Pharmacokinetics of Intraperitoneal Cefalothin and Cefazolin in Patients Being Treated for Peritoneal Dialysis-Associated Peritonitis.

UNLABELLED: ♦ BACKGROUND: The standard treatment of peritoneal dialysis (PD)-associated peritonitis (PD-peritonitis) is intraperitoneal (IP) administration of antibiotics. Only limited data on the pharmacokinetics and appropriateness of contemporary dose recommendations of IP cefalothin and cefazolin exist. The aim of this study was to describe the pharmacokinetics of IP cefalothin and cefazolin in patients treated for PD-peritonitis. ♦ METHODS: As per international guidelines, IP cefalothin or cefazolin 15 mg/kg once daily was dosed with gentamicin in a 6-hour dwell to patients with PD-peritonitis during routine care. Serial plasma and PD effluent samples were collected over the first 24 hours of therapy. Antibiotic concentrations were quantified using a validated chromatographic method with pharmacokinetic analysis performed using a non-compartmental approach. ♦ RESULTS: Nineteen patients were included (cefalothin n = 8, cefazolin n = 11). The median bioavailability for both antibiotics exceeded 92%, but other pharmacokinetic parameters varied markedly between antibiotics. Both antibiotics achieved high PD effluent concentrations throughout the antibiotic dwell. Cefazolin had a smaller volume of distribution compared with cefalothin (14 vs 40 L, p = 0.003). The median trough total plasma antibiotic concentration for cefazolin and cefalothin during the dwell differed (plasma 56 vs 13 mg/L, p < 0.0001) despite a similar concentration in PD effluent (37 vs 38 mg/L, p = 0.58). Lower antibiotic concentrations were noted during PD dwells not containing antibiotic, particularly cefalothin, which was frequently undetectable in plasma and PD effluent. The median duration that the unbound antibiotic concentration was above the minimum inhibitory concentration (MIC) was approximately 13% (plasma) and 25% (IP) for cefalothin, and 100% (plasma and IP) for cefazolin, of the dosing interval. ♦ CONCLUSIONS: When IP cefalothin or cefazolin is allowed to dwell for 6 hours, sufficient PD effluent concentrations are present for common pathogens during this time. However, with once-daily IP dosing, in contrast to cefazolin, there is a risk of subtherapeutic plasma and PD effluent cefalothin concentrations, so more frequent dosing may be required.

Determination of Cefalothin and Cefazolin in Human Plasma, Urine and Peritoneal Dialysate by UHPLC-MS/MS: application to a pilot pharmacokinetic study in humans.

An ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the analysis of cefazolin and cefalothin in human plasma (total and unbound), urine and peritoneal dialysate has been developed and validated. Total plasma concentrations are measured following protein precipitation and are suitable for the concentration range of 1-500 µg/mL. Unbound concentrations are measured from ultra-filtered plasma acquired using Centrifree(®) devices and are suitable for the concentration range of 0.1-500 µg/mL for cefazolin and 1-500 µg/mL for cefalothin. The urine method is suitable for a concentration range of 0.1-20 mg/mL for cefazolin and 0.2-20 mg/mL for cefalothin. Peritoneal dialysate concentrations are measured using direct injection, and are suitable for the concentration range of 0.2-100 µg/mL for both cefazolin and cefalothin. The cefazolin and cefalothin plasma (total and unbound), urine and peritoneal dialysate results are reported for recovery, inter-assay precision and accuracy, and the lower limit of quantification, linearity, stability and matrix effects, with all results meeting acceptance criteria. The method was used successfully in a pilot pharmacokinetic study with patients with peritoneal dialysis-associated peritonitis, receiving either intraperitoneal cefazolin or cefalothin. Copyright © 2015 John Wiley & Sons, Ltd.

Comparación de concentración mínima inhibitoria y concentración plasmática de cefalotina mediante un modelo matemático / Comparison of the minimal inhibitory concentration and the plasma cephalotin concentration through a mathematical model

Introducción: el uso de fármacos fuera de rangos terapéuticos es un problema hospitalario, pues pocas veces se tienen en cuenta parámetros antropométricos del paciente, determinantes en las concentraciones del medicamento. Objetivo: aplicar un modelo matemático basado en parámetros del paciente, para determinar las posibles concentraciones plasmáticas de cefalotina y compárarlas con las concentraciones mínimas inhibitorias de los microrganismos aislados. Métodos: se seleccionó un grupo de pacientes del sexo masculino entre 18 y 50 años de edad con tratamiento profiláctico posquirúrgico con cefalotina. Se recopiló la información: dosis de cefalotina, peso, talla, edad, hematócrito. Se calcularon volumen extracelular, plasmático y sanguíneo según el modelo informado por Hedin. Luego se calculó la concentración plasmática de cefalotina usando el modelo propuesto en el presente estudio y se comparó con la concentración mínima inhibitoria de los microorganismos aislados. Resultados: se analizaron 24 pacientes con promedio de edad 32,6 años ± 8, peso de 69 kg ± 7,51, talla de 168,87 cm ± 7,10. El 56,3 por ciento de los microorganismos presentó resistencia a concentraciones ³ 32 µg/mL. El agente más común fue Escherichia coli de 18 cepas aisladas. La comparación del volumen de distribución y la concentración plasmática de cefalotina calculada con el modelo informado por Hedin y el desarrollado en presente trabajo, no presentó diferencia significativa después de aplicar la prueba t de Student, con p< 0,05. Conclusiones: al comparar las concentraciones teóricas de cefalotina para uso profiláctico posquirúrgico intrahospitalario, calculadas con el modelo planteado, se encontró que estas no permitieron superar la concentración mínima inhibitoria de los microorganismos aislados(AU)

Introduction: the use of drugs out of therapeutic ranges is a hospital problem since the anthropometric parameters of patients, which are determinants in the drug concentrations, are rarely taken into consideration. Objectives: to implement a mathematical model based on the patient's parameters in order to determine the possible plasma cephalotine concentrations and to compare them with the minimum inhibitory concentrations for isolated microorganisms. Methods: a group of male patients aged 18 to 50 years under postsurgical prophylactic treatment with cephalotine was selected. Data was collected on cephalotin dosage, weight, size, age and hematocrit. Extracellular, plasma and blood volumes were estimated by the Hedin's informed model. Additionally, the plasma cephalotin concentration was measured by using the model suggested in this study and then compared with the minimum inhibitory concentration for the isolated microorganisms. Results: twenty four patients aged 32.6 years ± 8, weighing 69 kg ± 7.51, with size of 168.87 cm ± 7.10 were analyzed. Resistance to concentrations equal to or higher than 32 µg/mL was observed in 56.3 percent of microorganisms. The most common agent was Escherichia coli in 18 isolated strains. The comparison of the distribution volume and of the plasma cephalotin concentration estimated with the Hedin's informed model and with the model devised in the present paper did not show significant differences according to Student's t test result, with p< 0.05. Conclusions: the comparison of the theoretical concentrations of cephalotine for in-hospital postsurgical prophylactic use estimated by the model yielded that these concentrations did not allow overcoming the minimum inhibitory concentration for the isolated microorganisms(AU)

Unbound cephalothin pharmacokinetics in adult burn patients are related to the elapsed time after injury.

Cephalothin (cefalotin) pharmacokinetics were evaluated for nine severely burned patients (42% +/- 9% mean burn areas) and five healthy volunteers by using non-plasma-protein-bound concentration-time profiles. Burn patients gave increased mean residence times (36%) and reduced total clearances (25%). Mean residence times and distribution volumes increased between 1 and 4 days posttrauma, suggesting that burn patient pharmacokinetics change during the initial fluid resuscitation phase of treatment.

Tissue accumulation of cephalothin in burns: a comparative study by microdialysis of subcutaneous interstitial fluid cephalothin concentrations in burn patients and healthy volunteers.

Burn tissue sites are a potential source of bacteremia during debridement surgery. Burn injury is likely to affect the distribution of antibiotics to tissues, but direct evidence of this is lacking. The aim of this study was to directly evaluate the influence of burn trauma on the distribution of cephalothin to peripheral tissues. We used subcutaneous microdialysis techniques to monitor interstitial fluid concentrations of cephalothin in the burnt and nonburnt tissues of adult patients with severe burns following parenteral administration of 1 g cephalothin for surgical prophylaxis. Analogous simultaneous studies conducted with healthy adult volunteers provided reference tissue concentration data. Equivalent tissue exposures were seen for burn and nonburn sites, giving overall median interstitial cephalothin concentrations (from 0 to 240 min) of 2.84 mg/liter and 3.06 mg/liter, respectively. A lower overall median interstitial cephalothin concentration of 0.54 mg/liter was observed for healthy individuals, and the patient nonburnt tissue and volunteer control tissue cephalothin concentrations exhibited significantly different data distributions (P < 0.001; Kolmogorov-Smirnov nonparametric test). The duration of tissue residence for cephalothin was longer for burn patients than for healthy volunteers. The results demonstrate the potential fallibility of using healthy population models to extrapolate tissue pharmacodynamic predictions from plasma data for burn patients.

Inadequate antimicrobial prophylaxis during surgery: a study of beta-lactam levels during burn debridement.

OBJECTIVES: To determine how long single-dose prophylactic antibiotic regimens for burns surgery maintained plasma concentrations above the MICs for target organisms during surgery. PATIENTS AND METHODS: We monitored antibiotic plasma concentrations in 12 patients (mean +/- SD 43 +/- 12% total burn surface area) throughout debridement surgery after administration of the standard prophylactic antibiotic dosing regimens of either 1 g of intravenous cefalotin or 4.5 g of intravenous piperacillin/tazobactam. RESULTS: The eschar debridement and grafting procedures ranged in duration from 2.25 to over 8.5 h. The duration of total plasma cefalotin concentration above an MIC of 0.2 mg/L for Staphylococcus aureus was 6.49 +/- 2.85 h, whereas the mean duration of total plasma piperacillin concentration above an MIC of 64 mg/L for Pseudomonas aeruginosa was only 1.15 +/- 0.59 h. None of the patients dosed with piperacillin/tazobactam was adequately protected for the duration of their surgery and adequate prophylaxis was only evident in four of the nine patients administered cefalotin. CONCLUSIONS: These results suggest a need to review antibiotic prophylaxis dosage regimens for burns surgery and the adoption of regimens that will minimize the risk of infection in this high-risk patient group. It is suggested that the antibiotic prophylaxis guideline for burn debridement surgery be modified to include re-dosing or a continuous infusion of beta-lactam antibiotics.

Determination of unbound cephalothin in rat blood by on-line microdialysis and microbore liquid chromatography.

A method of analysis for the determination of unbound cephalothin in rat blood has been developed. The method was fully automated using an on-line microdialysis procedure. A microdialysis probe was inserted into the jugular vein/right atrium of male Sprague-Dawley rats to examine the unbound cephalothin level in the rat blood after cephalothin administration (50 mg/kg, i.v.). Dialysates were directly input to a liquid chromatographic system using an on-line injector. Samples were eluted with a mobile phase containing methanol-acetonitrile-100 mM monosodium phosphate (pH 5.0) (20:20:60, v/v). The UV wavelength was set at 254 nm for monitoring the analyte. Using the retrograde method, at infusion concentrations of 1 and 5 microg/ml of cephalothin, the in vivo microdialysis recoveries were 48.4+/-4.5% and 52.9+/-4.7% for the rat blood (n=6). Intra- and inter-assay accuracy and precision of the analyses were < or = 10% in the range of 0.01 through 10 microg/ml. Pharmacokinetic parameters were calculated from the recovery corrected dialysate concentrations of cephalothin versus time data. The results suggest that the pharmacokinetics of unbound cephalothin in blood fitted best to the two-compartmental model following cephalothin administration (50 mg/kg, i.v.).

Transferability of cephalothin to the alveolar cavity in thoroughbreds.

Five Thoroughbreds were classified into 4 groups according to the administration method used for saline solution (saline), ambroxol, and cephalothin sodium (cephalothin). In group A, cephalothin was injected intravenously after oral administration of ambroxol. In group B, cephalothin was injected intravenously after oral administration of saline. Groups C and D were used as control groups. The dose of cephalothin or ambroxol was clinically administrated. Venous blood and bronchoalveolar lavage fluid (BALF) were sampled from each group. In groups A and B, cephalothin concentrations in plasma reached their maximum level 5 min after cephalothin administration and then declined over time. In plasma obtained from groups A and B, there were no significant differences in pharmacokinetic parameters (T1/2, Kel, Vd). By contrast, cephalothin concentrations in BALF reached their peak at 180 min after cephalothin administration in both groups A and B and maintained a relatively high level even after 300 min. These findings indicate that cephalothin requires a relatively long period of time to move from the blood stream to the alveolar cavity, but once transferred to the alveolar cavity, it is preserved for a long time. In groups A and B, cephalothin concentrations in BALF were approximately at the same level. However, in group A, total protein in BALF was lower at 60, 180, and 300 min than the other groups. Then, cephalothin concentration was adjusted to total protein in BALF. After adjustment to total protein in BALF, group A showed a concentration level of cephalothin approximately 1.5-fold higher than that of group B. This suggests that the transferability of cephalothin to the alveolar cavity improves as a result of the oral administration of ambroxol.

Resistência a drogas e produçäo de bacteriocinas em linhagens de Escherichia coli e Enterobacter isoladas de indivíduos hospitalizados / Drug resistance and colicin production by Escherichia coli and Enterobacter isolated from hospitalized humans

Escherichia coli e Enterobacter foram isolados de grupos de indivíduos hospitalizados (H), recém-hospitalizados (P), sendo estudados quanto ao perfil de resistência às drogas ampicilina, cefalotina, cloranfenicol, estreptomicina, tetraciclina, gentamicina, canamicina e ao bicloreto de mercúrio, por meio da técnica de diluiçäo em meio sólido, e quanto à produçäo de colicinas. A resistência aos antibióticos betalactâmicos foi maior nas amostras isoladas dos grupos de portadores näo-hospitalizados (P) (modelo ampicilina-cefalosporina), em especial para o gênero Enterobacter. Por outro lado, a freqüencia das amostras colicinogênicas descresceu no grupo H em comparaçäo com amostras colicinogênicas decresceu no grupo H em comparaçäo com as amostras do grupo P. É provável que, em ambientes seletivos pela presença de elevadas concentraçöes de antibióticos, as linhagens portadoras de fenótipos sejam selecionadas e a colicinogênese, deslocada ou substituída, sendo mantida em ambientes näo-seletivos, devido à competitividade as linhagens de uma mesma espécie

Cephalothin and cefazolin in vitro antibacterial activity and pharmacokinetics in dogs.

The periods of time that cephalothin and cefazolin serum concentration remained above minimum inhibitory concentration (MIC) for beta hemolytic, coagulase positive staphylococcal, and Escherichia coli clinical isolates were compared. Cephalothin and cefazolin were similarly very effective in vitro against staphylococcal isolates, with an MIC90 of 0.12 microgram/mL and 0.25 microgram/mL, respectively. In contrast, cefazolin was more effective than cephalothin against E coli isolates; the cefazolin MIC90 for E coli was 16 micrograms/mL and for cephalothin 64 micrograms/mL. Cefazolin (20 mg/kg intravenously [i.v.]) serum concentration remained more than MIC90 for E coli isolates significantly longer than serum concentration of cephalothin (40 mg/kg i.v.) (P < .001).

Whole-blood platelet aggregation, buccal mucosa bleeding time, and serum cephalothin concentration in dogs receiving a presurgical antibiotic protocol.

Whole-blood platelet aggregation (using the impedance method) and adenosine triphosphate (ATP) release, buccal mucosal bleeding time (BT), and serum cephalothin concentration were measured in 21 adult female Beagles before (PRE) and 1 hour (1 HR) after IV administration of cephalothin (22 mg/kg). A second injection of cephalothin (22 mg/kg) was given 3 hours after the first, and blood samples were obtained 1 hour (4 HR, 4 hours after the first injection) and 3 hours (6 HR, 6 hours after the first injection) after the second injection. Samples of jugular blood were obtained from each dog, using citrate as an anticoagulant. A platelet count was obtained for each sample. Platelet aggregation and ATP released from the aggregating platelets were measured within 1 hour of sample collection, using a whole-blood aggregometer. Adenosine diphosphate (ADP) and collagen were used as aggregating agents. Aggregation was measured over 6 minutes for each aggregating agent; ATP release in response to collagen, but not to ADP, was measured over the same period. For 1 HR samples, there was a significant (P < 0.01) reduction from PRE values in the ability of platelets to aggregate in response to ADP. Bleeding time was determined, using a published procedure, with each dog as its own control. Bleeding time during the same period was found to be significantly increased over PRE values for 1 HR (P < 0.01) and 6 HR (P < 0.02) samples. There was no significant difference between BT for 1 HR and 4 HR samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Molecular basis of the efficacy of cefaclor against Haemophilus influenzae.

Cefaclor sustained its inhibitory activity against a beta-lactamase-producing strain of Haemophilus influenzae. Although a relatively high permeability coefficient was calculated for ampicillin compared with that calculated for cefaclor, the resulting periplasmic concentration of cefaclor was 5.7 times that of ampicillin. The efficacy of cefaclor may be due to its higher beta-lactamase resistance, which allows it to achieve a greater periplasmic concentration and adequate binding to crucial penicillin-binding proteins.

[Serum levels of oxacillin and cephalothin in patients with extracorporeal circulation during surgery]. / Sérové hladiny oxacilinu a cefalotinu u nemocných operovaných v mimotelním obehu.

The authors investigated the oxacillin and cephalotine serum levels in patients operated under conditions of extracorporeal circulation. They found that the time for which the patients are adequately protected against staphylococcal infection is in oxacillin cca 180 mins. and in cephalotine 150 mins. after administration of the first dose of antibiotic. They recommend to administer a second dose of the antibiotic along with protamine sulphate after removal of the aortal cannula to obtain a maximum concentration of the antibiotic in the newly formed blood clots. If the surgical operation lasts longer, they recommend to administer the antibiotic in the given time interval regardless of the operation and to administer a third dose when removing the cannula. The authors investigated a total of 30 patients. In one case they encountered an early and in another case a urinary infection.

[Clinical laboratory approach for estimating effective administrative dose of cephalothin. Reevaluation of MIC break points in 4 category system of disc susceptibility test].

The reliability of the cephalothin (CET) disc susceptibility test in estimating approximate values of MICs was studied using various clinical isolates totaling 248 strains and using Showa discs (8 mm diameter containing 30 micrograms of CET) and Difco discs (6 mm diameter containing 30 micrograms of CET). Clinical significance of a 4 category system for the interpretation of the CET disc tests, which is widely used in Japan, was reevaluated to determine whether this system would be suitable or not for the evaluation of proper dose levels of administration. The results obtained with the disc methods were compared with MICs determined using the agar dilution method at an inoculum level of 10(6) CFU/ml. The results of the CET disc susceptibility test were well correlated with MICs, showing the reliability of the disc method to estimate approximate values of MICs. Break points in MIC values proposed for the classification of bacteria into 4 categories of susceptibility are ( ) MIC less than or equal to 3 micrograms/ml, (++) MIC greater than 3-15 micrograms/ml, (+) MIC greater than 15-60 micrograms/ml, (-) MIC greater than 60 micrograms/ml. With the Showa disc susceptibility test, 15 out of the 248 strains (6.0%) tested showed false positive results and 6 strains (2.4%) showed false negative results. With the Difco disc test, 18 out of the 248 strains (7.3%) tested showed false positive results and 6 (2.4%) showed false negative results. Excluding Enterococcus faecalis from the test, results because better in the quantitative estimation of MICs, resulting false positive rates of 3.2% (Showa), and 4.4% (Difco). A 3 category system of the interpretation of disc test is generally used in the USA and Europe. MIC break points proposed for the classification of the CET test are sensitive, MIC less than or equal to 8 micrograms/ml, and resistance, MIC greater than or equal to 32 micrograms/ml. With the Showa disc susceptibility test, 14 out of the 248 strains (5.6%) tested showed false positive results and 6 strains (2.4%) showed false negative results. With the Difco disc test 7 out of the 248 strains (2.8%) showed false positive results and 21 strains (8.5%) showed false negative results. In this study, MIC70S of CET against Staphylococcus aureus and Staphylococcus epidermidis were 1.56 and 0.78 micrograms/ml, respectively. CET was not so effective against Gram-negative rods except Klebsiella pneumoniae, Proteus mirabilis and Escherichia coli. MIC70S against K. pneumoniae, P. mirabilis, and E. coli were 6.25, 3.13, and 3.13 micrograms/ml, respectively.

Nitrogen losses and cephalothin absorption in peritonitis treated by hourly peritoneal dialysis.

The effects of peritonitis on dialysate nitrogen losses were investigated. Eight patients who developed peritonitis while undergoing peritoneal dialysis were compared to seven noninfected dialysis patients. Dialysate protein losses increased during peritonitis, but nitrogen losses into the dialysate did not increase. These findings were caused by reduced urea nitrogen losses in the peritonitis group, which proportionately, more than made up for the increased nitrogen losses from protein. We speculate that the smaller loss of urea nitrogen was due to diminished intake of food. Cephalothin uptake from the peritoneal cavity was unaltered by peritonitis and a dialysate flow rate of 2 L/hour averaged 26 +/- 2 mL/minute and 27 +/- 2 mL/minute in the noninfected and infected groups, respectively.

[Data averaging in pharmacokinetic analysis: the population pharmacokinetics of cephalothin and cefazolin]. / Usrednenie dannykh pri farmakokineticheskom analize: populiatsionnaia farmakokinetika tsefalotina i tsefazolina.

Cephalothin and cefazolin pharmacokinetics was studied in cats after intravenous administration in doses of 20 and 75 mg/kg. The antibiotic serum concentrations were determined microbiologically. It was shown that the antibiotic pharmacokinetics within the above dose ranges was linear. The data on the antibiotic pharmacokinetics were described by bioexponential equations. Various methods for estimating population pharmacokinetic parameters were compared. Two approaches were used in estimating the population parameters: (1) averaging of individual concentrations followed by determining a single set of the parameters (naive pooled data approach) and (2) calculating of the parameters for an individual concentration/time set followed by the parameter averaging (two-stage approach). With the use of every approach the geometric mean of the parameters was calculated along with the arithmetic one. When the two-stage approach was used the population parameters were estimated with two procedures: averaging of the hybrid parameters (macroconstants) and averaging of the microconstants. Estimation of the population parameters as a geometric mean of the individual parameters, proved to be the most preferable approach.

Penetration of cephalothin and cefoxitin into experimental infections with Bacteroides fragilis.

The in vitro activities of cephalothin and cefoxitin against Bacteroides fragilis were studied by time-kill curves and measurement of residual drugs in culture supernatants. Cefoxitin was bactericidal, causing a decrease of 10(7) in viable counts over 24 hr. Cephalothin caused an initial decrease of 10(2) B. fragilis at 2 hr; this change was followed by growth of the organism within 24 hr back to the number present before addition of cephalothin. The concentration of cephalothin in broth decreased rapidly within 2 hr and was undetectable within 24 hr, whereas the level of cefoxitin decreased only 25% over the 24-hr period. Penetration of these drugs into perforated ping pong balls implanted intraperitoneally in rabbits was studied. Three weeks after implantation the reservoirs were infected with B. fragilis. After intramuscular administration of five doses of antibiotic, the penetration of cephalothin, as measured by bioassay, in uninfected and infected capsules was 16% and 2%, respectively, of the peak serum concentration; similar findings were noted with cefoxitin. For determination of the rate of breakdown within the infected site, radiolabeled antibiotic was injected into the capsule, and the concentrations of bioactive and radioactive drug were determined. With radiolabeled cephalothin there was a rapid decrease in bioactivity during the initial 60 min, and no active drug was measurable after 2 hr. In contrast, only 40% of cefoxitin was inactivated at the end of 6 hr. The results indicate that levels of cephalothin and cefoxitin are reduced significantly in sites infected with B. fragilis. The decrease appears to be mediated by both a decrease in penetration and inactivation at the site of infection.

Cefoxitin and cephalothin: antimicrobial activity, human pharmacokinetics, and toxicology.

Cefoxitin, a semisynthetic cephamycin, has been compared with the widely used parenteral cephalosporin, cephalothin, in terms of antibacterial activity, human pharmacokinetics, and toxicity. For both compounds, minimal inhibitory concentrations were within the therapeutic range against the 156 gram-positive cocci tested (except group D streptococci), but cephalothin was 8 to 20 times more active. Regarding the 313 gram-negative organisms tested, both antibiotics were of approximately equal activity against cephalothin-susceptible strains, but cefoxitin was outstandingly superior against Providencia spp. and indole-producing Proteus spp., and markedly better against Serratia marcescens and Bacteroides fragilis. Against these organisms, cefoxitin but not cephalothin would be expected to be therapeutically valuable. Antibiotic activity levels in the serum and urine of 18 human volunteers after parenteral administration were higher and more prolonged in the case of cefoxitin, which had an average terminal serum half-life of about 45 min and a urinary recovery of about 90%. Cefoxitin was entirely nontoxic and, given intramuscularly, slightly less painful then cephalothin. These preliminary results suggest that cephamycins may prove to be a significant chemotherapeutic advance.

Effects of rate of infusion and probenecid on serum levels, renal excretion, and tolerance of intravenous doses of cefoxitin in humans: comparison with cephalothin.

Using a randomized crossover design, 1-g intravenous doses of cephalothin and cefoxitin, a cephalosporinase-resistant cephamycin, were infused into 12 normal adult males over periods of 120, 30, and 3 min, the last with and without prior intravenous infusions of probenecid (1 g). Mean peak serum concentrations of antibiotic activity after cephalothin infusions were 23, 56, 103, and 102 mug/ml, respectively, and after cefoxitin infusions they were 27, 74, 115, and 125 mug/ml, respectively. Probenecid treatment prolonged the terminal serum half-life of cephalothin-like activity from 0.52 to 1.0 h, and of cefoxitin from 0.68 to 1.4 h. In contrast to cephalothin, which was found to be metabolized about 25% to the less active desacetyl form, cefoxitin was metabolized less than 2% to the virtually inactive descarbamyl form, as judged from urinary recoveries. Neither antibiotic displayed detectable organ toxicity. Of 300 recent clinical isolates of gram-negative bacilli other than Pseudomonas spp., 83% were susceptible to cephalothin but 95% were susceptible to cefoxitin. Organisms resistant to cephalothin but susceptible to cefoxitin included strains of Escherichia coli, Proteus vulgaris, Klebsiella spp., Serratia marcescens, Enterobacter spp., and Bacteroides spp.