Cefoperazone or cefoperazone-sulbactam as perioperative antibiotic prophylaxis in transurethral surgery.
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The cefoperazone-sulbactam combination. In vitro qualities including beta-lactamase stability, antimicrobial activity, and interpretive criteria for disk diffusion tests.
Three concentrations of the penicillanic acid sulfone, sulbactam were tested in combination with cefoperazone against 632 recent clinical bacterial isolates. Cefoperazone was effective alone (less than or equal to 16 micrograms/mL) against 95% of Enterobacteriaceae and combined with 4 micrograms/mL sulbactam inhibited 99.5% of strains. This coverage of enteric bacilli was superior to timentin (99.1%), ceftazidime (98.2%), and tobramycin (90.9%). The minimum inhibitory concentrations (MICs) of cefoperazone-susceptible strains also were markedly decreased by sulbactam (overall MIC90s, 8.0 micrograms/mL for cefoperazone and 1.0 microgram/mL for cefoperazone and 4.0 micrograms/mL for sulbactam). Sulbactam also expanded the spectrum of cefoperazone against Acinetobacter species, some rare Pseudomonas species, and Bacteroides fragilis group species. Sulbactam had direct antimicrobial activity against the acinetobacters and Pseudomonas acidovorans, but the increased activity of cefoperazone-sulbactam against some other Pseudomonas species and anaerobes was attributed to beta-lactamase inhibition. The cefoperazone MICs against beta-lactamase producing Staphylococcus species also were lowered to the level of enzyme-deficient strains. Cefoperazone bactericidal activity was improved by 4.0 micrograms/mL sulbactam, and no antagonism was observed. beta-lactamase hydrolysis studies confirmed a slow hydrolysis of cefoperazone only by TEM beta-lactamases and a high-grade resistance to enzyme breakdown by sulbactam. Differential beta-lactamase affinity studies for cefoperazone and sulbactam showed potential efficacy and applications to plasmid-mediated TEM and OXA enzymes and only marginal effective sulbactam inhibition of Pseudomonas and Klebsiella species enzymes. Disk diffusion studies on 556 strains confirmed the applicability of the cefoperazone 75-micrograms disk to testing routine isolates other than enterococci and methicillin-resistant Staphylococcus aureus. The addition of 4.0 micrograms sulbactam/mL in a fixed concentration to dilution test systems and 15 micrograms sulbactam to the 75 micrograms cefoperazone disk were recommended for in vitro tests. Susceptibility and resistant interpretive criteria for the disk and dilution tests can be applied with confidence. Only 0.4% false-susceptibility errors and a 97.5% absolute interpretive agreement were achieved using the 75 micrograms cefoperazone/15 micrograms sulbactam disk.
Anti-Bacterial Agents↗
The effect of liposomal cefoperazone against Pseudomonas aeruginosa in a granulocytopenic mouse model of acute lung infection.
The therapeutic efficacy of liposomal cefoperazone against Pseudomonas aeruginosa was investigated in a granulocytopenic mouse model of acute lung infection. Granulocytopenia was induced in mice by intraperitoneal (i.p.) injection of 200 mg/kg cyclophosphamide. Mice were challenged by exposure to an aerosol containing P. aeruginosa and were treated i.p. with liposomal cefoperazone prepared by the dehydration-rehydration method. The half-life of free cefoperazone in the lungs following i.p. administration of the liposomal drug was significantly lengthened (13 min vs. 261 min), and the cefoperazone activity in the lungs remained above the MIC longer after administration of liposomal cefoperazone than after treatment with cefoperazone. Liposomal cefoperazone was more effective than cefoperazone alone in preventing death of granulocytopenic mice from lethal pulmonary challenge with P. aeruginosa (75% vs. 38% survival, p = 0.031). Finally, P. aeruginosa was cleared faster from the lungs of mice treated with liposomal cefoperazone when compared with those treated with cefoperazone. This study shows that incorporation of cefoperazone into liposomes enhances the activity of the antibiotic against P. aeruginosa in a granulocytopenic host.
Acute Disease↗
Aztreonam, cefoperazone, and gentamicin in the treatment of experimental Enterobacter aerogenes endocarditis in rabbits.
The effectiveness of aztreonam, cefoperazone, and gentamicin alone and in combination was evaluated in Enterobacter aerogenes endocarditis in rabbits. The minimal inhibitory concentration/minimal bactericidal concentration ratios for E. aerogenes were as follows: aztreonam, 0.4/0.4 microgram/ml; cefoperazone, 0.8/0.8 microgram/ml; and gentamicin, 3.1/3.1 micrograms/ml. With an inoculum of 10(9) organisms per ml, aztreonam and cefoperazone were equivalent in reducing titers of E. aerogenes in broth, and both drugs demonstrated an increased rate of reduction when gentamicin was added; gentamicin alone was least effective. E. aerogenes endocarditis in rabbits was treated intramuscularly with aztreonam (60 mg/kg) every 6 h, with cefoperazone (60 mg/kg) every 6 h, with gentamicin (1.7 mg/kg) every 8 h, and with aztreonam plus gentamicin or cefoperazone plus gentamicin for 5 and 10 days, respectively. All of the therapeutic regimens were effective in reducing vegetation titers as compared with untreated controls. Aztreonam plus gentamicin was more effective than either aztreonam or gentamicin alone. Cefoperazone plus gentamicin was more effective than cefoperazone alone but was not more effective than gentamicin alone. Neither aztreonam and cefoperazone nor aztreonam and gentamicin differed significantly, but gentamicin was significantly more effective than cefoperazone. Aztreonam plus gentamicin did not differ significantly in effectiveness from cefoperazone plus gentamicin. Aztreonam gave a peak level of about 135 micrograms/ml and a half-life of 0.7 h. Cefoperazone gave a peak level of about 155 micrograms/ml and a half-life of 1.1 h. Gentamicin gave a peak level of 7.4 micrograms/ml and a half-life of 1.3 h.
Animals↗
Pharmacokinetics of cefoperazone: a review.
The pharmacokinetics of cefoperazone in normal subjects, and in patients with hepatic and renal dysfunction are reviewed. After intravenous administration of 2 g of cefoperazone, levels in serum ranged from 202 to 375 microgram/ml depending on the period of drug administration. After intramuscular injection of 2 g of cefoperazone, the mean peak serum level was 111 microgram/ml at 1.5 hours. At 12 hours after dosing, mean serum levels were still 2 to 4 microgram/ml. Cefoperazone was 90% bound to serum proteins. The apparent volume of distribution was 10 to 13L. The half-life of the drug varied from 1.6 to 2.4 hours; serum clearance was between 75 and 96 ml/min. Urinary excretion was rapid, but only 15 to 36% of the cefoperazone dose was recovered in the urine. Renal clearance ranged from 14 to 25 ml/min. Urine levels of cefoperazone in excess of 32 microgram/ml were maintained for at least 12 hours. Biliary levels of cefoperazone were many-fold higher than serum levels; peak bile concentrations from 675 to 6000 microgram/ml were obtained. Severe hepatic dysfunction was associated with a 2- to 4-fold increase in the half-life of cefoperazone. In patients with relatively complete biliary obstruction, over 90% of the dose was recovered in the urine. In contrast, the serum kinetics of cefoperazone were not significantly altered in patients with renal impairment. The human pharmacology of cefoperazone is similar to cephazolin in terms of serum concentrations, half-life, protein binding, and apparent volume of distribution, but markedly different in terms of biliary and renal excretion. Since biliary excretion is normally the primary route of cefoperazone elimination, dosage modification should only be required in the presence of severe biliary obstruction or concomitant renal and hepatic dysfunction.
Bile↗
In vitro antimicrobial activity of cefoperazone-sulbactam combinations against 554 clinical isolates including a review and beta-lactamase studies.
Cefoperazone was tested against 554 clinical isolates alone and with sulbactam in three combinations. The addition of sulbactam in low concentrations (less than or equal to 4 micrograms/ml) improved the spectrum of cefoperazone principally against gram-negative bacilli such as Acinetobacter species, some Pseudomonas species, and beta-lactamase-positive Enterobacteriaceae. Nearly all of the spectrum increase was achieved at a sulbactam level of less than or equal to 2 micrograms/ml. Sulbactam was found to be an effective antimicrobial agent against Acinetobacter species (MIC50, 1.0 microgram/ml), Pseudomonas acidovorans (MIC50, 2.0 micrograms/ml), Neisseria gonorrhoeae (MIC50, less than or equal to 0.5 microgram/ml), and N. meningitidis (MIC50, less than or equal to 0.5 microgram/ml). Sulbactam had a higher affinity and binding constant for the plasmid-mediated beta-lactamases such as TEM-1 and TEM-2 compared to cefoperazone (greater than or equal to 10-fold difference). This finding was important as cefoperazone can be hydrolyzed at a moderate rate by the highly efficient TEM enzymes (less than 2% of clinical Escherichia coli isolates). Sulbactam increased the susceptibility (less than or equal to 16 micrograms/ml) of 220 isolates of Enterobacteriaceae to cefoperazone from 88.6 to 96.3% when 4.0 micrograms/ml of sulbactam was added. The cefoperazone antimicrobial activity was also increased against the nonenteric bacilli from a 69.5 to a 87.4% total inhibition. MICs among cefoperazone-susceptible gram-negative and gram-positive strains were routinely decreased 2- to 32-fold, as calculated from MIC90 results. Therefore, sulbactam should predictably increase the antimicrobial spectrum and clinical effectiveness of cefoperazone against nosocomial and other pathogens such as the plasmid-containing enteric bacilli, Bacteroides species and Acinetobacter species, and possibly provide the opportunity to reduce dosage schedules for infecting species already susceptible to cefoperazone alone.
Bacteria↗
Cefoperazone: a review of its antimicrobial spectrum, beta-lactamase stability, enzyme inhibition, and other in vitro characteristics.
The in vitro qualities of cefoperazone were reviewed on the basis of international medical literature and some new observations. Cefoperazone is highly active against the Enterobacteriaceae. Its activity against Staphylococcus aureus is comparable to that of the other newer cephem antibiotics. Cefoperazone is also active against all beta-hemolytic streptococci and Streptococcus pneumoniae and is relatively inactive against methicillin-resistant S. aureus and enterococci. Against Pseudomonas aeruginosa cefoperazone is at least fourfold more active than cefotaxime or moxalactam and is approximately as active as azlocillin or piperacillin. Haemophilus and Neisseria species, regardless of beta-lactamase production, are highly susceptible to cefoperazone. Against the Bacteroides fragilis group, cefoperazone is either very active or quite inactive because of endemic variations. The drug is slightly less stable to some beta-lactamases than are cefotaxime-like or 7-methoxy cephem drugs. Cefoperazone is a bactericidal beta-lactam, and its minimal inhibitory concentrations are influenced only by high inoculum concentrations of beta-lactamase-producing strains. Its ability to permeate bacterial cell membranes appears similar to that of cefotaxime. Synergy studies with cefoperazone plus beta-lactamase inhibitors or aminoglycosides against Enterobacteriaceae and P. aeruginosa show enhanced killing. Cefoperazone is 70%-94% protein bound and has high affinities for bacterial penicillin-binding proteins 3, 1a, 2, and 1 bs.
Anaerobiosis↗
Comparison of cefoperazone plus sulbactam with clindamycin plus gentamicin as treatment for intra-abdominal infections.
This study compared the safety and efficacy of cefoperazone plus sulbactam with that of clindamycin plus gentamicin in the treatment of intra-abdominal infection. Seventy-six patients were included in the analysis of an open, randomized, comparative, single-site trial. Forty-seven patients received cefoperazone-sulbactam, and 29 patients received clindamycin plus gentamicin. Thirty-three patients (70%) who received cefoperazone-sulbactam and 15 patients (52%) who received clindamycin plus gentamicin were cured of infection, did not suffer a relapse within one month after the end of treatment, and did not receive any other antibiotics during the follow-up period (P = 0.17). In patients treated with cefoperazone-sulbactam there were four cases of superinfection, one patient had a prolonged prothrombin time, six patients had a poor response, two patients received antibiotics during follow-up, and one patient died during follow-up because of cancer. Treatment with clindamycin plus gentamicin was associated with five cases of superinfection, four patients had a poor response, four patients had a drug reaction, and one patient required antibiotics in the follow-up period. Serum levels of cefoperazone-sulbactam measured at one and three hours after dosing were consistent with earlier findings in normal volunteers. Two hundred and one pathogens were isolated, and 17 of 122 aerobic isolates (14%) were resistant to cefoperazone-sulbactam, and 17 of 122 (14%) were resistant to both clindamycin and gentamicin. Eleven of 79 (14%) anaerobic isolates were resistant to cefoperazone, none was resistant to cefoperazone-sulbactam, and 10 of 79 (13%) were resistant to clindamycin. The results of this study show that cefoperazone-sulbactam is an effective and safe alternative to clindamycin plus gentamicin in the treatment of intra-abdominal infections.
Abdomen↗
Serum bactericidal activity of ceftazidime and cefoperazone alone or in combination with amikacin against Pseudomonas aeruginosa and Klebsiella pneumoniae.
Sera of volunteers receiving ceftazidime (2 g) or amikacin (500 mg), alone or in combination, or cefoperazone (2, 4, or 6 g) or cefoperazone (2 g) with amikacin (500 mg) were evaluated for bactericidal activity against Klebsiella pneumoniae and Pseudomonas aeruginosa. Serum bactericidal activities were similar for ceftazidime and ceftazidime plus amikacin, but were definitely lower for amikacin alone. Against P. aeruginosa, a 6-g dose of cefoperazone resulted in a higher frequency of peak serum bactericidal activities greater than or equal to 1:8 than a 2-g dose of cefoperazone plus amikacin. Killing studies, performed in 1:8 diluted serum, demonstrated a higher killing rate for cefoperazone plus amikacin than for a 6-g dose of cefoperazone, the more resistant P. aeruginosa excepted. Emergence of resistance was found with a 2-g dose of cefoperazone for K. pneumoniae and with a 6-g dose of cefoperazone for P. aeruginosa, but not with cefoperazone plus amikacin.
Amikacin↗
Enoxacin compared with cefoperazone for the treatment of experimental Enterobacter aerogenes endocarditis.
This study compared enoxacin administered orally with cefoperazone administered intramuscularly for the treatment of Enterobacter aerogenes endocarditis in rabbits. The MICs and MBCs of both enoxacin and cefoperazone for an inoculum of 10(5) CFU/ml of the E. aerogenes strain used were 0.8 micrograms/ml, respectively. With an inoculum of 10(8) organisms per ml, enoxacin at 2 and 5 micrograms/ml and cefoperazone at 60 and 155 micrograms/ml were effective in reducing titers of E. aerogenes in broth. E. aerogenes endocarditis in rabbits was treated with enoxacin (100 or 25 mg/kg orally every 6 h) or cefoperazone (60 mg/kg intramuscularly every 6 h) for 5 or 10 days. Enoxacin at 100 and 25 mg/kg significantly reduced bacterial titers of vegetations compared with those of untreated controls. Enoxacin at 100 mg/kg was significantly more effective than enoxacin at 25 mg/kg and cefoperazone. Enoxacin at 25 mg/kg and cefoperazone did not differ significantly. Cefoperazone and controls did not differ significantly. In uninfected rabbits single doses of cefoperazone achieved much higher concentrations in serum than single doses of enoxacin (25 and 100 mg/kg). The half-lives of enoxacin at 25 and 100 mg/kg were approximately three times longer than that of cefoperazone.
Animals↗
Pharmacokinetics of cefoperazone in the parturient.
Limited pharmacokinetic data for cefoperazone are available from the parturient. Because cefoperazone has a dual excretory pattern, primarily via the biliary system and secondarily via the kidney, pregnancy-induced physiologic alterations can influence its deposition and clearance. Twelve term parturients receiving cefoperazone prophylaxis after cesarean section were selected for study. After 2 g of cefoperazone was administered for 1 h intravenously, serial blood samples were assayed by high-pressure liquid chromatography. Plasma protein binding of cefoperazone was studied in vitro. The mean peak cefoperazone concentration +/- standard deviation was 169.9 +/- 60.4 micrograms/ml. The mean half-life was 152 min. Total serum clearance was 80.8 +/- 30.8 ml/min. The steady-state volume of distribution was 14.2 +/- 6.0 liters. All subjects had detectable trough levels at the end of the dosage interval, with a mean value of 6.5 +/- 5.2 micrograms/ml. Protein binding of cefoperazone for parturients was 74.3 +/- 10.9%, compared with 87.7 +/- 3.2% in nonpregnant controls (P less than 0.05). These data suggest that cefoperazone deposition can be greatly influenced by pregnancy. However, unlike several other new antimicrobial agents whose excretions are mainly renal, the cefoperazone half-life and thus trough concentration for the parturient more closely resemble that for the nonpregnant subject.
Adult↗
Resistance to cefoperazone-sulbactam in Klebsiella pneumoniae: evidence for enhanced resistance resulting from the coexistence of two different resistance mechanisms.
We investigated the in vitro activity and the in vivo efficacy of the beta-lactam-beta-lactamase inhibitor combination cefoperazone-sulbactam against an isogenic series of Klebsiella pneumoniae strains. Both cefoperazone and cefoperazone-sulbactam were active in vitro against a susceptible clinical strain, and the combination was highly effective in the treatment of rat intra-abdominal abscesses. Loss of expression of a 39-kDa outer membrane protein resulted in at least a fourfold increase in the MICs of cefoperazone and cefoperazone-sulbactam but did not appreciably affect the in vivo efficacy of either regimen. Introduction of plasmid RP4, which encodes the TEM-2 beta-lactamase, into the susceptible strain resulted in the loss of in vitro activity and in vivo efficacy for cefoperazone. The in vitro activity of cefoperazone-sulbactam against this strain was diminished, but the antibiotic combination remained highly active in vivo. Introduction of RP4 into the strain lacking the 39-kDa outer membrane protein resulted in a fourfold increase in the in vitro MIC of cefoperazone-sulbactam in comparison with the beta-lactamase-producing susceptible strain and resulted in a loss of in vivo efficacy against infections caused by this strain. These results suggest that the combination of different resistance mechanisms, neither of which alone results in substantially diminished cefoperazone-sulbactam efficacy in vivo, can cause in vivo resistance to the beta-lactam-beta-lactamase inhibitor combination in K. pneumoniae.
Abscess↗
Pharmacokinetics of cefoperazone and sulbactam in liver transplant patients.
The authors evaluated the pharmacokinetics of cefoperazone and sulbactam in 9 liver transplant patients. Cefoperazone and sulbactam were administered as an intravenous infusion over 30 minutes every 12 hours for six doses, and multiple blood samples were collected immediately after the first dose (administered during the surgery) and after the last dose. The concentrations of cefoperazone and sulbactam in serum and, when possible, in urine and bile collected over one dosing interval were measured by high-pressure liquid chromatography. The concentration of cefaperazone ranged from 436 to 4118 microg/ml, and sulbactam ranged from 3.3 to 8.7 microg/ml in the bile samples. The intraoperative clearance of cefoperazone (0.53+/-0.18 ml/min/kg) was significantly higher than the postoperative clearance (0.21+/-0.23 ml/min/kg). The half-life of cefaperazone, although not statistically significantly different, was prolonged in all patients during the postoperative period. The clearance of sulbactam (1.51+/-0.51 ml/min/kg) was lower than what is reported in patients with normal renal function but was comparable to what has been reported in patients with renal impairment and in critically ill patients. There were no significant differences in any of the pharmacokinetic parameters of sulbactam during and after surgery. The pharmacokinetic parameters of cefoperazone and sulbactam were significantly altered in liver transplant patients compared to what has been reported in normal subjects but were similar to what has been reported in patients with liver and renal impairment. There was a significant impairment in the biliary excretion of cefoperazone during the postoperative period in liver transplant patients. Although the percentage of the dose of cefoperazone excreted in the bile was drastically reduced, the biliary concentrations were generally high and above the MIC for most organisms. Given that both renal and hepatic elimination of cefoperazone is decreased, leading to a lower clearance and longer half-life in liver transplant patients, lower doses (1-2 g per day) of cefoperazone may be sufficient in liver transplant patients during the immediate postoperative period.
Adult↗
The influence of chronic lobular hepatitis on pharmacokinetics of cefoperazone--a novel galactose single-point method as a measure of residual liver function.
Cefoperazone is a semisynthetic cephalosporin antibiotic containing a piperazine side chain, which results in antipseudomonal activity. Unlike the other cephalosporins, it is mainly cleared by the liver (60-80%) and it may be more sensitive to changes in the liver function and/or plasma protein binding than other cephalosporins, which are not primarily cleared by the liver. In order to study the influence of chronic lobular hepatitis on the pharmacokinetics of cefoperazone, a dose of 1 g of cefoperazone was administered to 11 normal, healthy volunteers and 16 subjects with chronic lobular hepatitis. In each volunteer or patient, a novel galactose single-point (GSP) method, the galactose elimination capacity (GEC) test, and the modified galactose elimination capacity (MGEC) test were also performed as a measure of residual liver function. Cefoperazone was administered intravenously over a period of 3-5 min. Blood and urine samples were collected at appropriate intervals after drug administration and stored at -30 degrees C until high-pressure liquid chromatographic (HPLC) analysis. The cefoperazone hepatic clearance, mean residence time, and renal clearance in hepatitis patients were significantly different from those of normal healthy volunteers, whereas the plasma protein binding was unaltered between the two groups. Urinary excretion of cefoperazone showed a highly significant increase in patients, 23.95 +/- 5.06% and 37.54 +/- 13.61% for normal men and hepatitis patients respectively. Hepatic clearance and fraction excreted in urine significantly correlated with values of GSP and MGEC respectively (p < 0.05). These results suggest (i) cefoperazone kinetics was significantly altered in patients with chronic lobular hepatitis; (ii) GSP, a novel simple, clinically useful quantitative liver function test, can predict the cefoperazone hepatic clearance in patients with liver dysfunction.
Adult↗
A randomized, controlled trial of cefoperazone vs. cefamandole-tobramycin in the treatment of putative, severe infections with gram-negative bacilli.
Cefoperazone was compared with the combination of cefamandole and tobramycin in a prospective, randomized study of putative, severe, gram-negative bacillary infections. We attempted to exclude patients with granulocytopenia or infections due to Pseudomonas species. A total of 118 isolates (94 gram-negative bacilli and 24 gram-positive cocci) caused infection in 99 of the 120 patients studied. Cefoperazone (16 micrograms/ml) was active against 93% of the organisms tested; cefamandole (16 micrograms/ml) and/or tobramycin (4 micrograms/ml) was active against 95%. Infection was cured or improved in 77% of cefoperazone-treated patients and 81% of cefamandole-tobramycin-treated patients. Bacteremia was cured or improved in 61% of cefoperazone-treated patients and in 63% of cefamandole-tobramycin-treated patients. Adverse reactions included five cases of probable antibiotic-associated nephrotoxicity in the cefamandole-tobramycin group; there were no such cases in the cefoperazone group. One patient given cefoperazone plus eight other drugs became granulocytopenic, but the condition resolved when all medications were stopped. This analysis suggests that cefoperazone alone may be as effective as cefamandole plus tobramycin in the treatment of severe infections with gram-negative bacilli and is less nephrotoxic. The role of cefoperazone in patients with granulocytopenia or infections due to Pseudomonas aeruginosa was not evaluated.
Adolescent↗
Cefoperazone compared with ampicillin plus tobramycin for severe biliary tract infections.
In a prospective, randomized, multicenter study, the efficacy and safety of cefoperazone and the combination ampicillin-tobramycin as initial therapy for patients with severe acute biliary tract infections were compared. Of 77 patients initially entered in the study, definite severe biliary tract infection was confirmed in 67. Sixty-four patients completed treatment. At the end of treatment, 35 of 36 (97%) patients given cefoperazone and 23 of 28 (82%) given ampicillin-tobramycin were cured of their infection (P = 0.07). Pathogens were recovered from the bile in 32 patients; microbiological cures were observed in 18 of 19 (94%) patients receiving cefoperazone and 8 of 13 (62%) receiving ampicillin-tobramycin (P = 0.03). Thirteen patients had septicemia. None (0%) of the eight septicemic patients from the cefoperazone group, but two of five (40%) from the ampicillin-tobramycin group, were clinical failures. Of the isolated pathogens, 51% were resistant to ampicillin, while the resistance rate was 4% for tobramycin and 1% for cefoperazone (P less than 0.001). Biliary concentrations of cefoperazone were maintained at high levels--236 +/- 87 micrograms/ml up to 12 h after administration. Even in the presence of severe obstruction, cefoperazone levels in the bile and gallbladder wall were above MICs for most pathogens. Cefoperazone may be considered as an excellent alternative in the therapy of severe biliary tract infections.
Acute Disease↗
Comparison of N-methylthiotetrazole dispositions in healthy volunteers following single intravenous doses of moxalactam, cefoperazone, and cefotetan.
The N-methylthiotetrazole side chain (NMTT) that is present on several cephalosporins has been implicated in the development of antibiotic-associated hypoprothrombinemia. A randomized three-way crossover trial was conducted to compare the release of the NMTT side chain from three NMTT-containing antibiotics. Single 2-g doses of moxalactam, cefoperazone, and cefotetan were given, followed by serial blood and urine sampling. The concentrations of the parent compound and the NMTT side chain in plasma, urine, and the reconstituted antibiotic solution were determined by high-pressure liquid chromatography. Peak NMTT concentrations ranged from 0.42 to 16.50 micrograms/ml and were significantly higher after moxalactam administration than after cefoperazone or cefotetan administration (P less than 0.01). The NMTT trough concentrations (12.5 h) ranged from nondetectable to 2.47 micrograms/ml and tended to be greater following cefoperazone administration. The amounts of NMTT administered (e.g., the amount in the reconstituted antibiotic solution) were 25.8 +/- 1.4, 15.2 +/- 0.9, and 22.1 +/- 3.0 mg following moxalactam, cefoperazone, and cefotetan administration, respectively (P less than 0.01). In contrast, urinary recoveries of NMTT were 57.4 +/- 26.2, 73.6 +/- 44.3, and 29.7 +/- 22.9 mg following moxalactam, cefoperazone, and cefotetan, respectively. The amount of NMTT formed in vivo and excreted unchanged, as assessed by subtracting in vitro NMTT formation from NMTT urinary recovery, was significantly higher after cefoperazone than after moxalactam or cefotetan administration (P less than 0.05). The discrepancy between in vitro NMTT production (moxalactam > cefotetan > cefoperazone) and the amount of NMTT formed in vivo and excreted unchanged (cefoperazone > moxalactam > cefotetan) demonstrated that the in vivo production of NMTT is dependent on the disposition of the parent cephalosporin.
Adult↗
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↗