MR imaging and diffusion-weighted imaging changes in metronidazole (Flagyl)-induced cerebellar toxicity.

We describe a case demonstrating reversible MR imaging findings, including diffusion-weighted imaging changes in association with metronidazole (Flagyl) toxicity. The diagnosis of metronidazole toxicity was made clinically and supported by the MR imaging findings. Quantitative apparent diffusion coefficient (ADC) maps demonstrated edema with associated increased ADC values within the dentate nuclei of the cerebellum on initial imaging. Follow-up imaging performed 8 weeks after cessation of metronidazole therapy demonstrated resolution of imaging findings, including diffusion changes.

Randomized controlled monocentric comparison of once daily ceftriaxone with tobramycin and cefotaxime three times daily with tobramycin in neutropenic fever.

A prospective, randomized, controlled monocentric trial was performed to evaluate the efficacy and safety of once daily ceftriaxone 2 g plus tobramycin 5 mg/kg in comparison to cefotaxime 2 g t.i.d. plus tobramycin 5 mg/kg qd in the treatment of neutropenic fever. In cases of fever > or = 38.5 degrees C and a neutrophil count below 1000/microliter, patients with hematological malignancies were assigned to ceftriaxone or cefotaxime, each with tobramycin. The primary endpoint was defined as defervescence < 37.5 degrees C on day 4-6 followed by at least 7 afebrile days. Secondary endpoints were overall response, defined as defervescence on day 25 and toxicity. There were 160 episodes of 114 patients included. Fever of unknown origin accounted for 79 episodes (51%), microbiologically defined infection for 36 (23%), clinically defined infection for 27 (17%), and both clinically and microbiologically defined infection for 14 episodes (9%). On an intent-to-treat basis 156 episodes could be evaluated for the primary endpoint. Ceftriaxone plus tobramycin and cefotaxime plus tobramycin resulted in a primary response in 46.9% and 45.3%, respectively. Overall response was achieved on study day 25 in 87.7% and 80%, respectively. No significant difference in toxicity was observed. Once-daily ceftriaxone plus tobramycin was not inferior to cefotaxime t.i.d. plus tobramycin qd in the empirical treatment of neutropenic fever.

The effect of fosfomycin on glycopeptide antibiotic-induced nephrotoxicity in rats.

The effect of coadministration of fosfomycin (FOM) on glycopeptide antibiotic-induced nephrotoxicity for 3 days was investigated in rats. To induce nephrotoxicity in a short time, gentamicin (GM) was also coadministered. In the present study, FOM decreased glycopeptide antibiotic-induced nephrotoxicity as shown by reduced urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) as well as fewer histopathological signs of nephrotoxicity in the groups treated with the combination of glycopeptide and FOM as compared with a glycopeptide alone. In addition, the higher the dose of FOM, the more it decreased urinary NAG levels, suggesting that the role of FOM in alleviating nephrotoxicity is dose dependent. The accumulation of teicoplanin and vancomycin was significantly lower in the renal cortex of rats treated with the combination of glycopeptide antibiotics and FOM as compared with glycopeptide antibiotics alone (P < 0.05). In conclusion, the concomitant administration of FOM and glycopeptide antibiotics may help to achieve a chemotherapeutic strategy that reduces the nephrotoxic effects of glycopeptide antibiotics.

The Candida albicans INT1 gene facilitates cecal colonization in endotoxin-treated mice.

Increased intestinal colonization with Candida albicans is believed to be a major predisposing factor to systemic candidiasis. Previous evidence has implicated the C. albicans INT1 gene in hyphal development, epithelial adherence, and mouse virulence. The effect of INT1 on mouse cecal colonization was measured using a parent strain (CAF2, INT1/INT1), an int1 deletion homozygote (CAG3, int1/int1), and a heterozygous reintegrant (CAG5, int1/int1 + INT1). Forty-eight hours after oral inoculation of 10(7) C. albicans into normal mice, only low numbers of each strain were recovered from the cecal flora. In mice pretreated with oral bacitracin/streptomycin, cecal colonization of each C. albicans strain was increased compared to the corresponding strain inoculated into untreated mice, with the CAF2 parent strain greater (P < 0.01) than the two mutant strains, and with the heterozygous and homozygous mutants not different from each other. In mice pretreated with parenteral lipopolysaccharide (LPS), in addition to oral antibiotics, numbers of cecal CAF2, CAG5, and CAG3 were increased (P < 0.01) compared to the corresponding strain inoculated into mice treated with antibiotics alone. In LPS-treated mice, numbers of cecal C. albicans CAF2 (INT1/INT1) were greater (P < 0.05) than C. albicans CAG3 (int1/int1). Thus, parenteral LPS had an additive effect on C. albicans cecal colonization in antibiotic-treated mice, and the presence of two functional copies of the INT1 gene appeared to facilitate colonization in both antibiotic-treated mice and in mice treated with antibiotics plus parenteral endotoxin.

Synercid Aventis.

Rhône-Poulenc Rorer (RPR) developed Synercid (RP-59500), an injectable synergistic combination of quinupristin and dalfopristin as a treatment for a variety of infections caused by Gram-positive anaerobic bacteria. The treatment was approved in the UK in July 1999, for use in patients with nosocomial pneumonia, skin and soft tissue infections and clinically significant infections due to Enterococcus faecium when there is no other active antibacterial agent [337556,335257]. It was launched in the UK and the US in September 1999 [342899]. In December 1999, Synercid successfully completed the Mutual Recognition Procedure in the EU under Aventis Pharma for use in patients with these infections [351525]. In September 2000, Merrill Lynch predicted first-year sales in 1999 of Euro 15 million, rising to Euro 171 million in 2004 [384874]. In January 1999, BT Alex Brown predicted sales of US $88 million in 1999 rising to US $450 million in 2002 [318220]. In April 1999, ABN Amro predicted annual sales of DM 30 million in 1999, rising to DM 150 million in 2002 [328676].

[Nephrotoxicity and drug interaction of vancomycin (2)].

Vancomycin hydrochloride (VCM) has an antibacterial action against Gram positive bacteria, e.g., Methicillin-resistant Staphylococcus aureus (MRSA). In the clinical situation, there are patients with serious infections, being infected with not only MRSA, but also with Gram negative bacteria like Pseudomonas aeruginosa. Because VCM has the adverse reaction of nephrotoxicity, we are apprehensive about using VCM with other antibiotics, which might increase this problem. Therefore, the nephrotoxic effects and pharmacokinetics of VCM were examined in rabbits and compared with those in rabbits administered with VCM and other antibiotics. Responses indicating nephrotoxicity such as increases of serum creatinine concentration and BUN and morphological changes of the kidney were induced by the single injection of VCM at 300 mg/kg, i.v. In contrast, no abnormality of clinical data and morphological alteration were observed in the groups injected with VCM and imipenem (IPM)-cilastatin sodium (CS), flomoxef sodium (FMOX) or fosfomycin sodium (FOM). This was not true for groups injected with VCM and ceftazidime, cefpimizole sodium (CPIZ) or cefoperazone sodium. Clearance of VCM increased obviously in the groups injected with VCM and IPM-CS, FMOX or FOM, but decreased in those given VCM and CPIZ. Since the renal concentrations of VCM in the groups that were administered VCM with IPM-CS, FMOX or FOM were lower than that in the control group, IPM-CS, FMOX and FOM may decrease the nephrotoxicity of VCM by inhibiting its uptake into the kidney.

[Nephrotoxicity and drug interaction of vancomycin].

We examined drug interactions of vancomycin hydrochloride (VCM) in the rabbit kidney. VCM has an antibacterial action against Gram positive bacteria, but composite infection patients must be jointly treated with antibiotics that are effective on Gram negative bacteria, e.g., imipenem (IPM)-cilastatin sodium (CS) compounding agent. Both VCM and IPM have the adverse reaction of nephrotoxicity, whereas CS restrains the nephrotoxicity of IPM. To clarify the interactions, we examined the nephrotoxicity and pharmacokinetics of VCM in the rabbit and compared them with those in rabbits administered VCM with CS or IPM-CS. Symptoms of nephrotoxicity such as an increase of serum creatinine concentration and BUN and a morphological change of the kidney were observed with iv. injection of VCM at 300 mg/kg. However, no abnormality of clinical data and morphological alteration were observed in the groups injected with VCM plus CS or IPM-CS. Clearance and urinary excretion of VCM obviously increased in the groups injected with VCM plus CS or IPM-CS. In addition, it was estimated that VCM was actively transported by observation of the uptake in rabbit renal slices. Furthermore, the uptake rate of VCM in the renal cortex was significantly decreased by CS. Together with the above findings, it is suggested that the restraint effect of VCM uptake into nephrocytes by CS is one of the decreasing mechanisms of the nephrotoxic effect of VCM.

Noncytotoxic combinations of topical antimicrobial agents for use with cultured skin substitutes.

Cultured skin grafts are destroyed more easily than split-thickness skin grafts by common burn wound organisms, including gram-negative and gram-positive bacteria and fungi. To increase the survival and engraftment of cultured skin grafts, formulations of antimicrobial agents were tested for cytotoxicity to cultured human keratinocytes and fibroblasts and for activity against common organisms from burn wounds. On the basis of previous studies, a base formulation containing neomycin (40 micrograms/ml), polymyxin B (700 U/ml), and mupirocin (40 micrograms/ml) was prepared, to which ciprofloxacin (20 micrograms/ml) or norfloxacin (20 micrograms/ml) and amphotericin B (0.25 microgram/ml) or nystatin (100 U/ml) were added. Toxicity to cultured human cells was determined by the growth response of cell cultures (n = 6) to each drug combination over 4 days. Activity against clinical isolates (n = 40) of Staphylococcus aureus, Pseudomonas aeruginosa, other gram-negative bacteria, and Candida spp. was determined by the wet disc assay. Analysis of variance testing showed no significant differences in the growth of keratinocytes or fibroblasts under control or experimental conditions. Medium without antimicrobial agents was not effective against any of the 40 microbial strains tested. The base formulation was effective against all bacterial strains tested but against none of the fungi, while all experimental formulations were effective against all microbial strains tested. These findings suggest that neomycin, mupirocin, and polymyxin B may be combined with a quinolone and an antimycotic agent to provide broad antimicrobial activity for a formulation for topical use with cultured skin on burns. However, the formulations described here are strictly experimental and are not recommended for clinical use without further evaluation.

[Susceptibility of bacterial isolates from the equine respiratory tract to trimethoprim, sulfadoxine, sulfadimethoxine and combinations of these compounds]. / Empfindlichkeit bakterieller Krankheitserreger aus dem Respirationstrakt von Pferden gegenüber Trimethoprim, Sulfadoxin, Sulfadimethoxin und Kombinationen dieser Wirkstoffe.

Using a broth microdilution technique, the in vitro susceptibility of bacterial isolates from the equine respiratory tract to trimethoprim, sulfadoxine, sulfadimethoxine, and combinations of these compounds was determined. The bacterial strains (n = 88) isolated recently from horses with respiratory symptoms belonged to the following species: Streptococcus equi subsp. zooepidemicus (n = 34), Streptococcus equi subsp. equi (n = 22), Staphylococcus aureus (n = 9), Klebsiella pneumoniae (n = 7), Rhodococcus equi (n = 4), Pseudomonas spp. (n = 3) and Escherichia coli (n = 3). In addition, two isolates of Enterobacter spp. and one isolate of Streptococcus equisimilis, Staphylococcus intermedius, Proteus mirabilis and Serratia marcescens were examined. For determination of susceptibility of an organism the following minimal inhibitory concentrations (MIC) were fixed as limiting values: Trimethoprim < or = 0.5 microgram/ml, sulfadoxine < or = 32 micrograms/ml, sulfadimethoxine < or = 32 micrograms/ml, trimethoprim/sulfadoxine < or = 0.5/32 micrograms/ml, trimethoprim/sulfadimethoxine < or = 0.5/32 micrograms/ml. As expected, Rhodococcus-equi-isolates were resistant to the antimicrobials tested. However, most of the clinically more common isolates showed a high degree of susceptibility to the combinations. The fractional inhibitory concentration (FIC) indices indicated synergism of the combination-partners in a wide range. According to these in vitro results, application of trimethoprim/sulfonamide combinations for the initial therapy of equine respiratory tract infections can be recommended.

[Single-dose toxicity studies of tazobactam/piperacillin and tazobactam].

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor. Tazobactam/Piperacillin (TAZ/PIPC) is a formulation consisting of TAZ and PIPC in a ratio of 1:4. Singe-dose toxicity studies in TAZ/PIPC and TAZ were carried out using mice and rats of both sexes and male dogs. The results were as follows. 1. A common clinical sign in mice and rats administered TAZ/PIPC or TAZ by all routes was soft stool. Other signs in mice and rats included a decrease in spontaneous motor activity and/or a decreased respiratory rate for the intraperitoneal (i.p.), subcutaneous (s.c.) or intravenous (i.v.) route. The animals administered by the i.v. route showed tremor for mice and clonic convulsion for rats before death. Hyperemia, hemorrhage or edema of the lung, and hemorrhage of the digestive tract were observed in these animals at necropsy. An enlargement of the spleen was seen in some of the surviving animals treated with TAZ/PIPC. 2. In dogs, TAZ/PIPC caused vomiting, and TAZ caused vomiting, respiratory abnormality, soft stool and diarrhea by the intravenous (i.v.) administration. 3. TAZ/PIPC or TAZ caused clinical signs such as the loss of hair at the injection site for the s.c. route, and necrosis of the tail for the i.v. route in mice and rats, also caused limping of the injected anterior limb in dogs. Necrosis and hemorrhage at the injection site, and peritonitis by the i.p. injection were observed at necropsy. These findings were due to the irritation of TAZ/PIPC or TAZ.(ABSTRACT TRUNCATED AT 250 WORDS)

[A six-month intraperitoneal repeated dose toxicity study of tazobactam/piperacillin and tazobactam in rats].

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor. Tazobactam/Piperacillin (TAZ/PIPC) is a formulation consisting of TAZ and PIPC in a ratio of 1:4. A six-month intraperitoneal repeated dose toxicity study of TAZ/PIPC and TAZ including a one-month recovery period were carried out using male and female rats. The doses were 200, 400 and 800 mg/kg/day for TAZ/PIPC, and 40, 80 and 160 mg/kg/day for TAZ. The results were as follows. 1. No test article-related deaths occurred during the study period. No effect on clinical finding of survival rats was evident. 2. There was no dose-related increases of food consumption in both the males and females given TAZ/PIPC and PIPC. Slight reductions in body weight gain occurred in males given 800 mg/kg/day of TAZ/PIPC. 3. Decreases in erythrocyte, hemoglobin and hematocrit, and increases in reticulocytes were seen only at study termination in the group given 800 mg/kg/day of TAZ/PIPC. Increases in reticulocytes were seen only at study termination in the females given 80 or 160 mg/kg/day of TAZ. 4. A decrease in triglyceride levels was observed in the males given 800 mg/kg/day of TAZ/PIPC or 160 mg/kg/day of TAZ. 5. The ophthalmoscopic examination or urinalysis show no test article-related changes. 6. Enlarged ceca in all groups of animals given TAZ/PIPC and in the females given 160 mg/kg/day of TAZ were observed. 7. An increase of relative organ weight in liver was noted in the males and females given 800 mg/kg/day of TAZ/PIPC, in the males given 80 or 160 mg/kg/day of TAZ and in the females given 160 mg/kg/day of TAZ. 8. In the hepatocytes, accumulation of PAS-positive materials which was identified histochemically and ultrastructurally as glycogen, was present in the males given 800 mg/kg/day of TAZ/PIPC and in the males given 80 or 160 mg/kg/day of TAZ. 9. After a one-month recovery period, the changes of liver had generally disappeared, suggesting that they were reversible. 10. From the histopathological changes of liver, the no-toxic dose level in both the males and females was 400 mg/kg/day and 40 mg/kg/day for TAZ/PIPC and TAZ, respectively.

[A six-month intravenous repeated dose toxicity study of tazobactam/piperacillin and tazobactam in dogs].

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor. Tazobactam/Piperacillin (TAZ/PIPC) is a formulation consisting of TAZ and PIPC in a ratio of 1:4. A six-month intravenous repeated dose toxicity study of TAZ/PIPC and TAZ including a one-month recovery period were carried out using male and female dogs. The doses were 200, 400 and 800 mg/kg/day for TAZ/PIPC, and 40, 80 and 160 mg/kg/day for TAZ. The results were as follows. 1. No test article-related deaths occurred during the study period. No effects on clinical findings, body weight and food consumption were evident. 2. No test article-related changes were noted in hematological, serum biochemical and urinalysis evaluations, and opthalmological and electrocardiographic examinations. 3. There were no test article-related changes in macroscopic findings or organ weight. 4. The histopathological examination revealed deposition of marked PAS-positive aggregates in liver cells of dogs given 400 mg/kg/day or more of TAZ/PIPC and 80 mg/kg/day or more of TAZ. Electron micrographs of hepatocytes revealed glycogen granules to be accumulated in the cytoplasm, and an increase of smooth endoplasmic reticulum. 5. After a one-month recovery period, the histopathological changes had generally disappeared, suggesting that they were reversible. 6. From the histopathological changes of liver, the no-toxic dose levels for TAZ/PIPC and TAZ were 200 mg/kg/day and 40 mg/kg/day, respectively.

[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)

[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.

[Mutagenicity tests of tazobactam/piperacillin, tazobactam and piperacillin].

As a part of safety tests of tazobactam/piperacillin (TAZ/PIPC), the reverse mutation tests using bacteria, the chromosomal aberration tests using cultured cells and the micronucleus tests using male mice were conducted in order to evaluate the in vitro and in vivo mutagenicity of TAZ, PIPC, TAZ/PIPC. 1. The reverse mutation tests were carried out on TAZ, PIPC and TAZ/PIPC at dose ranges, where few antibacterial effects could be detected, using Salmonella typhimurium strains TA100, TA1535, TA98 and TA1537, and Escherichia coli WP2uvrA. All of three test articles showed that no significant increases were observed in the number of colonies in all tester strains in both systems, with and without mammalian metabolic activation (S9 Mix), as compared with solvent controls. 2. The chromosomal aberration tests were carried out on these test articles using cultured Chinese hamster lung cells (CHL). The cells were treated with TAZ, PIPC or TAZ/PIPC at the doses of 2.5, 5.0 and 10 mM with and without S9 Mix. In the test of PIPC with S9 Mix, the dose of 1.25 mM was set in addition to the three doses. The incidences of structural- and numeral-aberration were 0-3% in the absence or presence of mammalian metabolic activation system, and no significant increases were observed in the incidence of chromosomal aberrations as compared with solvent controls. 3. The micronucleus tests were carried out at doses of 625-5000 mg/kg of TAZ or TAZ/PIPC, or at 625-2500 mg/kg of PIPC. The femoral marrow cells were 48 h after administering intravenously to CD-1 male mice. The frequencies of polychromatic erythrocyte with micronuclei were 0.02-0.17%, 0.02-0.10% and 0.03-0.07% in the groups treated with TAZ, PIPC and TAZ/PIPC, respectively, and no significant increases were observed with dose dependence. The results indicated that these test articles were negative in the assessment standard using the background data. 4. The present study indicates that TAZ, PIPC and TAZ/PIPC have no in vitro and in vivo mutagenic potential.

Nephrotoxicity of gentamicin and co-trimoxazole combination in rats.

1. The nephrotoxicity of gentamicin is well known. However, little information is available regarding the combined effects of gentamicin plus co-trimoxazole (sulfamethoxazole-trimethoprim). Therefore, Wistar rats were treated daily with 100 mg/kg gentamicin or 100 mg/kg gentamicin plus 30 mg/kg trimethoprim-150 mg/kg sulfamethoxazole for 14 days. 2. Serum biochemical parameters were measured on days 0, 8 and 15, and histopathological examinations of kidneys were performed on day 15, one day following end of treatment. Gentamicin treated rats exhibited a 63% increase in blood urea nitrogen (BUN), a 124% increase in uric acid, and a 63% decrease in serum potassium levels on day 15. 3. The combination of gentamicin plus co-trimoxazole partially ameliorated these effects. With the three drug combination no change occurred in BUN, and only a 30% decrease occurred in serum potassium levels. 4. While serum creatinine levels significantly increased following gentamicin, the co-administration of co-trimoxazole resulted in a significant decrease (30%) in creatinine. Histopathological examinations of kidneys suggested a lower degree of nephrotoxicity in rats treated with gentamicin plus co-trimoxazole as compared to animals treated with gentamicin alone. 5. The results support the importance of monitoring serum biochemical parameters when treating with gentamicin or gentamicin plus co-trimoxazole.

[A study on nephrotoxicity of arbekacin and vancomycin in rats].

Nephrotoxicities of arbekacin (ABK) and/or vancomycin (VCM) were examined by administrating rats intravenously with single doses or 10 times repeated daily doses. ABK was found less toxic to kidney than VCM, and the toxicity was strengthened by combined treatment with VCM and ABK. Fosfomycin decreased the nephrotoxicity when added to the single or combined treatment with ABK and VCM.

A comparative study of enzymuria, in the rat, of the drug combinations amikacin/vancomycin and amikacin/teicoplanin.

The aim of this study was to compare nephrotoxicity of the combinations amikacin/vancomycin and amikacin/teicoplanin. Eighteen male Wistar rats were divided into 3 groups of 6 animals each. The first group received 50 mg.kg-1 of amikacin (i.m. route) and 100 mg.kg-1 of vancomycin (i.p. route). The second group received 50 mg.kg-1 of amikacin (i.m. route) and 40 mg.kg-1 of teicoplanin (i.p. route). The third group received an isotonic solution of sodium chloride. The antibiotics were injected for a period of 6 days. Urine samples of animals were taken 24 h before the beginning of the experiment, then every day, throughout the duration of the treatment (6 days), continuing for an additional 3 days following completion of the administration of the drugs. There were no significant modifications in the urinary excretions of alanine aminopeptidase and the creatinine between the 3 groups; but in the group receiving amikacin/teicoplanin, we observed between days 3 and 8 an increase in the excretion of N-acetyl-beta-D- glucosaminidase when compared to the group receiving amikacin/vancomycin (p < or = 0.05) and to the control group (p < or = 0.01).