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Pharmacokinetics of intravenously administered cefmetazole and cefoxitin and effects of probenecid on cefmetazole elimination.

Sixteen healthy male volunteers participated in a randomized, balanced, three-way crossover study comparing the pharmacokinetics of cefmetazole, cefoxitin, and cefmetazole with probenecid pretreatment. Single 2-g doses of cefmetazole sodium and cefoxitin sodium were given intravenously as a 5-min infusion. Concentrations of cefmetazole and cefoxitin were determined by using a specific semiautomated high-performance liquid chromatographic method. Concentration-time profiles of cefmetazole and cefoxitin declined in a biexponential manner from peak levels. Compared with cefoxitin, cefmetazole had a significantly (P less than 0.05) higher mean (+/- standard error of the mean) peak concentration in serum (290 +/- 11 versus 244 +/- 10 micrograms/ml), a longer terminal disposition half-life (1.50 +/- 0.14 versus 0.81 +/- 0.04 h), lower systemic clearance (111.7 +/- 4.7 versus 279 +/- 12 ml/min) and renal clearance (78.7 +/- 4.3 versus 221 +/- 14 ml/min) of intact drug, and a slightly smaller steady-state volume of distribution (10.3 +/- 0.21 versus 12.8 +/- 0.48 liters). Mean recoveries of cefmetazole and cefoxitin in urine were approximately 71 and 77%, respectively. Pretreatment of volunteers with probenecid (1 g orally) significantly (P less than 0.05) increased concentrations of cefmetazole in serum 1 h after drug administration without significantly increasing maximum concentrations in serum. Mean areas under the concentration-time curve (466 +/- 27 versus 295 +/- 13 micrograms.h/ml) and terminal disposition half-lives (2.27 +/- 0.13 versus 1.50 +/- 0.14 h) of cefmetazole increased. Systemic clearance (72.1 +/- 4.0 versus 111.7 +/- 4.7 ml/min) and renal clearance (47.4 +/- 4.0 versus 78.7 +/- 4.3 ml/min) of intact antibiotic decreased. Mean recoveries (65.9 +/- 3.7 versus 71.0 +/- 3.2%) of intact cefmetazole in urine were not significantly (P > 0.05) different. Elimination of cefmetazole in urine was also significantly prolonged by probenecid, with substantial concentrations of cefmetazole (>/= 20 micrograms/ml) found in the 12- to 24-h urine collection for 14 to 16 volunteers. The results show that cefmetazole remains at clinically relevant concentrations (1 to 2 micrograms/ml) approximately twice as long as cefoxitin, that serum cefmetazole can be maintained longer at clinically significant concentrations with preadministration of probenecid, and that cefmetazole is partially eliminated by renal tubule secretion.

Adult↗

Pharmacokinetics of single-dose cefmetazole following intramuscular administration of cefmetazole sodium to healthy male volunteers.

The tolerance and pharmacokinetics of cefmetazole were studied in healthy male volunteers who received a placebo (sterile saline) or a single dose of cefmetazole sodium intramuscularly. Drug-treated volunteers received one of four doses, 0.375, 0.750, 1, or 2 g. The drug was well tolerated, with no adverse medical events or laboratory changes observed during the study that could affect the pharmacokinetic interpretation of the data. Cefmetazole concentrations were determined by using a specific high-performance liquid chromatographic method. Serum cefmetazole concentrations were well described by a one-compartment open model with first-order absorption and elimination. Cefmetazole was rapidly absorbed in most volunteers, with a mean time to maximum concentration in serum of 1.24 +/- 0.12 h (+/- standard error of the mean), and the mean maximum concentration in serum increased from 17.0 +/- 1.6 to 74.2 +/- 9.5 micrograms/ml over the 0.375- to 2-g dose range. Maximum concentrations in serum, areas under serum concentration-time curve, and urinary excretion of intact drug increased in proportion to cefmetazole sodium dose. Times at which maximum concentrations in serum occurred, apparent volumes of distribution, steady-state volumes of distribution, absorption and elimination half-lives, and systemic clearances did not change significantly (P greater than 0.05) with drug dose. Although absorption and elimination half-lives were not significantly different in 10 of 40 volunteers (P greater than 0.05), in a majority of subjects elimination half-lives were approximately 10 times longer than absorption half-lives. The mean recovery of intact drug in urine ranged from 68.8 to 86.0% over the dose range studied, with a mean recovery over all doses of 77.1 +/- 2.4%. Rental clearances were significantly lower (P < 0.05) for the two lowest doses (93.0 and 84.3 versus 115.0 and 118.0 ml/min); these differences are not considered clinically important. The results of this study indicate that cefmetazole pharmacokinetics are linear after administration of single intramuscular doses ranging from 0.375 to 2 g, that clinically relevant concentrations of cefmetazole in serum (1 to 2 micrograms/ml) persist in a majority of volunteers for more than 8 h after administration of 0.750-g or higher doses, and that clinically relevant concentrations of cefmetazole continue to be excreted in urine 8 to 12 h after administration of 0.375- to 2-g doses.

Adolescent↗

[The evaluation of cefmetazole in clinical use. The study group of cefmetazole in clinical use].

To study the clinical effect of cefmetazole (CMZ), we treated with CMZ 1,926 patients with various infections involving the respiratory tract, gastrointestinal tract, liver and biliary tract, skin and soft tissue and others. The marked effect rate was 56.5%, and the effect rate 33.7%. The sensitivity test of CMZ was also performed in vitro. Staphylococcus aureus, streptococcus, staphylococcus epidermis, E. coli, S. typhi, B. salmonella, B. shigella, B. Klebsiella pneumoniae, B. proteus, etc. were sensitive to CMZ. Injecting CMZ can prevent the infection of operation. The study of the adverse reaction of CMZ showed, an adverse reaction rate of 4.2% (the gastrointestinal tract, allergy, kidney and nervous system). These results suggested that CMZ is an antibiotic of broad spectrum, high efficacy and low toxicity. It is effective in treating sensitive bacterial infection, unknown pathogenic infection and mixed bacterial infection, and preventing infection in surgery.

Adolescent↗

Stability of cefmetazole-doxycycline mixtures in sodium chloride and dextrose injections.

This study involved the mixing of cefmetazole 1 and 2 Gm with doxycycline 100 and 200 mg, in sodium chloride and dextrose injections. The mixtures were stored either at ambient temperature for 96 h or at 4 degrees C for 168 h followed by 8 h at ambient temperature. HPLC assay of both cefmetazole and doxycycline levels were performed at prescribed sampling times. Cefmetazole 1 Gm in doxycycline 100 and 200 mg mixtures, in sodium chloride injection was not stable up to 4 h, but cefmetazole 2 Gm in doxycycline 100 and 200 mg mixtures, in sodium chloride injection was stable for up to 24 h. The cefmetazole controls were stable for 72 h in sodium chloride injection. Cefmetazole 1 Gm with doxycycline 100 mg, in dextrose injection was stable up to 72 h. The 2 Gm cefmetazole and 100 mg doxycycline mixture in dextrose injection was stable for 96 h. Cefmetazole 1 Gm and doxycycline 200 mg in dextrose injection was stable up to 96 h, but the 2 Gm cefmetazole-200 mg doxycycline mixture was only stable for 72 h. Cefmetazole controls in dextrose injection were stable for 24 h. Doxycycline 100 and 200 mg were stable with cefmetazole 1 and 2 Gm, in both sodium chloride and dextrose injections for 96 h at ambient temperature. Doxycycline control solutions were also stable for 96 h. Cefmetazole 1 and 2 Gm and doxycycline 100 and 200 mg were generally stable in both sodium chloride and dextrose injections at 4 degrees C for 168 h, and at ambient temperature for 8 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Cefmetazole↗

Review of the in-vitro spectrum and characteristics of cefmetazole (CS-1170).

The in-vitro antimicrobial qualities of cefmetazole are summarized from a review of over 30 publications. Cefmetazole, a 7 alpha-methoxy cephalosporin, is shown to have an antimicrobial spectrum closely resembling cefoxitin's. However, cefmetazole is approximately two- to eight-fold more active than cefoxitin against commonly isolated species such as Escherichia coli, Klebsiella spp., Proteus mirabilis, Staphylococcus aureus, pyogenic streptococci, pneumococci, and Haemophilus influenzae. Cefmetazole is also active against anaerobic pathogens, Neisseria spp., Citrobacter diversus, indole-positive Proteus spp. and Branhamella catarrhalis. Cefmetazole is bactericidal against aerobic and anaerobic pathogens. Its MICs and MBCs are minimally influenced by high inoculum concentrations. beta-Lactamases failed to hydrolyze cefmetazole significantly and cefmetazole is considered the most stable of the cephamycin drugs. Some Bacteroides strains produce beta-lactamases that are uniquely inhibited by cefmetazole. In-vitro tests with cefmetazole have been evaluated and interpretive criteria established for NCCLS methods: susceptible greater than or equal to 18 mm (less than or equal to 8.0 mg/l) and resistant less than or equal to 14 mm (greater than or equal to 32 mg/l). The consistent cross-resistance and -susceptibility observed between cefmetazole and cefoxitin requires the testing of only one of these agents routinely. Quality control guidelines for cefmetazole disc diffusion (30 micrograms disc) and dilution tests are summarized in this review.

Bacteria↗

Disposition of cefmetazole in healthy volunteers and patients with impaired renal function.

The disposition of cefmetazole was studied in 25 subjects with various degrees of renal function after a 1,000-mg, constant-rate, 30-min intravenous infusion of cefmetazole sodium. In six subjects with creatinine clearance (CLCR) of greater than 90 ml/min per 1.73 m2 (group 1), the terminal elimination half-life (t1/2 beta) was 1.31 +/- 0.54 h (mean +/- standard deviation), cefmetazole total body clearance (CLP) was 132.8 +/- 25.1 ml/min per 1.73 m2, and volume of distribution at steady state was 0.165 +/- 0.025 liter/kg. The fraction of dose excreted unchanged in the urine was 84.0% +/- 26.1%. Subjects with CLCRS of 40 to 69 (group 2, n = 6) and 10 to 39 (group 3, n = 6) ml/min per 1.73 m2 demonstrated prolongation of the t1/2 beta (3.62 +/- 1.06 and 5.93 +/- 1.81 h, respectively) and significant reductions in cefmetazole CLP (52.8 +/- 14.3 and 30.2 +/- 10.2 ml/min per 1.73 m2, respectively), compared with group 1. In seven subjects on chronic hemodialysis (group 4) studied during an interdialytic period, the cefmetazole t1/2 beta was increased to 24.10 +/- 8.12 h and the CLP was reduced to 6.8 +/- 2.1 ml/min per 1.73 m2. Cefmetazole CLP correlated positively with CLCR (r = 0.951, P less than 0.001): CLP = (1.181 . CLCR) -- 0.287. The disposition of cefmetazole was also assessed in six group 4 subjects during an intradialytic period. The t1/2 beta during hemodialysis (2.09 +/- 0.69 h) was significantly shorter than that observed during the interdialytic period. The hemodialysis clearance of cefmetazole was 86.1 +/- 20.1 ml/min, and the fraction of cefmetazole removed during hemodialysis was 59.8% +/- 5.9%. It is recommended that patients with renal insufficiency received standard doses of cefmetazole at extended intervals and patients on maintenance hemodialysis received standard doses after hemodialysis.

Adolescent↗

[Clinical evaluation of cefmetazole in urological infections].

Clinical efficacy of Cefmetazole was evaluated at four university hospitals and their related hospitals in Nagoya. For the treatment of urinary tract infections with or without complications, 177 patients were administered Cefmetazole. Of these patients, 69 had chronic complicated urinary tract infection defined in the UTI manual and 20 had simple acute pyelonephritis. The other urological infections for which Cefmetazole was administered included prostatitis, epididymitis, urosepsis and wound infections. Fifty four patients were given Cefmetazole intravenously after urological operation to prevent wound and urinary tract infections. The overall clinical efficacy of Cefmetazole for UTI was 76.8%; 84.4% for group 1, 85.7% for group 3, 75% for group 4, 44.4% for group 5 and 66.6% for group 6. In acute pyelonephritis due to E. coli, Klebsiella, Serratia, S. aureus, alpha-Streptococcus and S. epidermidis all patients were cured by Cefmetazole administration. Clinical efficacy of Cefmetazole was assessed to be excellent in 6 cases of prostatitis and 6 cases of acute epididymitis. E. Coli, Serratia and some organisms disappeared from blood after the administration of Cefmetazole but Pseudomonas persisted even after treatment. Postoperative administration of Cefmetazole was effective for eradication of bacteria from the urine in 26 out of 30 patients and in prevention of infection in 24 cases. After the administration of Cefmetazole skin eruption was observed in one patient and nausea in another. Slight elevation of GOT, GPT and total bilirubin was noted in 3 of the 177 patients after medication.

Adult↗

Cefmetazole (CS-1170), a "new" cephamycin with a decade of clinical experience.

In vitro and in vivo study results were reviewed from cefmetazole, a "new" parenteral cephamycin. Cefmetazole's spectrum of activity was comparable to that of second-generation cephalosporins, which includes clinical coverage of many Enterobacteriaceae, Staphylococcus spp., streptococci, Haemophilus spp., pathogenic Neisseria, Branhamella catarrhalis, and anaerobic bacteria. Cefmetazole was generally more potent (two- to eightfold) than cefoxitin against organisms within their spectrums and was particularly active for staphylococci (MIC90, 2.0 micrograms/ml). Methicillin-resistant S. aureus strains were more susceptible to cefmetazole alone or in combination (fosfomycin) than any other cephamycin. Cefmetazole has demonstrated excellent stability to aerobic and anaerobic organism-produced beta-lactamases. It also inhibits Type I cephalosporinases and, uniquely, some other cephalosporinases produced by the Bacteroides. This superior stability, enzyme interaction, and better penetration into bacterial cells results in a sustained bactericidal effect and a capacity for more infrequent dosing. The cefmetazole serum elimination half-life was 1.5 hr, also justifying use at greater than or equal to 8-hr intervals. Clinical trials in the United States and Japan demonstrated an acceptably high cefmetazole infection cure rate (88% to 100%), especially in direct comparative studies with cefoxitin. Cefmetazole was also proven very effective in minimizing infectious wound morbidity (prophylaxis) using 2 g single- or multidose regimens. Adverse drug reactions were usually minor; in the Japanese surveillance trial (118,318 patients) the rate was only 2.2% (8.8% in United States). Cefmetazole has been extensively and safely used in Japan since 1980.

Bacteria↗

Biliary excretion and choleretic effect of cefmetazole in rats.

The effect of cefmetazole, a broad-spectrum cephalosporin, on bile flow and composition in rats was studied. Intravenous injection of cefmetazole at doses ranging from 40 to 400 mumol/kg of body weight led to an increase in its biliary concentration and excretion rate, with a maximum at 30 min after injection. Excretion of cefmetazole into bile was associated with a marked choleresis. The magnitude of the increase in bile flow was dose dependent, with a maximal increase at a dose of 200 mumol/kg. Cefmetazole administration did not affect the secretion of bile acids or their osmotic activities, whereas the bile acid-independent bile flow increased by 49% at a dose of 200 mumol/kg. Cefmetazole administration at a dose of 200 mumol/kg significantly increased the biliary outputs of sodium, potassium, chloride, and bicarbonate (+36, +56, +28, and +31%, respectively) compared with outputs of controls. A linear relationship was observed between bile flow and cefmetazole excretion, 44 microliters of bile being produced per mumol of cefmetazole excreted into bile. Our results demonstrate that cefmetazole induces choleresis by stimulating bile acid-independent bile flow. This effect appears to be partly due to the osmotic properties of cefmetazole transported into bile.

Animals↗

High-performance liquid chromatographic method for determination of cefmetazole in human serum.

A fast, specific, sensitive high-performance liquid chromatographic method for the determination of cefmetazole in human serum was developed. The serum samples were deproteinized by adding 5% trichloroacetic acid in methanol containing barbital as an internal standard and were injected onto a reverse-phase column (mu-Bondapak C18) with a mobile phase of 10 to 15% acetonitrile in 0.005 M citrate buffer (pH 5.4). Eluted components were detected by UV absorption at 254 nm. Cefmetazole and the internal standard were separated from interfering serum components by this method. The peak height ratio of cefmetazole to the internal standard was proportional to the cefmetazole concentration in the range from 0.4 to 100 micrograms/ml. Serum samples obtained from three patients after a single intravenous injection of cefmetazole were assayed by this method and by a microbiological method. There was a good correlation between two assay methods (correlation, coefficient, 0.98). The stability of cefmetazole in human serum was (correlation coefficient, 0.98). The stability of cefmetazole in human serum was also determined by this method. Cefmetazole was stable in human serum for 2 weeks at 4 degrees C or for at least 8 weeks if it was kept frozen. As the high-performance liquid chromatography method is simple, specific, accurate, and reproducible, it appears to be more suitable for routine assay of cephalosporins than other assay methods.

Biological Assay↗

Antibacterial activity of cefmetazole alone and in combination with fosfomycin against methicillin- and cephem-resistant Staphylococcus aureus.

In vitro and in vivo antibacterial activities of cefmetazole alone and in combination with fosfomycin against methicillin- and cephem-resistant (MR) strains of Staphylococcus aureus were investigated, and the mechanism of synergistic effect between cefmetazole and fosfomycin was also studied. Cefmetazole inhibited the growth of 71 strains of MR S. aureus at concentrations ranging from 1.56 to 50 micrograms/ml; the antibacterial activity of cefmetazole against these strains was enhanced approximately 4 times with the addition of fosfomycin at a concentration of 1.56 micrograms/ml. The binding affinity of cefmetazole for the penicillin-binding protein 2' fraction specific for MR S. aureus was higher than that of methicillin, cloxacillin, cefazolin, and cefotaxime. A synergy experiment in vitro was performed by checkerboard titration with Mueller-Hinton agar plates containing various concentrations and ratios of cefmetazole and fosfomycin. The fractional inhibitory concentration index ranged from 0.09 to 0.75. Exposure of cefmetazole plus fosfomycin to exponentially growing cultures at a concentration at which both antibiotics had no bactericidal effect when given alone exerted bactericidal action. Combined administration of cefmetazole with fosfomycin at a ratio of 1:1 against systemic MR S. aureus infections with mice showed an excellent therapeutic efficacy as compared with administration of either antibiotic alone. Penicillin-binding protein 2', 2, and 4 fractions were scarcely detectable in MR S. aureus strains grown in the presence of fosfomycin at concentrations of 0.25 MIC and 0.5 MIC, respectively.

Animals↗

Comparative evaluation of the pharmacokinetics of N-methylthiotetrazole following administration of cefoperazone, cefotetan, and cefmetazole.

The comparative pharmacokinetics and in vivo production of N-methylthiotetrazole (NMTT) were evaluated following administration of cefoperazone, cefotetan, and cefmetazole. In a randomized-crossover manner, 11 healthy male volunteers received single 2-g intravenous doses of each agent and serial blood and urine samples were collected. Concentrations of NMTT and the parent compound in plasma, urine, and the reconstituted antibiotic solution were determined by high-pressure liquid chromatography. The amounts of NMTT administered were 6.06 +/- 0.46, 14.4 +/- 0.87, and 17.4 +/- 1.06 mg for cefoperazone, cefotetan, and cefmetazole, respectively (P less than 0.05). The mean NMTT plasma concentration-time profiles following administration of each cephalosporin were markedly different. Six hours after dosing, NMTT concentrations in plasma following cefoperazone administration were higher than those following administration of cefmetazole and cefotetan. Urinary recoveries of NMTT averaged 137.0 +/- 37.1, 38.3 +/- 6.98, and 25.2 +/- 5.95 mg following administration of cefoperazone, cefotetan, and cefmetazole, respectively (P less than 0.01). The apparent amount of NMTT produced in vivo, calculated by subtracting the amount of NMTT administered from the amount of NMTT excreted in urine, was significantly lower following cefmetazole administration than after administration of cefoperazone and cefotetan (P less than 0.01). The discrepancy between in vitro NMTT production (cefmetazole greater than cefotetan greater than cefoperazone) and the amount of NMTT formed in vivo and excreted unchanged (cefoperazone greater than cefotetan greater than cefmetazole) suggests that in vivo production of NMTT is dependent on the disposition of the parent cephalosporin. These results further suggest that cephalosporins which undergo extensive biliary excretion, such as cefoperazone, are associated with the greatest amount of in vivo NMTT release, whereas cephalosporins which are primarily renally excreted, such as cefmetazole, are associated with the lowest in vivo production of NMTT.

Adult↗

Clinical experience with cefmetazole sodium in the United States: an overview.

The clinical development programme for cefmetazole sodium included over 4000 patients treated by 78 investigators. Cefmetazole therapy was compared with that of cefoxitin sodium (cefoxitin) for the treatment of urinary tract, skin and soft tissue, lower respiratory, abdominal, and gynaecological infections (with cefoxitin-sensitive pathogens) and for the prevention of postoperative wound infection in patients undergoing surgical procedures. Both cefmetazole and cefoxitin were administered intravenously in all studies. Cefmetazole was as effective as cefoxitin in the treatment of the infections studied. In the surgical wound infection prophylaxis studies, multiple-dose cefmetazole therapy was more effective than multiple-dose cefoxitin therapy in patients undergoing lower gastrointestinal surgery; this difference approached statistical significance. Both multiple-dose and single-dose cefmetazole therapy were as effective as multiple-dose cefoxitin treatment in the other types of surgery studied. Clinical laboratory findings and adverse medical events reported among cefmetazole patients were similar to those observed in patients treated with cefoxitin.

Bacterial Infections↗

Absorption, distribution, excretion and metabolism of cefmetazole in cynomolgus monkeys.

The pharmacokinetics and metabolic fate of cefmetazole (CS-1170, CMZ) were studied in cynomolgus monkeys by means of combination of radio- and bioassay techniques and that of three radioactive drugs labeled at the different moiety of the molecule. The plasma level of radioactivity after intramuscular injection of cefmetazole[methoxyl-14C] (50 mg/kg) reached the maximum level (185 microgram/ml) after 10 minutes and declined with a half-life of about 48 minutes. In the thin-layer chromatography of the plasma extracts, a single radioactive spot was detected corresponding to unchanged cefmetazole. Repeated intravenous administration for one and two weeks showed no effect on the plasma levels and half-lives. More than 75% of the intravenous or intramuscular dose was recovered in the urine by both radio- and bioassay, the most part being excreted during the first 3 hours period. On the TLC of urine, 93--97% was detected as unchanged cefmetazole. In the bile, the most part (less than 80%) was detected as unchanged cefmetazole. In the feces, about 15% of the dose was recovered, in which 30--40% was detected as intact cefmetazole. The metabolic fate of [3-35S] and [7-35S]cefmetazole was described and discussed. The whole-body autoradiography in the monkeys was also presented.

Animals↗

Compatibility of cefmetazole sodium with commonly used drugs during Y-site delivery.

The compatibility of cefmetazole sodium and selected other drugs during Y-site delivery was evaluated. Cefmetazole 100 mg/mL (as the sodium salt) in sterile water for injection and each of 34 drugs or solutions commonly used with it were mixed together by Y-site injection. Secondary drugs were administered at selected concentrations and rates and delivered by the method (i.v. push, i.v. infusion, or syringe pump) commonly used for the drug at the institution where the study was done. Each injection set included a filter system with a 0.8-micron filter disk. Tests were done in triplicate. After each test, the Y injection site and the tubing after it were visually inspected for precipitate and color change. If no particles or color change was detected, the filter disk was observed under a microscope. Drugs were deemed compatible with cefmetazole if unaided observation detected no color change or particles and the number of particles detected by microscopic examination was below that specified in USP guidelines. A precipitate formed when cefmetazole sodium mixed with diphenhydramine hydrochloride, droperidol, erythromycin (50 mg/mL, as the lactobionate), haloperidol lactate, prochlorperazine edisylate, promethazine hydrochloride, or vancomycin (50 mg/mL, as the hydrochloride salt). No particles or color change was detected by unaided observation of mixtures containing dobutamine or erythromycin 10 mg/mL, but the number of particles detected by microscopic examination exceeded USP limits. All other drugs tested were compatible with cefmetazole. Cefmetazole 100 mg/mL (as the sodium salt) in sterile water for injection was shown to be compatible with 25 of 34 tested drug solutions during Y-site delivery.

Cefmetazole↗

Preclinical safety studies of cefmetazole.

In order to assess the safety of cefmetazole, preclinical multiple-dose parenteral studies, varying from one to three months in length, were conducted in Sprague-Dawley rats and beagle dogs. Although the largest doses used were in multiples of several times the weight-adjusted doses intended for humans, cefmetazole was generally well tolerated. The principal adverse effect noted in the adult rats receiving the largest doses (2000 and 2500 mg/kg/day) of cefmetazole was slight elevation of serum alanine aminotransferase. Infant rats injected subcutaneously with 300 mg/kg/day or more of cefmetazole for 35 consecutive days had reversible reductions in testicular weight and maturation of spermatogenesis, but not lasting discernible effect on reproductive function. The most consistent effects of longterm multiple dosing with cefmetazole in dogs consisted of vomiting and retching during dosing and reversible haematological changes (mild regenerative anaemia, positive Coombs' test, clinically-silent thrombocytopenia) in a number of the dogs. These findings supported the interpretation that cefmetazole was acceptably safe for clinical studies in humans.

Animals↗