known classes of antibiotics: an optimistic approach for the future

New antibiotic agents are desperately needed to treat the multidrug-resistant pathogens that continue to emerge at alarming rates. Many of the agents that have entered full clinical development since 1995 have been members of previously accepted classes of antibiotics. Among these are a new aminoglycoside (plazomicin), anti-MRSA cephalosporins (ceftobiprole and ceftaroline), a monocyclic β-lactam (BAL30072), the β-lactamase inhibitor combination of tazobactam with the anti-pseudomonal cephalosporin ceftolozane, β-lactam combinations with new non-β-lactam inhibitors (MK-7655 with imipenem, and avibactam with ceftazidime and ceftaroline), new macrolides (cethromycin and solithromycin), oxazolidinones (tedizolid phosphate and radezolid), and quinolones (delafloxacin, nemonoxacin and JNJ-Q2). Resistance and safety issues have been circumvented by some of these new agents that have well-established mechanisms of action and defined pathways leading toward regulatory approval.

The inhibitory effect of Streptomyces chromofuscus on β-lactamase of Pseudomonas aeruginosa ATCC-10145

Seventy un-repeated Streptomyces isolates were isolated from different agricultural regions in Riyadh city. Amoxicillin-resistant Pseudomonas aeruginosa ATCC-10145 was obtained with minimum inhibitory concentration (MIC) > 1000 µg.ml-1. Streptomycesisolates were screened for producing β-lactamase inhibitory effect against P. aeruginosaATCC-10145. There were ten Streptomyces isolates which had inhibitory effect. Although, one Streptomyces isolate has been considered the most potent, this was identified by using biochemical characteristics as Streptomyces chromofuscus. Optimization factors for maximum yield of β-lactamase inhibitory protein were studied. The best incubation period at 7th day, incubation temperature at 28°C, pH value at 6.8, the best carbon source was galactose and the best nitrogen source was prolin. The highest amount of β-lactamase inhibitory protein was precipitated at 40% of saturated ammonium sulphate. The purification was carried out by using both diethyl-aminoethyl-cellulose and sephadex G-200 column chromatography, respectively. The β-lactamase inhibitory protein was separated at 32 kDa. The purified β-lactamase inhibitory protein was characterized as tazobactam. The combination of tazobactam at 128 mg.L-1 and amoxicillin at 125 µg.ml-1(in vitro) leads to growth inhibition of amoxicillin-resistant P. aeruginosa and make it very sensitive to the amoxicillin. Key words: Amoxicillin, enzyme inhibitors, protein purification, tazobactam

Dosing of piperacillin/tazobactam in a morbidly obese patient

The combination of piperacillin and tazobactam has been shown to be efficacious for the treatment of intra-abdominal infections, skin and soft tissue infections, bacteraemia and pneumonia. The pharmacokinetics (PK) of piperacillin/tazobactam have been extensively investigated in both healthy volunteers and in distinct patient settings. 1 Like other b-lactams, piperacillin/tazobactam displays time-dependent pharmacodynamics (PD), whereby duration of time that concentrations remain above the MIC correlates best with bacterial kill and efficacy. The PK/PD target associated with a high probability of therapeutic success is defined as free concentrations above the MIC for 50% of the dosing interval (50% fT .MIC). 2 In case of more severe infections or when poor penetration into infected tissues is expected, 30%‐ 40% fT . 4‐5 ×MIC should ideally be attained. 2 It is not clear whether these targets are reached in morbidly obese patients as published information on optimal dosing in this subset of patients is rare. A 33-year-old morbidly obese patient (220 kg, 1.9 m and body mass index 55 kg/m 2 ) was transferred to our orthopaedic ward with a surgical site infection following a transfemoral amputation of the left leg following a car accident. He has provided written, informed consent for the details given here to be published. The patient had been empirically started on amoxicillin/ clavulanic acid; however, despite 8 days of treatment, necrosis increased and markers of infection were still raised (C-reactive

Emergence of extended spectrum beta-lactamase (ESBLs) producing Proteus in raw milk of Doon Valley

The present study deals with the determination of extended spectrum of ß-lactamase (ESBL) producing Proteus in raw milk of Doon Valley. ESBL producing isolates were screened by double disc approximation test using commercially available ß-lactam (Piperacillin) and ß-lactam/ß-lactamase inhibitor combination (Piperacillin/ Tazobactam). All isolates of Proteus sp. were reported to resistant against Methicillin and were sensitive to Piperacillin, Cephotaxime, Ceftazidime, and Cefoperazone. This indicates that all the isolates were able to produce ß-lactamase in low and higher amount. This amount of ß-lactamase is inactivated by Tazobactam (ß-lactamase inhibitor) and the zone of inhibition with Piperacillin/Tazobactam combination was greater as compared to Piperacillin alone. There was a significant difference (>4 mm) in zone of inhibition was reported with Piperacillin and in combination of Piperacillin and Tazobactam. Hence, the overall emergence of ß-lactamase producing Proteus sp. in raw milk of Dehradun city was 100%, which is an alarming situation for public health and needs serious concern.

Evolution

When a patient's symptoms apparently progressed with treatment, it was necessary to determine whether her original problem had been supplanted by a new one. Three weeks after undergoing coronary artery bypass grafting, a 60-year-old woman from Bangladesh was admitted to the hospital with chest pain. She was noted to have left upper extremity warmth, erythema, and swelling. Vancomycin was ordered, but the erythema and warmth failed to improve after 4 days of therapy. As a result, a combination of piperacillin and tazobactam was added to the vancomycin.

Impact of tazobactam pharmacokinetics on the antimicrobial effect of piperacillin–tazobactam combinations

Pharmacokinetic–pharmacodynamic (PK–PD) modelling was used to study the impact of the pharmacokinetics of tazobactam on the antimicrobial effect of piperacillin–tazobactam combinations. An in vitro experiment using a novel dilution system was performed to compare the effects of two conditions of the combination therapy against Escherichia coli ATCC35218, a β-lactamase producing bacterium. Both conditions simulated the same initial concentrations of piperacillin and tazobactam, but different elimination half-lives for tazobactam. The killing and regrowth kinetics of E. coli clearly indicated that there is a difference in the antimicrobial effects when there is a difference in the pharmacokinetics of tazobactam in the combination therapy. The results show that for equal piperacillin exposure, different tazobactam half-lives will have a significant effect on antimicrobial outcome.

Effects of Freezing, Long-Term Storage, and Microwave Thawing on the Stability of Piperacillin Plus Tazobactam in 5% Dextrose for Infusion

Background: A combination of piperacillin with tazobactam is often administered to hospital patients by infusion. Advance preparation of IV solutions of these drugs could be an efficient way to improve the quality, time management, and cost associated with drug delivery, but little is known about the stability of these drugs after freezing followed by microwave thawing. Objective: The purpose of the study was to investigate how a process of freezing, long-term storage, and microwave thawing affects the stability of piperacillin with tazobactam in 5% dextrose for infusion. Methods: Five replicates of a mixtures of 4 g piperacillin and 0.5 g tazobactam in 20 mL of water plus 100 mL of 5% dextrose were prepared and stored in polyvinyl chloride (PVC) bags. The stability of the mixtures was studied after freezing for 3 months at -20°C followed by thawing in a microwave oven and additional storage at 4°C for up to 60 days. The concentrations of piperacillin and tazobactam in each sample were measured by high-pressure liquid chromatography. The samples were inspected visually, and pH was measured. Results: After 3 months of storage at -20°C, microwave thawing, and 35 days of storage at 4°C, more than 90% of the initial concentration of both piperacillin and tazobactam remained. At this point, the lower 95% confidence limit of the best-fit line by linear regression of percent remaining was 90.1% for piperacillin and 90.3% for tazobactam. The pH decreased by 1.16 units over 35 days of storage at 4°C, but no colour change of precipitation was observed. From 35 to 60 days, the concentrations of both piperacillin and tazobactam fell below the acceptable limit and pH values continued to decrease slightly. Conclusions: The combination of piperacillin (4 g/120 mL) and tazobactam (0.5 g/120 mL) in 5% dextrose stored in PVC bags, frozen for 3 months at -20°C, thawed in a microwave oven, and then stored at 4°C for an additional 35 days retained more than 90% of the initial concentration of each drug. This should allow for advance preparation of this drug combination.

Penetration of piperacillin and tazobactam into pneumonic human lung tissue measured by in vivo microdialysis.

The pharmacokinetic profile of antibiotics at the site of anti-infective action is one of the most important determinants of drug response, since it correlates with antimicrobial effect. Up to now, only limited information on the lung tissue pharmacokinetics of antibiotic agents has been available. The aim of this study was to measure, using a new microdialysis-based approach, antibiotic penetration into the extracellular space fluid of pneumonic human lung parenchyma. The lung penetration of a combination of piperacillin and tazobactam, substances with low protein binding, was determined in five patients suffering from pneumonia and metapneumonic pleural empyema. The condition was treated by decortication after lateral thoracotomy. Intra-, or post-operatively, respectively, two microdialysis probes were inserted into pneumonic lung tissue, and into healthy skeletal muscle to obtain reference values. Serum and microdialysis samples were collected at 20-min intervals for at last 8 h following i.v. administration of a single dose of 4 g piperacillin and 500 mg tazobactam. The mean free interstitial concentration profiles of piperacillin in infected lung tissue and serum showed a maximal tissue concentration (Cmax) of 176.0 +/- 105.0 mg l-1 and 326.0 +/- 60.6 mg l-1, respectively. The mean AUC (area under the curve) for infected lung tissue was 288.0 +/- 167.0 mg.h l-1 and for serum 470.0 +/- 142.0 mg.h l-1. There was a statistically significant difference between AUC (lung) and AUC (serum) (P = 0.018) as well as between AUC (lung) and AUC (muscle) (P = 0.043). The intrapulmonary concentrations of piperacillin and tazobactam exceeded the minimum inhibitory concentrations (MIC) for most relevant bacteria for 4-6 h. The procedure was well tolerated by all patients and no adverse events or microdialysis-associated side-effects were observed. This microdialysis technique enabled continuous tissue pharmacokinetic measurement of free, unbound anti-infective agents in the lung tissue of patients with pneumonia. The present data corroborate the use of piperacillin and tazobactam in the treatment of lung infections caused by extracellular bacteria and demonstrate the distribution of piperacillin and tazobactam in the interstitial space of pneumonic lung tissue.

Evaluating Possible Pharmacokinetic Interactions between Tobramycin, Piperacillin, and a Combination of Piperacillin and Tazobactam in Patients with Various Degrees of Renal Impairment

A study was performed to further investigate the apparent instability of tobramycin when coadministered with piperacillin/tazobactam in subjects with renal impairment. Twenty‐six otherwise healthy volunteers between 23 and 74 years of age were studied. Eight subjects had moderate renal impairment, 10 had mild renal impairment, and 8 had normal renal function. Each subject received single doses of piperacillin/tazobactam and tobramycin alone as well as combined doses in a randomized, three‐way crossover design. The subjects with normal renal function also received combined doses of piperacillin and tobramycin. Considerable care was taken to protect against in vitro inactivation of plasma and urine samples after collection. No systematic changes in pharmacokinetic parameters were observed. It is concluded that piperacillin, either alone or with tazobactam, did not change the pharmacokinetics of tobramycin in subjects with renal impairment. The apparent in vivo inactivation of tobramycin in the presence of piperacillin or piperacillin/tazobactam reported by others may be an artifact of ex vivo inactivation.

Benzocaine-Induced Methemoglobinemia

Benzocaine-Induced Methemoglobinemia

Activity of a broad-spectrum cephalosporin (Ro 48-8391) alone and in combination with two novel β-lactamase inhibitors (Ro 48-5545 and Ro 48-8724)

The susceptibility of a group of β-lactamase–producing and drug-resistant Gram-positive and Gram-negative organisms was tested against a novel cephalosporin (Ro 48-8391) alone and in combination with two bridged carbacephem β-lactamase inhibitors (Ro 48-5545 or Ro 48-8724) and compared with that of ceftriaxone, ceftazidime, and cefepime (representative “third- and fourth-generation” cephalosporins), imipenem, and a combination of piperacillin and tazobactam. Five hundred and one selected clinical isolates were tested using the reference broth microdilution method (National Committee for Clinical Laboratory Standards). Ro 48-8391 has a spectrum of activity and potency most similar to ceftriaxone but with improved activity against Gram-positive species. The two β-lactamase inhibitors, Ro 48-5545 and Ro 48-8724, have modest antimicrobial activity. When combined with Ro 48-8391, the β-lactamase inhibitor Ro 48-8724 was superior to the combination of Ro 48-8391 and Ro 48-5545 in spectrum and enzyme inhibition against extended spectrum β-lactamase enzyme-producing Escherichia coli and Klebsiella pneumoniae, and against Enterobacteriaceae with “stably derepressed” Bush-Jacoby-Medeiros gr. 1 enzymes (ceftazidime-resistant Enterobacter and Citrobacter). Ro 48-5545 and Ro 48-8724 appear to be promising β-lactamase inhibitors with potential application against chromosomal- and plasmid-mediated enzymes. Ro 48-8391, although superior to some currently available “third-generation” cephems, was not a well-matched active codrug because of limited activity against several commonly isolated species of clinically important bacteria. Further efforts are necessary to find a penicillin or cephem with activity more complementary to that of the tested β-lactamase inhibitors and the Ro 48-8391 compound could be focused for therapeutic use in serious streptococcal infections.

Piperacillin/tazobactam: a new beta-lactam/beta-lactamase inhibitor combination.

To discuss the antimicrobial activity, pharmacokinetics, clinical efficacy, and adverse effect profile of piperacillin/tazobactam, a new beta-lactan/beta-lactamase inhibitor combination. Literature was identified by MEDLINE search of the medical literature, review of selected references, and data provided by the manufacturer. In vitro susceptibility data were surveyed from studies following the methods of the National Committee for Clinical Laboratory Standards. Data evaluating clinical efficacy were selected from all published trials and abstracts. Additional information concerning safety, chemistry, and pharmacokinetics was reviewed. The antimicrobial activity of piperacillin is enhanced by addition of tazobactam against gram-positive, gram-negative, and anaerobic bacteria. Tazobactam is active against a broad spectrum of plasmid and chromosomally mediated enzymes and has minimal ability to induce class I chromosomally mediated beta-lactamase enzymes. Piperacillin/tazobactam's expanded activity appears encouraging in the treatment of mixed aerobic and anaerobic infections. Direct comparisons of ticarcillin/clavulanate and piperacillin/tazobactam for the treatment of lower respiratory tract infections showed piperacillin/tazobactam to be clinically superior, and in the treatment of skin and soft tissue infections the 2 agents were comparable. For the treatment of intraabdominal infections, piperacillin/tazobactam was at least as effective as imipenem/cilastatin and clindamycin plus gentamicin. The combination of tazobactam with piperacillin results in an antimicrobial agent with enhanced activity against most beta-lactamase-producing organisms. Preliminary data indicate that piperacillin/tazobactam has proven clinical efficacy in the treatment of a variety of infections, especially polymicrobic infections.

Inoculum effects on Etests and agar dilution minimum inhibitory concentrations piperacillin and Piperacillin-Tazobactam against Staphylococcus aureus

Inoculum effects notoriously occur with beta-lactamase-positive staphylococci in dilution susceptibility tests with substrate beta-lactams. Etests, like dilution experiments, demonstrated such effects with piperacillin and, to a lesser extent, with its tazobactam combinations. When Etests were used with the recommended inoculum of approximately 10(6) colony-forming units (CFU/plate, the minimum inhibitory concentrations (MICs) of piperacillin-tazobactam found for beta-lactamase-positive Staphylococcus aureus isolates resembled those found by agar dilution for inocula of 10(4) CFU/spot but were two- to eightfold below those found by agar dilution for inocula of 10(6) CFU/spot; MICs of piperacillin itself by Etest were about fourfold below even those found by agar dilution with inocula of 10(4) CFU/spot. Inoculum effects for beta-lactamase-negative S. aureus were minimal by both methods.

Piperacillin–tazobactam combination approved by FDA

Journal Article Piperacillin–tazobactam combination approved by FDA Get access American Journal of Hospital Pharmacy, Volume 51, Issue 3, 1 February 1994, Page 290, https://doi.org/10.1093/ajhp/51.3.290 Published: 01 February 1994

Reproductive and developmental toxicity studies of tazobactam/piperacillin or tazobactam (3)--Perinatal and postnatal study in rats with intraperitoneal administration

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor and piperacillin (PIPC) is an antibiotics which is used in clinical field widely. The combination of TAZ and PIPC (TAZ/PIPC), which is combined with TAZ and PIPC at rate of 1:4, has been developed because of PIPC is unstable to various beta-lactamases. Perinatal and postnatal toxicity were studied in rats given daily intraperitoneal doses of TAZ/PIPC (200, 800 or 1600 mg/kg/day) or TAZ (40, 320 or 1280 mg/kg/day). TAZ/PIPC or TAZ were given from day 17 of pregnancy through day 21 of lactation. Total daily doses were administered in two equally divided doses. In this study, evaluation of the late stage of gestation, parturition, lactation and maternal behavior in adult rats and postnatal evaluation of the growth and development, and reproductive performance of the F1 generation occurred. In the TAZ/PIPC, maternal toxicity (decreased food consumption) was observed at 800 and 1600 mg/kg groups during perinatal period. A slight decrease in body weight gain during perinatal period and increased pup mortality and decreased pup weight in lactation period were observed at 1600 mg/kg group. An increase in stillbirths also was observed at 1600 mg/kg group. In the TAZ, maternal toxicity (decreased food consumption) was observed at all dosage groups during perinatal period. A decrease in body weight gain also were observed during perinatal period at 1280 mg/kg group. At maternotoxic doses of 320 and 1280 mg/kg groups, decreased pup weight were observed during lactation period. An increase in stillbirths also was observed at 1280 mg/kg group. Transient, significant decrease in pup body weights at 1280 mg/kg group in early postweaning period. No other effects occurred for the F1 generation rats. In conclusion, perinatal development and postnatal growth and development of offspring were affected only at the intermediate and high doses that caused maternal toxicity in this study. Therefore it is seemed that non-observed effect dose levels (NOELs) of TAZ/PIPC for dams is less than 200 mg/kg/day and that of TAZ is less than 40 mg/mg/day, and NOELs of TAZ/PIPC is 200 mg/kg/day and that of TAZ is 40 mg/kg/day for offspring under the condition of this study.

Reproductive and developmental toxicity studies of tazobactam/piperacillin or tazobactam (2)--Teratological study in rats with intravenously administration

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor and piperacillin (PIPC) is an antibiotics which is used in clinical field widely. The combination of TAZ and PIPC (TAZ/PIPC), which is combined with TAZ and PIPC at rate of 1:4, has been developed because of PIPC is unstable to various beta-lactamases. Teratogenic potential were studied in rats given daily intravenous doses of TAZ/PIPC (625, 1250, 2500 or 3750 mg/kg/day) or TAZ (125, 500 or 3000 mg/kg/day). TAZ/PIPC or TAZ were given from day 7 to day 17 of pregnancy. Total daily doses were administered in two equally divided doses. The study includes postnatal evaluation of the growth and development and reproductive performance of the F1 generation. Maternal deaths occurred in all groups given TAZ/PIPC. The incidence (range of 3 to 6 animals/group) was not dose dependent. Maternal body weight was decreased in rats receiving 3000 mg/kg of TAZ and food consumption was reduced in all drug-treated groups. Slight decreases in fetal body weights were observed at some doses that caused maternal body-weight or food-consumption decreases (2500 or 3750 mg/kg of TAZ/PIPC, 3000 mg/kg of TAZ). But these depressions of fetal body weights were not significant from control data. There were no fetal malformations or variations attributable to the test articles. Postnatal growth and development, behavior and reproductive performance of the F1 generation were not affected by the administration of TAZ/PIPC or TAZ. In conclusion, TAZ/PIPC or TAZ was not teratogenic in the rats. It is seemed that non-observed effect dose levels (NOELs) of TAZ/PIPC and TAZ for dams is less than 625 and 125 mg/kg/day in general toxicity respectively, however, NOELs of TAZ/PIPC is 3750 mg/kg/day or more and that of TAZ is 300 mg/kg/day or more for their offspring under the condition of this study.

Reproductive and developmental toxicity studies of tazobactam/piperacillin or tazobactam(1)--Fertility and general reproduction study in rats with intraperitoneal administration

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor and piperacillin (PIPC) is an antibiotics which is used in clinical field widely. The combination of TAZ and PIPC (TAZ/PIPC), which is combined with TAZ and PIPC at rate of 1:4, has been developed because of PIPC is unstable to various beta-lactamases. Fertility and general reproductive performance were studied in rats given daily intraperitoneal doses of TAZ/PIPC (200, 800 or 1600 mg/kg/day) or TAZ (40, 160 or 640 mg/kg/day). TAZ/PIPC or TAZ were given during premating period (70 days in males and 15 days in females), the pairing period (in males and females) and the gestation and lactation periods (in females). Total daily doses were administered in two equally divided doses. The study includes evaluation of the F1 generation and the F2 generation through weaning. In the TAZ/PIPC, maternal toxicity (decreased food consumption) was observed at 200 mg/kg and above dosage groups. At maternotoxic doses of 800 and 1600 mg/kg groups, increased resorptions, decreased live litter size, and increased fetal variations (reversible changes in ribs) were observed. Reversible delays in ossification of caudal vertebrae were also observed at 1600 mg/kg group. In the TAZ, maternal toxicities were observed at 160 mg/kg group (decreased food consumption) and 640 mg/kg group (decreased body weight gain and food consumption). Furthermore, necropsy (raised and/or colored areas present in the cecum) revealed slight increases at 40 mg/kg and above dosage groups. Slight decreases in implantations and resultant slight decreases in live litter size, reversible delays in renal development, and increased stillbirths were observed at 640 mg/kg group. Postnatal growth and development, behavior and reproductive performance of the F1 generation were not affected by the administration of TAZ/PIPC or TAZ. There were no effects on any of the fetal or pup parameters evaluated in the F2 generation. In conclusion, mating behavior and fertility were not affected by TAZ/PIPC or TAZ in this study. TAZ/PIPC or TAZ caused adverse change in reproductive performance of the F0 generation only at doses that caused maternal toxicity. The F1 and F2 generation were not affected.(ABSTRACT TRUNCATED AT 400 WORDS)