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PubMed1975

Relation of beta-lactamase activity to antimicrobial susceptibility in Serratia marcescens.

One-hundred clinical isolates of Serratia marcescens were tested for susceptibility to cephalothin, carbenicillin, ticarcillin, ampicillin, and cefoxitin. The majority of the 100 isolates (>/=70%) were susceptible to carbenicillin, ticarcillin, and cefoxitin; less than one-half were susceptible to ampicillin; none were susceptible to cephalothin. Ten isolates from the 100 organisms tested were selectively assayed for their beta-lactamase activity. Enzyme activity was measured using either iodometric or spectrophotometric methods, and the microbiological assay technique. It was concluded that beta-lactamase production was not the sole determinant in beta-lactam antibiotic resistance. Resistance without demonstrable beta-lactamase was evident in strains for cephalothin, ampicillin, and cefoxitin. In addition, one strain which was susceptible to all antibiotics except cephalothin, elaborated considerable beta-lactamase activity.

Amidohydrolases↗
PubMed1976

Nephrotoxicity of cephalosporin-gentamicin combinations in rats.

TO STUDY THE POSSIBILITY THAT CEPHALOSPORINS AUGMENT THE NEPHROTOXICITY OF GENTAMICIN, GROUPS OF RATS WERE GIVEN FOUR HOURLY SUBCUTANEOUS DOSES OF: gentamicin (5 mg/kg), gentamicin plus cephalothin (100 mg/kg), gentamicin plus cefazolin (20 mg/kg), gentamicin plus cefazolin (50 mg/kg), gentamicin plus cephaloridine (50 mg/kg), or saline diluent for 15 days. Periodic measurements were made of urine volume, urine osmolality, urine protein excretion and lysosomal enzymuria, as well as blood urea nitrogen, creatinine clearance, and drug concentrations in renal cortex and medulla. Tissue was examined by light and electron microscopy. Enzymuria and proteinuria increased early in the course of all treatment groups, whereas urine osmolality declined. No distinct patterns of these variables were discernable among the groups. Gentamicin alone, gentamicin plus cephalothin, and gentamicin plus cefazolin (20 mg/kg) caused the same significant fall in glomerular filtrate rate from control values by day 15 (P < 0.05). Gentamicin plus cefazolin (50 mg/kg) and gentamicin plus cephaloridine failed to cause a decline in glomerular filtration rate compared with controls (P > 0.05). Gentamicin concentrations in renal cortex were 5 to 10 times higher than those in medulla in all groups. Cephaloridine and cefazolin (50 mg/kg) also displayed a gradient pattern in renal cortex, whereas cephalothin and cefazolin (20 mg/kg) did not. Cytosegrosomes with myeloid figures were characteristic ultra-structural changes seen in all groups; however, they tended to be smaller with less numerous myeloid bodies in the groups receiving gentamicin plus cephalothin, cefazolin (50 mg/kg), or cephaloridine. Cephalosporins did not augment gentamicin toxicity. High doses of cefazolin and cephaloridine protected kidneys from gentamicin nephrotoxicity. The protection may involve intracellular drug interaction within the renal cortex.

Animals↗
PubMed2005

Patterns of antimicrobial resistance observed in Escherichia coli isolates obtained from domestic- and wild-animal fecal samples, human septage, and surface water.

A repeated cross-sectional study was conducted to determine the patterns of antimicrobial resistance in 1,286 Escherichia coli strains isolated from human septage, wildlife, domestic animals, farm environments, and surface water in the Red Cedar watershed in Michigan. Isolation and identification of E. coli were done by using enrichment media, selective media, and biochemical tests. Antimicrobial susceptibility testing by the disk diffusion method was conducted for neomycin, gentamicin, streptomycin, chloramphenicol, ofloxacin, trimethoprim-sulfamethoxazole, tetracycline, ampicillin, nalidixic acid, nitrofurantoin, cephalothin, and sulfisoxazole. Resistance to at least one antimicrobial agent was demonstrated in isolates from livestock, companion animals, human septage, wildlife, and surface water. In general, E. coli isolates from domestic species showed resistance to the largest number of antimicrobial agents compared to isolates from human septage, wildlife, and surface water. The agents to which resistance was demonstrated most frequently were tetracycline, cephalothin, sulfisoxazole, and streptomycin. There were similarities in the patterns of resistance in fecal samples and farm environment samples by animal, and the levels of cephalothin-resistant isolates were higher in farm environment samples than in fecal samples. Multidrug resistance was seen in a variety of sources, and the highest levels of multidrug-resistant E. coli were observed for swine fecal samples. The fact that water sample isolates were resistant only to cephalothin may suggest that the resistance patterns for farm environment samples may be more representative of the risk of contamination of surface waters with antimicrobial agent-resistant bacteria.

Animals↗
PubMed1984

Antibiotic therapy of fulminant E. coli K1 sepsis in infant rabbits.

A model of overwhelming E. coli K1 sepsis and early meningitis was developed in infant rabbits and used to compare clinical and bacteriologic efficacy of ampicillin, moxalactam, cephalothin and chloramphenicol. Intraperitoneal injection of 10(7) E. coli K1 into 1- or 2-wk-old rabbits produced a rapidly progressive infection which, if left untreated, produced bacteremia in 100% of animals, meningitis in 78%, and mortality in 100%. Therapy was initiated 4 h after ip infection at which time mean bacterial concentration (log10 CFU/ml) ranged from 4.4-4.8 in the blood and from 1.8-2.3 in the cerebral spinal fluid (CSF). Pre-treatment frequency of bacteremia (100%) and meningitis (17-23%) was similar for all experimental groups. Antibiotic concentrations in blood and CSF 2 h after a dose exceeded the E. coli minimum inhibitory concentration with the exception of CSF cephalothin, which was undetectable. Moxalactam, ampicillin, and chloramphenicol significantly reduced the incidence of bacteremia and meningitis relative to cephalothin or saline controls (P less than 0.02). Mortality rates among the former three groups were high (64-82%) but significantly less than in saline or cephalothin-treated rabbits (100%). In this neonatal model of fulminant sepsis with early meningitis, moxalactam provided no therapeutic advantage over ampicillin or chloramphenicol.

Animals↗
PubMed1976

Ceftezole, a new cephalosporin C derivative II. Distribution and excretion in parenteral administration.

The distribution of ceftezole in blood and tissues and its excretion after intramuscular or intravenous administration of single doses of 10 and 20 mg/kg were compared with those of cefazolin, cephaloridine and cephalothin. Blood levels of ceftezole in rats and rabbits were lower than those of cefazolin, and higher than those of cephaloridine and cephalothin. Retention time of ceftezole in the blood was somewhat shorter than that of cefazolin. However, blood levels of ceftezole in dogs were nearly the same as those of cefazolin and cephaloridine. The rate of urinary excretion of ceftezole in 24-hour urine after administration in rats and rabbits was found to be higher than those of the other antibiotics tested. In dogs, however, the rate of urinary excretion of ceftezole was nearly the same as that of cefazolin and higher than those of cephaloridine and cephalothin. The biliary excretion of ceftezole in rats and dogs was much higher than those of cephaloridine and cephalothin, but lower than that of cefazolin. Tissue distribution of ceftezole in rats was compared with that of the other antibiotics by intramuscular and intravenous administration. The initial level of ceftezole in the kidneys was found to be substantially higher than those of the other antibiotics. The initial level of ceftezole in the liver and lungs was also slightly higher than those of the other drugs when administered intramuscularly. Tissue levels of ceftezole were somewhat lower than those of cefazolin in rabbits after intravenous administration. Ceftezole attained a higher maximum level in rat lymph by intramuscular administration than the other antibiotics tested. The maximum concentration of ceftezole present in the exudate in the rat inflammatory pouch was higher than that of cefazolin. In rabbits with cerebrospinal meningitis induced by infection of Streptococcus pyogenes, the level of ceftezole in the cerebrospinal fluid was several times higher than that in normal rabbits. The serum level and urinary excretion of ceftezole was examined in 6 healthy male volunteers after intramuscular administration of a single dose of 500 mg. Ceftezole attained a mean maximum serum level of 22.9 mug/ml 30 minutes after administration and disappeared from the blood in about 6 hours. It was excreted rapidly in the urine. The concentration in 1-hour urine was the highest (mean level: 2,667 mug/ml) and the total excretion rate was 92.6%. No metabolites with antimicrobial activity were observed in the urine. No changes in the pattern of plasma level and urinary excretion and no accumulation in the tissues were observed after repeated intramuscular administration of 20 mg/kg of ceftezole in rabbits, 26 times, for 14 days.

Animals↗
PubMed1977

Pharmacokinetics of five cephalosporins in healthy male volunteers.

This paper deals with data on the pharmacokinetics of cephazolin, cephalothin, cephapirin, cephaloridine and cephradine after i.m. injection of a single dose of 0.5 g in healthy male volunteers. Peak serum concentrations occurred 45 min after the administration and were 31.52 microgram/ml for cephazolin, 17.32 microgram/ml for cephaloridine, 13.98 microgram/ml for cephapirin, 9.51 microgram/ml for cephradine and 8.60 microgram/ml for cephalothin. The average half-lives were found to be 2.07, 1.80, 0.98, 1.24 and 0.97 h, respectively. The percentage of protein binding was found to be 82 for cephazolin, 59 for cephalothin, 51 for cephapirin, 31 for cephaloridine and only 10 for cephradine, half an hour after drug administration. The total urine recovery of the above cephalosporins, within 24 h, was 91.9% for cephradine, 81.9% for cephaloridine, 73.3% for cephazolin, 69.5% for cephapirin and 51.2% for cephalothin.

Adult↗
PubMed1980

[Yersinia enterocolitica: the influence of incubation temperature on antibiotic susceptibility, beta-lactamase activity and growth characteristics (author's transl)].

The influence of incubation temperature (37, 30 and 22 degrees C) on antibiotic susceptibility, beta-lactamase activity and growth characteristics was studied on 43 unselected strains of Y. enterocolitica (Serovar O:3 and O:9) freshly isolated from cliical specimens. Antibiotic susceptibility was measured by the disc diffusion technique and by a broth dilution test (MIC). Beta-lactamase activity was detected with chromogenic cephacetrile using standard curves prepared for 37, 30 and 22 degrees C. Continuous increase of beta-lactamase activity was found when incubation temperatures were lowered. All strains were found to be resistant by ampicillin and cephalothin at the three temperatues tested. Some strains showed an intermediate susceptibility to carbenicillin in the disc diffusion test. A temperature reduction of 37 to 30 degrees C significantly decreased the inhibitory zone diameters for the beta-lactam antibiotics ampicillin, carbenicillin and cephalothin, but also for other substances like tetracycline, chloramphenicole and cotrimoxazole. This suggests, that the observed decrease is caused by a better growth of Y. enterocolitica at 30 degrees C rather than increased beta-lactamase production. From 30 to 22 degrees C a further decrease in inhibitory zone diameters was only seen with ampicillin and carbenicillin. This seems to be mainly due to the increased B-lactamase activity observed at 22 degrees C. In contrast the resistance to cephalothin was apparently not influenced by this additional beta-lactamase activity. Resistance to cephalothin therefore depends probably more on other, not beta-lactamase-related, factors such as permeability variations of the outer membrane or modifications of binding proteins involved in the peptidolycan biosynthesis. The correlation between beta-lactamase activity at various incubation temperatures and resistance to beta-lactam antibiotics was less pronounced when the broth dilution test (MIC) was applied. Only carbenicillin showed significantly increasing MIC values from 30 to 22 degrees C. All the Y.e. strains investigated could be divided into two groups with respect to their beta-lactamase production characteristics. The first group showed continuously increasing beta-lactamase values at lower incubation temperatures. In the second group generally lower amounts of beta-lactamase values were found and temperature dependence was not observed. On the other hand variations in cell wall permeability, resulting in a diminished accessability of the cell wall bound enzymes must also be considered.

Anti-Bacterial Agents↗
PubMed1979

Chemical reactions in cephalosporin allergy: high-pressure liquid chromatographic analysis of cephalosporin aminolysis kinetics.

Cephalosporin reaction with protein amino groups is fundamental to cephalosporin allergy. Cephalothin and cefazolin reaction kinetics with epsilon-aminocaproic acid, B-alanine, and glycine in aqueous solution were investigated. All reactions were conducted at 35 degrees and 0.5 ionic strength and were followed by ion-exchange high-pressure liquid chromatography. The aminolysis rate constants can be expressed as terms representing uncatlyzed or water-catalyzed amine reaction, self-assited nucleophilic reaction, and hydroxide-ion-catalayzed nucleophilic amine attack on the beta-lactam moiety. Cephalothin and cefazolin react with amines as readily as penicillin G. The UV spectra of several cephalothin-glycine reaction products were recorded, and their possible structures are discussed.

Amines↗
PubMed1978

Effects of various cephalosporins on the proximal tubule of the human kidney.

Cephamandol 6.0 g, cephazolin 6.0 g or cephacetrile or cephalothin 8.0 g were administered as short-term infusions on 3 consecutive days to informed volunteers, who had no history or evidence of impairment of renal function. There were 15 subjects in the cephamandol, cephacetrile and cephalothin groups and 14 subjects in the cephazolin group. Alanine-aminopeptidase, a characteristic tubule enzyme, was determined in a 24-hour urine 2 days before administration, during the 3 day administration and on the 4 subsequent days. In addition, alanine-aminopeptidase was also estimated immunologically in concentrated urine with the aid of an anti-brush border antibody. Cephamandol, cephazolin and cephalothin were completely without effect on the proximal tubule. Cephacetrile, on the other hand, showed clear reactions in 9 out of 15 subjects, in the form of elevated AAP activity in urine and in 6 of the cases membrane elimination was demonstrable immunologically. After withdrawal of the medication, the values of the responder group returned spontaneously to normal, i.e. no cumulative effect was detected. These investigations show that elimination of alanine-aminopeptidase in the urine is a very sensitive index of the action of cephalosporins on renal tubules.

Adolescent↗
PubMed1991

Comparative in vitro activity of three cephalosporins against Staphylococcus aureus isolated from bovine mastitis.

This report compares the in vitro activity of three cephalosporins (cephalothin, cefoxitin and ceftriaxone) against 57 Staphylococcus aureus strains isolated from cows with clinical mastitis on the basis of the minimal inhibitory (MIC) and minimal bactericidal concentrations (MBC). The majority of the S aureus strains showed resistance to cefoxitin and ceftriaxone and sensitivity to cephalothin. The highest MICs and MBCs were found for cefoxitin and ceftriaxone. Antimicrobial tolerance (MBC/MIC greater than or equal to 32:1) was observed in relation to cephalothin and ceftriaxone. The data suggest that these cephalosporins may not be effective for the treatment of staphylococcal bovine mastitis. The precise definition of their antimicrobial efficacies requires more detailed in vitro and in vivo studies.

Animals↗
PubMed1986

The influence of cephem antibiotics on gentamicin nephrotoxicity in normal, acidotic, dehydrated, and unilaterally nephrectomized rats.

Normal, acidotic, dehydrated, or unilaterally nephrectomized rats (Sprague-Dawley) were injected with gentamicin (80 mg/kg/day) alone or in combination with cefoxitin (2 g/kg/day), cephalothin (2 g/kg/day), or cephaloridine (1 g/kg/day) once daily for 10 consecutive days. Serum creatinine levels and renal cortical concentrations of gentamicin were determined and histopathological examination of the kidneys was made. Gentamicin caused marked renal damage in all the groups of rats. In normal rats, all the cephem antibiotics significantly reduced both gentamicin nephrotoxicity and renal gentamicin levels. In acidotic, dehydrated, and unilaterally nephrectomized rats, cefoxitin still significantly reduced gentamicin nephrotoxicity without affecting renal gentamicin concentration, whereas cephalothin and cephaloridine did not show any significant reduction of nephrotoxicity or gentamicin concentration, but rather caused general deterioration of the animals. Hence, the intrinsic nephrotoxic potential of cefoxitin, cephalothin, and cephaloridine may contribute to the difference in the combined effect rather than the concentration of gentamicin in the kidney.

Acidosis↗
PubMed1995

A study of the nephrotoxicity of three cephalosporins in rabbits using 1H NMR spectroscopy.

Male New Zealand White rabbits received a single intravenous injection of 125 mg/kg cephaloridine, 500 mg/kg cefoperazone or 1000 mg/kg cephalothin. Histological examination of kidneys at 48 h post-dose confirmed the presence of bilateral necrosis of the proximal convoluted tubules in the cephaloridine-treated animals. 1H-NMR urinalysis of cephaloridine-treated rabbits detected drug-related resonances, decreased hippurate and increased glucose at 0-24 h post-dose accompanied by elevated levels of lactate, glycine, citrate, glutamine/glutamate and alanine at 24-48 h post-dose. No histopathological changes were observed following administration of cefoperazone or cephalothin. 1H-NMR spectra of urine collected from these animals showed drug-related resonances and decreased hippurate levels at 0-24 h post-dose, and increased glucose levels at 24-48 h post-dose. Analysis of urine by conventional clinical-chemistry failed to reveal any statistically significant differences between the treatment groups. Under the conditions of this study, the nephrotoxic effects of cephaloridine and the minimal effects of cefoperazone and cephalothin could be clearly distinguished by 1H-NMR urinalysis but not by conventional urinalysis.

Alanine↗
PubMed1985

Analytical interference of drugs in clinical chemistry: II--The interference of three cephalosporins with the determination of serum creatinine concentration by the Jaffé reaction.

It is well known that some cephalosporins interfere with the Jaffé reaction for creatinine measurement. This interference varies according to the thirteen instruments and eighteen methodologies studied. Our study has shown that: the proportion of picric acid, NaOH and serum have only a slight effect on the interference; the addition of a buffer to the NaOH solution increases the interference due to cephalothin and cephaloridine, but lessens that due to cefoxitin; dialysis decreases the interference; in kinetic methods, the choice of times at which readings are made influences the magnitude of the interference; a higher incubation temperature increases the effect of cefoxitin and decreases the effects of cephalothin and cephaloridine; pre-incubation with NaOH decreases the interference due to cefoxitin, but has no significant effect on the interference due to cephalothin or to cephaloridine.

Autoanalysis↗
PubMed1999

Beta-lactam degradation catalysed by Cd2+ ion in methanol.

Kinetic schemes are established for degradation catalysed by Cd2+ ions in methanolic medium for penicillin G, penicillin V and cephalothin, a cephalosporin. Methanolysis of penicillin V and cephalothin occurs with the formation of a single substrate-metal ion intermediate complex, SM, while degradation of penicillin G occurs with the initial formation of two complexes with different stoichiometry, SM and S2M. In each case. degradation is of first order with respect to SM with rate constant values equal to 0.079 min(-1), 0.120 min(-1) and 0.166 min(-1) at 20, 25 and 30 degrees C, respectively, for penicillin G; 0.061 min(-1) at 20 degrees C for penicillin V; and 2.0 x 10(-3) min(-1) at 20 degrees C for cephalothin. Activation energy for the decomposition process of the SM intermediate for penicillin G was calculated to be about 5.5 x 10(4) J/mol. Equilibrium constant values between SM compound and S2M at 20 degrees C (77.1 l/mol), 25 degrees C (45.3 l/mol) and at 30 degrees C (25.7 l/mol) were also calculated as well as the normal enthalpy of this equilibrium. With respect to the reaction products there is evidence that Cd2+ becomes part of their structure, forming complexes between Cd2+ and the product resulting from antibiotic methanolysis (L). Some characteristics of these complexes are discussed.

Anti-Bacterial Agents↗
PubMed1997

Transfer of antibiotic resistance and production of extended-spectrum beta-lactamase (ESBL) in nosocomial Klebsiella pneumoniae strains from two hospitals in Czech Republic.

Six Klebsiella pneumoniae strains were collected from two hospitals in Ostrava, Czech republic. Four strains (Nos. 209, 217, 218, 222) were isolated from sputa of critically ill patients from Municipal Hospital Vítkovice-Ostrava. They were resistant to cephalothin, cefotaxime, and ceftazidime (MIC > 100 mg x l-1). Strain No. 218 was intermediately resistant also to ofloxacin and aztreonam (MIC = 12.5 mg x l-1), strain No. 222 was resistant to aztreonam (MIC = 50 mg x l-1). Determinants of resistance to cephalothin, cefotaxime, aztreonam and ceftazidime were transferred to recipient strains of P. mirabilis P-38 rif+ and E. coli K-12 No. 3110 rif+ by all four strains. Synergy between clavulanate-cefotaxime, clavulanate-ceftazidime and clavulanate-aztreonam indicated production of ESBLs by these strains. Two strains, No. 214 and 224, from patients of the ICU in the University Hospital were resistant to cephalothin, cefotaxime and ceftazidime (MIC > 100 mg x l-1). Strain No. 214 was intermediately resistant to aztreonam and ofloxacin (MIC = 12.5 mg x l-1) and strain No. 224 was highly resistant to aztreonam (MIC = 50 mg x l-1). Synergy between clavulanate and cefotaxime as well as between clavulanate and aztreonam, but not between clavulanate and ceftazidime corresponds with non-transferable ceftazidime resistance in strains No. 214 and 224 and indicates different types of ESBL in strains from each of two hospitals.

Aztreonam↗
PubMedDate not supplied

Penetration of cefotaxime and moxalactam into cerebrospinal fluid of rabbits with experimentally induced Escherichia coli meningitis.

Penetration of the new beta-lactam antibiotics cefotaxime and moxalactam into cerebrospinal fluid (CSF) was studied in rabbits with experimentally produced Escherichia coli meningitis. Cefotaxime reached peak concentrations (mean +/- SEM) of 31.9 +/- 5.4 micrograms/ml in serum and 2.8 +/- 0.3 micrograms/ml in CSF after an infusion of 50 mg/kg per hr for 8 hr. Moxalactam, after an infusion of 12.5 mg/kg per hr iv, produced peaks of 31.0 +/- 13.1 micrograms/ml in serum and 9.7 +/- 1.2 micrograms/ml in CSF. Both drugs reduced the initial concentration of E. coli in the CSF by greater than 1,000-fold. An infusion of 100 mg/kg per hr of cephalothin produced a peak concentration of 76.5 +/- 15.2 micrograms/ml in serum but resulted in a concentration of only 0.17 +/- 0.05 micrograms/ml in CSF and had no bactericidal activity in CSF. Paper chromatography of CSF from cefotaxime-treated rabbits showed that 85.3% (+/- 3.1%) of the antibiotic activity was ascribed to desacetylcefotaxime, a metabolite that is less potent than the parent drug. Neither cefotaxime nor moxalactam was taken up in vitro by rabbit choroid plexus tissue, but cephalothin was taken up at a rate of 9.6 +/- 1.1 microgram/g per hr. Perhaps cefotaxime and moxalactam reached higher concentrations in CSF than did cephalothin because they are not removed from the CSF by the exit pump of the choroid plexus. The fact that levels of cefotaxime in CSF are lower than those of moxalactam could be attributed to the presence of desacetylcefotaxime, a metabolite that is less active than cefotaxime.

Animals↗
PubMedDate not supplied

Experimental chronic staphylococcal osteomyelitis in rabbits: treatment with rifampin alone and in combination with other antimicrobial agents.

The efficacy of rifampin alone and in combination with sisomicin, cephalothin, sisomicin and cephalothin, or trimethoprim was measured in an experimental model of chronic osteomyelitis due to Staphylococcus aureus in rabbits. Single-drug regimens used for 28 days were relatively ineffective (bone sterilization rate, 5%-55%). Combinations of rifampin with other agents were more effective (bone sterilization rate, 75%-100%). The combination of rifampin, sisomicin, and cephalothin given for only 14 days sterilized the bones of all treated rabbits. Staphylococci isolated from the bones of rabbits that had received rifampin alone or in combination with other antibiotics were highly resistant to rifampin; in contrast, these organisms remained sensitive to the other agents used. Results of in vitro studies of synergy correlated with in vivo results in some but not all instances. The results obtained with rifampin in the treatment of experimental chronic osteomyelitis caused by S. aureus suggest that clinical trials of this agent for the treatment of osteomyelitis in humans are warranted.

Animals↗
PubMed1975

Extraction of antibiotics from the circulation by liver and kidney: effect of probenecid.

An experimental canine model was designed to measure directly the uptake, storage, and excretion of antibiotics by the liver and kidney. At equilibirum the rate of uptake of penicillin G, cephalothin, and nafcillin by these organs was about 80% of the rate of intravenous infusion of each antibiotic. Penicillin G and cephalothin were extracted mainly by the kidneys, and nafcillin by the liver. Injection of probenecid virtually abolished the difference in concentration of antibiotic between afferent and efferent vessels of the liver and kidney after 30-45 min. Renal tubular secretion of penicillin G and cephalothin was suppressed, and their levels in renal tissue were increased. These findings militate against any primary limitation by probenecid of access of antibiotic to the renal parenchyma. A marked sustained increase (60%-70%) in the rate of portal flow followed injection of probenecid, and the concomitant percentage of nafcillin extracted by the liver declined significantly. Because of the circulatory changes, a specific effect of probenecid on acess of nafcillin to the liver could not be proved.

Animals↗