Cefazolin, a new semisynthetic cephalosporin antibiotic. 3. Absorption, excretion and tissue distribution in parenteral administration.
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Ampicillin↗
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Absorption, tissue concentration, and organ distribution of cefazolin.
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Adult↗
Studies on direct Coombs reaction by cefazolin in vitro.
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Animals↗
Does intraoperative blood loss affect antibiotic serum and tissue concentrations?
OBJECTIVE: To determine the effect of intraoperative blood loss on prophylactic cefazolin and gentamicin serum and tissue concentrations. DESIGN: A prospective study of elective spinal instrumentation surgical procedures with an expected large blood loss. SETTING: Tertiary care, inner-city university hospital. PATIENTS: Eleven adult patients who underwent an elective surgical procedure that involved spinal instrumentation. INTERVENTION: Standard perioperative administration of a combination of cefazolin and gentamicin. Serum and tissue samples were obtained consecutively throughout the surgical procedure. MAIN OUTCOME MEASURES: The effect of intraoperative blood loss on serum and tissue cefazolin and gentamicin concentrations and their pharmacokinetics. RESULTS: At the time of the incision, serum cefazolin concentrations were greater than tissue concentrations (P = .07). A mean dose of 1.8-mg/kg gentamicin yielded low or nontherapeutic serum and tissue gentamicin concentrations. Cefazolin and gentamicin were eliminated from the tissue compartment slower than from the serum compartment (P < .03), while the half-life of cefazolin was significantly (P = .06) longer in the tissue compartment. The volume of distribution of cefazolin was normal (ie, 12.5 L), while the volume of distribution of gentamicin was 5-fold greater than expected. At 60 minutes after the incision, blood loss correlated with cefazolin tissue concentrations (r = -0.66, P = .05). Blood loss correlated with the change in tissue antibiotic concentrations for cefazolin (r = 0.73, P = .04). In addition, the clearance of gentamicin from the tissues correlated with blood loss (r = 0.82, P = .01). CONCLUSIONS: Based on measured pharmacokinetic values, additional doses of cefazolin should be administered when the operation exceeds 3 hours and blood loss is greater than 1500 mL. Doses of gentamicin greater than 1.8 mg/kg should be administered more than 30 minutes prior to the surgical incision.
Adult↗
Effect of gastrointestinal maturation on absorption of beta-lactam antibiotics.
Gastrointestinal absorption of cefazolin, which is poorly absorbed in adults, and of cephradine, which is well absorbed in adults, was studied in rats during their development. Significantly higher concentrations of cefazolin in plasma after oral administration were observed in 1- and 2-week-old rats compared with 3-week-old and adult rats. A marked difference in the absorption of cefazolin by 2- and 3-week-old rats (at weaning period) was observed. No such marked difference in the absorption of cephradine by rats of various age groups was found. With cefazolin, a similar pattern of developmental change in jejunal uptake was observed. Cortisone, which causes early maturation of the intestinal membrane, was given as a preweaning injection to 2-week-old rats. This treatment decreased concentrations of cefazolin in plasma and jejunal uptake of cefazolin. Thus, the absorption of cefazolin in 1- and 2-week-old rats seems to depend on the permeability of the immature intestinal membrane before weaning. Cephradine absorption from the intestine of 1-week-old rats became saturated and inhibited by carnosine and glycylglycine when studied by the in situ loop method. Cefazolin absorption was proportional to luminally administered doses and was not affected by carnosine and glycylglycine. A nonsaturable process for cefazolin and a saturable process for cephradine were also observed in an in vitro uptake experiment.
Aging↗
Placebo-controlled, double-blind, randomized study of prophylactic antibiotics in elective abdominal hysterectomy.
To assess the efficacy of a single dose of ampicillin or cefazolin in preventing fever and infection after elective abdominal hysterectomy, we conducted a multicentre, randomized, double-blind, controlled trial at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University and Khon Kaen Regional Hospital. Three hundred and thirty patients scheduled for elective abdominal hysterectomy were randomly allocated into either placebo, ampicillin or cefazolin groups. Patients received sterile water (3 mL) or ampicillin (1 g) or cefazolin (1 g) intravenously according to random assignment 30 min before the operation. After the operation, all patients were assessed by blinded independent evaluators until discharged from the hospitals. Our main outcome measures were postoperative fever and infectious morbidity. We found that 321 patients (97.3% of recruited patients) were available for data analysis, 108 in placebo, 106 in ampicillin and 107 in cefazolin group. Febrile morbidity occurred in 13/108 (12.0%), 14/106 (13.2%) and 12/107 (11.2%) of patients in the placebo, ampicillin and cefazolin groups, respectively. There was no statistically significant difference in febrile morbidity between the three groups. Infectious morbidity was found in 29/108 (26.9%), 24/106 (22.6%) and 11/107 (10.3%) of patients in the placebo, ampicillin and cefazolin groups, respectively. There was a statistically significant difference between the placebo and cefazolin groups (P = 0.002). Between the placebo and ampicillin groups, the result was not significantly different (P = 0.476). There was a statistically significant difference between the cefazolin and ampicillin groups (P = 0.015). The common causes of infectious morbidity were urinary tract infection, vaginal cuff infection and surgical wound infection. We concluded that antibiotic prophylaxis by cefazolin should be recommended for elective total abdominal hysterectomy.
Adult↗
Antibiotic prophylaxis for surgery in morbidly obese patients.
The rate of wound infections in morbidly obese patients who underwent gastroplasty surgery at our institution was 16.5% compared with a rate of 2.5% in normal-weight patients who underwent clean-contaminated surgery. Both groups received 1 gm of cefazolin intramuscularly before surgery was performed. We hypothesized that this regimen of prophylaxis did not provide adequate tissue levels in the morbidly obese. Morbidly obese patients who were undergoing gastroplasty were randomly selected to receive 1 gm cefazolin in the buttock fat, buttock muscle, or by intravenous injection. A fourth group of morbidly obese patients received 2 gm of cefazolin intravenously. Normal-weight patients who were undergoing upper abdominal surgery received 1 gm of cefazolin intravenously. At incision and closure, both blood and tissue levels of cefazolin were significantly (p less than 0.001) lower for all morbidly obese patients who received 1 gm cefazolin when compared with the blood and tissue levels of the drug found in normal-weight patients. The cefazolin levels obtained were below the minimal inhibitory concentrations of greater than 2 micrograms/ml for gram-positive cocci and of greater than 4 micrograms/ml for gram-negative rods. Only when the morbidly obese patient received 2 gm cefazolin were both the serum and adipose tissue levels adequate. For a 4-month period, all morbidly obese patients received 2 gm cefazolin prophylaxis, and the wound infection rate dropped to 5.6% compared with the previous rate of 16.5% (p less than 0.03). We conclude that antibiotic prophylaxis must be specially tailored to the needs of these obese patients.
Adipose Tissue↗
Antibiotic prophylaxis and tourniquet inflation in total knee arthroplasty.
Twenty-four patients receiving total knee arthroplasty (TKA) were randomized into one of three groups based on tourniquet inflation one, two, or five minutes after administration 1 g cefazolin. Simultaneous serum, soft-tissue, and bone samples were obtained at regular intervals during surgery. All soft-tissue and bone samples were corrected for cefazolin content. The percentage of cefazolin penetration into soft tissue and bone was calculated using the area under the concentration time curve. Adequate cefazolin concentrations for soft tissue and bone were defined as greater than or equal to 4 x minimum inhibitory concentration90 (MIC90 = 1 microgram/ml) of cefazolin to Staphylococcus aureus and coagulase-negative staphylococci. Patients were similar in age, actual body weight, creatinine clearance, and length of tourniquet inflation. The median percentage of cefazolin penetration into soft tissue and bone for the five-, two-, and one-minute groups was 14.5% and 4.6%, 6.7% and 3.0%, and 5.9% and 4.6%, respectively; the percentage of penetration into soft tissue between the five- and one-minute groups was statistically significant. A higher percentage of patients achieved the desired cefazolin concentration (greater than or equal to 4 micrograms/g) if a five-minute interval was selected. The five-minute group achieved the highest mean ratios of concentration to MIC compared with the two- and one-minute groups, although the differences were not statistically significant. The standard 1 g of cefazolin with a five-minute interval between administration and tourniquet inflation resulted in adequate mean soft-tissue and bone concentrations for prophylaxis during TKA with a tourniquet time less than two hours. Additional doses are not warranted after tourniquet release.
Aged↗
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↗
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↗
Physiological modeling for indirect evaluation of drug tissular pharmacokinetics under non-steady-state conditions: an example of antimicrobial prophylaxis during liver surgery.
Cefazolin, a time-dependent first-generation cephalosporin with non-linear binding to albumin, is widely recommended for antimicrobial prophylaxis during liver surgery to decrease the incidence of postoperative wound infections. The recommended protocol (2 g IV at anesthesia induction followed by 1 g 4 h later) is expected to maintain the free cefazolin concentration in exposed intratissular fluids above its minimal inhibitory concentration (MIC) for potentially encountered microorganisms, from skin incision to skin closure. Since this dosing protocol fails to take into account either of patients status (total body weight and renal function) or of surgical and anesthetic consequences (variations of cardiac output and regional blood flows, progressive decrease of plasma albumin concentration) on cefazolin tissular pharmacokinetics, a physiological modeling study was conducted to investigate protocol suitability for liver surgery in six populations: obese (body mass index >34), renal insufficiency (GFR = 10, 30 or 50 ml min(-1)) and high intraoperative blood loss (three times that usually observed during this surgery) and none of these features referred to as controls. A previously validated physiologically based pharmacokinetic (PB-PK) model for cefazolin in humans was used and then further adapted to simulate obese or renal insufficiency patients as well as the consequences of general anesthesia and liver surgery on cefazolin pharmacokinetics. Clinical data required for simulation (intraoperative kinetics of percent expired isoflurane and plasma albumin concentration, mean intraoperative blood loss) were obtained from 10 patients who underwent right hepatectomy in our institution. Using a fixed MIC of 2 microg ml(-1) against potentially encountered bacteria, it was concluded that the recommended dosing schedule was suitable in all tested populations, including obese patients, although prolongation of the interval between injections appeared advisable for renal insufficiency patients. Furthermore, when a MIC of 3 microg ml(-1) was considered, the recommended cefazolin-dosing regimen failed to maintain sufficient free cefazolin concentrations in the interstitial fluids during surgery in all tested populations except renal insufficiency patients (GFR < 50 ml min(-1)).
Algorithms↗
Novel purification strategy for human PON1 and inhibition of the activity by cephalosporin and aminoglikozide derived antibiotics.
Human serum paraoxonase (PON1, EC 3.1.8.1.) is a high-density lipid (HDL)-associated, calcium-dependent enzyme; its physiological substrates are not known. In this study, a new purification strategy for human PON1 enzyme was developed using two-step procedures, namely ammonium sulfate precipitation and sepharose-4B-l-tyrosine-1-napthylamine hydrophobic interaction chromatography. SDS-polyacrylamide gel electrophoresis of the enzyme indicates a single band with an apparent MW of 43 kDa. Overall purification rate of our method was found 227-fold. The V(max) and K(m) of the purified enzyme were determined 227.27 EU and 4.16 mM, respectively. The in vitro effects of commonly used antibiotics, namely gentamycin sulfate and cefazolin sodium was also investigated on the purified human serum PON1 enzyme and human liver PON1 enzyme from human hepatoma cell (HepG2). Gentamycin sulfate and cefazolin sodium caused a dose- and time-dependent decrease on PON1 activity in HepG2 cells. Moreover, gentamycin sulfate and cefazolin sodium were effective inhibitors on purified human serum PON1 activity with IC(50) of 0.887 and 0.0084 values, respectively. The kinetics of interaction of gentamycin sulfate and cefazolin sodium with the purified human serum PON1 indicated a different inhibition pattern. Cefazolin sodium showed a competitive inhibition with K(i) of 0.012+/-0.00065 mM. However, Gentamycin sulfate was inhibited in non-competitive manner with K(i) of 0.026+/-0.015. In order to determine the inhibition statue of these drugs on a living system, the effects of same antibiotics on PON1 enzyme activity of mouse serum PON1 and liver PON1 were investigated in vivo. Gentamycin sulfate (3.2 mg/kg) and cefazolin sodium (106.25 mg/kg) leads to the significant decrease in mouse serum PON1 after 2, 4, 6 h and 2, 4 h drug administration, respectively. Cefazolin sodium did not exhibit any inhibition effect for the liver PON1, in vivo.
Ammonium Sulfate↗
Institution-specific patterns of infection and Gram's stain as guides for empiric treatment of patients hospitalized with typical community-acquired pneumonia.
STUDY OBJECTIVE: To determine the appropriateness of cefazolin as empiric treatment of typical, as opposed to atypical, bacterial community-acquired pneumonia at our institution. DESIGN: Combination of retrospective chart review and prospective determination of microbial susceptibilities and cefazolin-associated cost savings. SETTING: General acute-care referral hospital. PATIENTS: We evaluated the charts of patients discharged with a diagnosis of community-acquired pneumonia over a 10-year period. Gram's stains and culture results of sputum samples processed over 2 months were analyzed to determine the ability of the stains to predict positive Haemophilus influenzae cultures. The susceptibility and beta-lactamase status of clinical isolates of H. influenzae were determined. Cost savings of cefazolin as empiric treatment for community-acquired pneumonia were evaluated. MEASUREMENTS AND MAIN RESULTS: The frequency of H. influenzae pneumonia at our institution was 15% of the three major bacterial community-acquired pneumonias. Gram's stain was highly accurate in predicting the presence or absence of Haemophilus sp in sputum. Five patients had positive outcomes with cefazolin treatment despite being diagnosed with H. influenzae pneumonia. The organism isolates demonstrated intermediate sensitivity to cefazolin and 85% were beta-lactamase negative. Our program that encourages empiric use of cefazolin over cefuroxime for typical bacterial community-acquired pneumonia has allowed a modest projected annual cost savings of $24,000. CONCLUSIONS: We concluded that when Gram's stain of sputum does not show Haemophilus sp in patients with typical bacterial community-acquired pneumonia, empiric treatment with cefazolin is appropriate and results in cost savings.
Adult↗
Antimicrobial activity of rifabutin in combination with two and three other antimicrobial agents against strains of Mycobacterium paratuberculosis.
The inhibitory and bactericidal, synergistic, and antagonistic activities of rifabutin combined with ciprofloxacin, ethambutol, clofazimine, cefazolin, and amikacin in dual and triple combinations against various human and animal isolates of Mycobacterium paratuberculosis were determined. Synergism was observed when rifabutin was combined with either cefazolin or clofazimine in double combinations. The greatest amount of synergy occurred with the rifabutin-cefazolin combination in which bactericidal synergism was present with all strains. Of the triple combinations examined, only rifabutin in combination with ethambutol and cefazolin or streptomycin and cefazolin showed bactericidal synergism against most of the strains. Although antagonism was not observed in any double combination with rifabutin, antagonism was shown with several of the triple combinations. The rifabutin-cefazolin and rifabutin-streptomycin-cefazolin combinations were found to have the greatest bactericidal synergism at concentrations well within achievable serum and tissue levels and may be appropriate choices for chemotherapeutic use.
4-Quinolones↗
In vitro synergistic effects of double and triple combinations of beta-lactams, vancomycin, and netilmicin against methicillin-resistant Staphylococcus aureus strains.
Several studies have previously reported synergistic effects between vancomycin and a given beta-lactam or a given aminoglycoside against methicillin-resistant Staphylococcus aureus (MRSA) strains. The aim of our study was to exhaustively compare the effects of different combinations of a beta-lactam, vancomycin, and/or an aminoglycoside against 32 clinical MRSA strains with different aminoglycoside susceptibility patterns. The effects of 26 different beta-lactam-vancomycin and 8 different aminoglycoside-vancomycin combinations were first studied using a disk diffusion screening method. The best interactions with vancomycin were observed with either imipenem, cefazolin, or netilmicin. By checkerboard studies, imipenem-vancomycin and cefazolin-vancomycin each provided a synergistic bacteriostatic effect against 22 strains; the mean fractional inhibitory concentration (FIC) indexes were 0.35 and 0.46 for imipenem-vancomycin and cefazolin-vancomycin, respectively. The vancomycin-netilmicin combination provided an indifferent effect against all of the 32 strains tested; the mean of FIC index was 1. 096. The mean concentrations of imipenem, cefazolin, netilmicin, and vancomycin at which FIC indexes were calculated were clinically achievable. Killing experiments were then performed using imipenem, cefazolin, netilmicin, and vancomycin at one-half of the MIC, alone and in different combinations, against 10 strains. The vancomycin-netilmicin regimen was rarely bactericidal, even against strains susceptible to netilmicin. The imipenem-vancomycin and cefazolin-vancomycin combinations were strongly bactericidal against six and five strains, respectively. The addition of netilmicin markedly enhanced the killing activity of the combination of cefazolin or imipenem plus vancomycin, but only for the MRSA strains against which the beta-lactam-vancomycin combinations had no bactericidal effect. It is noteworthy that the latter strains were both susceptible to netilmicin and heterogeneously resistant to methicillin.
Anti-Bacterial Agents↗
Changing physician prescribing habits through a cost-effective first generation cephalosporin formulary.
Cephalosporin antibiotics account for a significant portion (approximately 10%) of our institution's drug budget. A 1985 survey demonstrated that 64% of our first generation injectable cephalosporin (FGIC) orders were for cefazolin. Of the cefazolin orders, approximately 77% used an "every 6 hour" dosage interval. It was thought that this dosage interval was associated with "physician habit" of prescribing similar agents "every 6 hours." By using an "every 8 hour" cefazolin dosage interval in most cases, significant cost savings in the hospital's drug budget could be realized. The Department of Pharmacy and the Pharmacy and Therapeutics (P&T) Committee developed and instituted an FGIC formulary procedure designed to promote the use of cefazolin with an "every 8 hour" dosing interval. Following presentation of literature guidelines to the P&T Committee, measurement of staff physician support through a written survey and presentation of extensive educational programs by the Department of Pharmacy, and FGIC formulary was implemented. The formulary policy included the automatic changing of every 6 hour cefazolin dosing intervals to every 8 hour intervals, with a physician option of "NO SUBSTITUTION." After implementation of the formulary policy, physician prescribing habits for FGIC's changed dramatically. Six months post-formulary, cefazolin accounted for 94% of FGIC prescriptions. Approximately 76% of cefazolin doses were being administered on an "every 8 hour" dosing interval as opposed to 21% prior to formulary implementation. Approximately $45,000 was saved during the first twelve months following formulary implementation. Physicians, pharmacists and nurses have supported the formulary policy.
Alabama↗
Five cephalosporins: pharmacokinetics and their relation to antibacterial potency.
In a group of adult volunteers, pharmacokinetic profiles of five cephalosporins were correlated with their minimal inhibitory concentrations (MICs90) against Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter aerogenes. Subjects received the following intravenous regimens in a randomized, crossover fashion: (1) 0.5 gm, 1 gm, or 2 gm of cefazolin; (2) 2 gm of cephalothin; (3) 1 gm of cephapirin; (4) 1 gm of cefoxitin; or (5) 0.5 gm of cefamandole. The 500-mg dose of cefazolin produced serum concentrations that exceeded those of any of the other cephalosporins at 0.5, 1, 2, 4, and 6 hours after administration. The area under the curve for this dose of cefazolin was at least twice that of any of the other antibiotics. Two hours after a 500-mg dose of cefazolin, serum levels exceeded the MIC90 for all seven groups of pathogens; at six hours, the 500-mg dose of cefazolin continued to achieve serum levels above the MIC90 against the majority of bacterial groups. In contrast, at two hours after administration none of the other cephalosporins maintained serum levels above the MIC90 for all pathogens; at six hours, the levels of cephapirin were adequate to inhibit the two streptococci, but serum levels of all other cephalosporins were inadequate to inhibit any of the pathogens. These data indicate that a 500-mg dose of cefazolin maintains serum levels above the MICs90 longer than any of the other cephalosporins tested and support the use of a 500-mg dose of cefazolin every eight hours for surgical prophylaxis and treatment of most community-acquired infections. Such a comparatively low dosage offers substantial savings to both patient and hospital.
Adult↗
Effects of furosemide on extravascular diffusion, protein binding and urinary excretion of cephalosporins and aminoglycosides in rabbits.
We studied the effects of furosemide on the disposition of cefazolin and gentamicin in rabbits. The following points were investigated: protein binding (PB) by ultracentrifugation in vitro; renal excretion and distribution in extravascular fluid (EF) obtained from s.c. tissue cages in vivo. Single i.m. injections of cefazolin (30 mg/kg) and gentamicin (1.5 mg/kg) alone or in combination with furosemide (0.5, 1 and 5 mg/kg) were made. After furosemide injection, blood and EF levels of gentamicin significantly decreased. Cefazolin blood levels were unchanged. Cefazolin appeared in EF earlier and at higher levels, up to 4 hr after furosemide injection, than when administered alone. Late cefazolin EF levels (8 and 12 hr) were reduced. All these effects were furosemide dose-dependent. Furosemide, in vitro, decreased cefazolin PG from 80 to 50%, whereas PB of gentamicin remained minimal (0--4%). Furosemide significantly increased the renal excretion of cefazolin and gentamicin without any effect on the glomerular filtration rate. A competitive effect of furosemide on the PB of cephradin and netilmicin was also demonstrated in vitro and in vivo. Our studies outline two kinds of interaction between furosemide and antibiotics. With protein-bound drugs, furosemide induced a competitive reduction of PB responsible for earlier EF diffusion and increased glomerular filtered load, but also induced an increased renal excretion by a tubular process. The latter was the only one induced by furosemide on unbound drugs (gentamicin).
Aminoglycosides↗