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Role of desacetylation in the detoxification of cephalothin in renal cells in culture.

The toxicity of three cephalosporin antibiotics to rabbit kidney cells in culture was compared to their known nephrotoxic potential in vivo (cephaloridine greater than cefazolin greater than cephalothin). While cephalothin is considered to be a relatively nonnephrotoxic cephalosporin when administered to many species including humans and rabbits, in several in vitro systems involving rabbit renal tissue, cephalothin was comparatively more toxic than anticipated based on in vivo data. Cephalothin is extensively desacetylated in rabbits to a less microbiologically active metabolite, desacetylcephalothin. When a microsomal S9 fraction from rabbit kidney was added to the in vitro assay in cultured rabbit renal cells, cephalothin was desacetylated and its toxicity to kidney cells was reduced. The addition of S9 in vitro provided a toxicity ranking of the cephalosporins that correlated with their known in vivo nephrotoxic potentials (cephaloridine greater than cefazolin greater than cephalothin). The in vitro detoxification of cephalothin by S9 was blocked by the coadministration of the esterase inhibitor, aminocarb. Desacetylcephalothin was relatively nontoxic to rabbit renal tissue in vitro. These results suggest that the desacetylation of cephalothin in vivo represents a previously unrecognized mechanism of detoxification of this cephalosporin antibiotic. Furthermore, this mechanism of detoxification may be applicable to other acetylated cephalosporins.

Acetylation↗

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.).

Animals↗

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.

Animals↗

Comparative studies of cefoxitin and cephalothin: an overview.

A comparative study of the efficacy and safety of cefoxitin and cephalothin in the treatment of serious infections was carried out by 21 investigators. A total of 320 patients were treated with cefoxitin, and 276 patients were treated with cephalothin. In each group 50% of patients could be evaluated. Patients were randomly allocated to groups in open fashion, and final analysis showed that the groups were comparable in terms of sex, age, severity of illness, and duration of therapy. The majority of pathogens isolated were susceptible to both agents, although 13% of gram-negative bacilli and anaerobes were susceptible to cefoxitin alone. The overall percentage of patients cured or improved by cephalothin was 93%; for cefoxitin the proportion was 91%. No statistical differences in response by type of organism or site of infection were shown. Cefoxitin was effective in treating infections and in eradicating the pathogenic bacteria. Cefoxitin was as well tolerated as cephalothin and produced no more adverse reactions or abnormal laboratory findings than did cephalothin. The results of this study demonstrate that cefoxitin is as effective in achieving bacteriologic and clinical cures as is cephalothin and also is effective in treatment of infections due to cephalothin-resistant bacteria.

Bacterial Infections↗

A study of cephalothin and desacetylcephalothin in cerebrospinal fluid in therapy for experimental pneumococcal meningitis.

One explanation for the failure of cephalothin to cure patients with bacterial meningitis is that desacetylcephalothin, as in vivo metabolite that has less antibacterial activity than the parent drug, penetrates more efficiently into cerebrospinal fluid (CSF); In experimental pneumococcal meningitis in rabbits, the peak levels of cephalothin and desacetylcephalothin in CSF after an intramuscular injection of 250 mg of cephalothin/kg were, respectively, 1.43 +/- 4.9 microgram/ml (2.8% of peak serum level) and 1.69 +/- 0.57 microgram/ml (2.2% of peak serum level). The observed half-life of desacetylcephalothin in CSF (3.32/hr) was longer (P less than 0.01) than that of cephalothin (0.72/hr). Choroid plexuses isolated from the lateral cerebral ventricles of rabbits with meningitis took up cephalothin in vitro more avidly than desacetylcephalothin (P less than 0.05), and metabolism of cephalothin to desacetylcephalothin by isolated choroid plexuses was demonstrated directly. Thus, intrathecal metabolism of cephalothin by the choroid plexus may contribute to the unsatisfactory performance of cephalothin in bacterial meningitis.

Animals↗

Sodium clavulanate potentiation of cephalosporin activity against clinical isolates of cephalothin-resistant Klebsiella pneumoniae.

Plasmid-carrying Klebsiella pneunomiae clinical isolates with agar dilution minimum inhibitory concentrations (MIC) of 32 mug/ml or greater were tested for in vitro potentiation of cephalothin activity by clavulanic acid (BRL-14151), an inhibitor of beta-lactamases. The addition of 10 mug of clavulanate per ml caused greater than a 500-fold reduction in geometric mean cephalothin agar dilution MIC, with lesser but significant reductions resulting from clavulanate concentrations of 5 or 1 mug/ml. Clavulanate-potentiated reduction of cephalothin MICs in broth against resistant Klebsiella were comparable to reduction in agar dilution MICs as a rule. However, a low concentration (1 mug/ml) of clavulanate produced cephalothin MICs in broth several-fold higher than by the agar dilution method. Modest cephalothin-potentiating effects of clavulanate on cephalothin-susceptible strains and on cefoxitin against cephalothin-resistant Klebsiella strongly suggested that the major effect of clavulanate was beta-lactamase inhibition.

Amidohydrolases↗

Susceptibility of clinical isolates of bacteria to cefoxitin and cephalothin.

The susceptibility of 4,929 unselected clinical isolates of bacteria to cefoxitin and cephalothin was determined by the single-disk method, using a computer-associated electronic zone analyzer to obtain, record, and process measurements of sizes of zones of inhibition. Both cefoxitin and cephalothin were effective against most gram-positive strains, including Staphylococcus aureus, S. epidermidis, micrococci, and all streptococci except enterococci. The three strains of Listeria monocytogenes tested were susceptible to cephalothin but resistant to cefoxitin. There was little difference between the cefoxitin and cephalothin susceptibility of Salmonellae, Citrobacter sp., Enterobacter sp., Proteus mirabilis, and Pseudomonas sp. Cefoxitin was more effective then cephalothin against Escherichia coli, Klebsiella sp., Serratia sp., indole-positive Proteus sp., Providence sp., Flavobacter sp., Herellea vaginicola, and Mima polymorpha. Cefoxitin also appeared to exhibit enhanced activity, as compared with cephalothin, against Bacteroides sp. Thus cefoxitin appears to have a very broad antibacterial spectrum which is greater than that of cephalothin, especially against gram-negative strains.

Anti-Bacterial Agents↗

In vitro activity effects of combinations of cephalothin, dicloxacillin, imipenem, vancomycin and amikacin against methicillin-resistant Staphylococcus spp. strains.

BACKGROUND: combinations of drugs has been proposed as an alternative for oxacillin-resistant staphylococci infections, however, limited information about in vitro combinations are available for multi-resistant strains. The objective of this study was to describe the interaction of beta-lactams in combination with vancomycin or amikacin against 26 oxacillin and amikacin-resistant nosocomial Staphylococcus spp. isolates. METHODS: activity of dicloxacillin plus amikacin, cephalothin plus amikacin, cephalothin plus vancomycin, imipenem plus vancomycin and vancomycin plus amikacin was evaluated by checkerboard synergy tests and the fractional inhibitory concentration index (FIC) was calculated. RESULTS: dicloxacillin plus amikacin, and cephalothin plus amikacin were synergistic or partially synergistic in 84.6% and 100% respectively. For nearly half of the isolates the mean concentrations of dicloxacillin, cephalothin and amikacin at which FIC indexes were calculated were achievable therapeutically. Vancomycin plus amikacin had synergistic effect only against two isolates, and partially synergistic in 38.6%. For the combinations vancomycin plus cephalothin and vancomycin plus imipenem the effect was additive in 76.9% and 80.7% respectively. CONCLUSION: in this study the checkerboard analysis showed that amikacin in combination with cephalothin or dicloxacillin was synergistic against most of the resistant strains of S. aureus and coagulase-negative Staphylococcus. Vancomycin in combination with a beta-lactam (cephalothin or imipenem) showed additivity. An indifferent effect predominated for the combination vancomycin plus amikacin. Even though a synergistic effect is expected when using a beta-lactam plus amikacin combination, it is possible that the effect cannot be clinically achievable. Careful selection of antimicrobial combinations and initial MICs are mandatory for future evaluations.

Amikacin↗

[Prevention using cephalothin in open-heart surgery].

To assay the efficiency of cephalothin prophylaxis in open-heart surgery, bacteriological examination of pressure-measurement units, intravenous catheter tips, and urine were made in 211 consecutive patients as well as blood cultures and sputum in suspected postoperative sepsis. Furthermore, cephalothin concentration in serum and tissue was determined in 12 consecutive adults with intact kidney function. Samples were taken before, during, and after the cardiopulmonary bypass, the tissue from the right atrium only before and after cardiopulmonary bypass. A high serum cephalothin level (80.04 +/- 23.35 microgram/ml) was measured 30 min after administration of 2 g cephalothin given as a 15-min-long i.v. infusion on induction of anesthesia. An antibiotic regimen - 4 X 2 g dose of cephalothin daily (first dose on induction of anesthesia) - provides a serum cephalothin level which is significantly higher than the cephalothin minimum inhibitory concentrations for most gram-positive organisms (0.475 microgram/ml) and so ensures an adequate antibiotic coverage throughout the surgical procedure and during the early postoperative phase of open-heart surgery.

Adult↗

Gentamicin-cephalothin drug reaction.

A case report describing the occurrence of nephrotoxicity in a 26-year-old black male with sickle cell anemia after concurrent i.v. administration of gentamicin sulfate and cephalothin sodium is presented. Cephalothin 1 g.i.v. every six hours was given for three days for a Klebsiella infection demonstrated by urine and blood culture to be cephalosporin sensitive. Cephalothin was then discontinued and gentamicin, after an i.v. loading dose of 2.6 mg/kg, was given for 14 days in a dosage of 1.3 mg/kg every eight hours. After cultures of pus aspirated from the right thigh demonstrated Klebsiella, 2 g of cephalothin was administered i.v. every six hours and gentamicin sulfate was discontinued. Gentamicin therapy was reinstituted two days later, at a dosage of 5 mg/kg/day. The gentamicin-cephalothin therapy was continued for nine days. The gentamicin dosage interval was increased from every eight to every 16 hours when serum creatinine and gentamicin levels became elevated. Gentamicin was discontinued entirely two days later because serum gentamicin levels were not decreasing. Previous case reports and studies of nephrotoxicity associated with concurrent gentamicin-cephalothin therapy are reviewed. Pharmacists should be alert to the possible increased incidence of nephrotoxicity occurring with concurrent genticin-cephalothin therapy.

Adult↗

Prophylactic cephalothin in gastrointestinal surgery.

A prospective study was carried out to evaluate the effect of a strictly standardized, short-term prophylactic treatment with cephalothin (Keflin) on the incidence of postoperative wound infections in gastrointestinal surgery. Achieved levels of cephalothin activity in serum and interstitial water were studied, and the sensitivity of isolated bacteria at the end of operation and from septic wounds was defined. Patients were divided at random into treatment and control groups. The treatment group received 2 g cephalothin at the induction of anesthesia and another 2 g, 5 and 10 hours after the primary infusion. The control group remained untreated. The rapid infusion of 2 g cephalothin resulted in high initial serum levels, which declined rapidly. Equilibration between intraand extravascular compartments occurred about 60-80 minutes after start of infusion. At that time the infused dose resulted in a cephalothin level of about 30 mug/ml in ECV and plasma, or about 30% of the initial concentration. Despite the prophylactic infusion of cephalothin, the frequency of wound infection in treated patients was the same as in the controls. Subdivision of the material according to type of surgery performed did not reveal any difference between untreated patients and controls. No shift towards cephalothin-resistant strains was observed in isolates from septic wounds in the treatment group.

Adolescent↗

[In vitro susceptibility of bacteroidaceae to cefoxitin and cephalothin (author's transl)].

The activity of the new cephamycin C derivatives cefoxitin against 102 clinical isolates of Bacteroidaceae (95 Bacteroides strains and 7 Fusobacterium-Sphaerophorus cultures) was determined by tube dilution and standardized agar diffusion tests and compared to that of cephalothin. Cefoxitin was more active than cephalothin against 56 Bacteroides fragilis strains, 19 Bacteroides thetaiota-omicron strains and two Bacteroides splanchnicus strains. The difference seemed less pronounced with five Bacteroides vulgatus and four Bacteroides variabilis cultures. Three Bacteroides melaninogenicus and six Bacteroides oralis strains displayed similar sensitivity to both cephalosporins. At concentrations of 32 microng/ml or less, cefoxitin inhibited 91% and cephalothin 33% of the Bacteroides strains. Two strains of Sphaerophorus varius were likewise much more sensitive to cefoxitin than to cephalothin (MIC values 8 micron8/ml of cefoxitin and 256 microng/ml of cephalothin). Three other Sphaerophorus strains (the species necrophorus and freundii/mortiferum) and two of Fusobacterium fusiforme (Fusobacterium nucleatum) strains were very similar in their susceptibility to both cephalosporins. Statistical analysis of the relationship between MIC and zone size diameter showed relatively high correlation coefficients for cefoxitin and cephalothin (r=-0.741 and r=-0.703 respectively).

Bacteroidaceae↗

beta-Lactam allergenic determinants: fine structural recognition of a cross-reacting determinant on benzylpenicillin and cephalothin.

BACKGROUND: An appreciation of the structural heterogeneity of allergenic determinants on penicillins and cephalosporins reveals the importance of side-chain groups and their involvement in many allergies to beta-lactam drugs. Although allergenic cross-reactions between penicillins and cephalosporins are known to occur, the precise molecular bases of such recognitions and cross-sensitivities have rarely been studied and identified. OBJECTIVES: The unexpected finding of a high incidence of positive IgE antibody reactions with both benzylpenicillin and cephalothin prompted serological and immunochemical studies to identify the chemical basis of antibody recognition of these drugs from the two different families of beta-lactam antibiotics. METHODS: Adsorption studies were employed to identify whether or not a single population of antibodies was involved in the recognition of benzylpenicillin and cephalothin. Identification of the fine structural features recognized by IgE antibodies was investigated by quantitative hapten inhibition studies employing carefully selected beta-lactam drugs, analogues and some other structurally related chemicals. RESULTS: Adsorption studies with penicilloic acid-solid phase clearly established that a single population of cross-reacting antibodies recognized both benzylpenicillin and cephalothin. Quantitative inhibition findings, especially with phenylacetic acid and 2-thiopheneacetic acid and with cephaloridine and cefoxitin, which have the same (2-thienyl)methyl side-chain as cephalothin, implicated the methylene group as the focus of the allergenic determinant recognized on benzylpenicillin and cephalothin. In addition to the methylene group, recognition graded into neighbouring structures including the amide group and extended weakly to the beta-lactam ring. CONCLUSIONS: Results confirmed that structural features as small as a methylene group may be allergenically important. In the present case, this group, making up only part of the different side-chains on benzylpenicillin and cephalothin, together with neighbouring structures extending toward the beta-lactam ring, accounted for the cross-reactivity seen between structures that, at first sight, appear to be not closely related. Such subtle, small, common structural features are likely to be immunologically recognized and implicated in allergic reactions to other drugs, including beta-lactam antibiotics.

Adsorption↗

Hemolysis induced by cefazolin and cephalothin in a patient with penicillin sensitivity.

A patient with penicillin sensitivity, who had never received a cephalosporin antibiotic previously, developed anemia and spherocytosis following the administration of cefazolin. Hemolysis abated when the drug was discontinued on the fourth day, and recurred on day six when cephalothin therapy was begun. IgG and complement components were present on the patient's erythrocytes, and IgG antibodies in her serum reacted with normal red blood cells which had been coated with benzylpenicillin, cefazolin or cephalothin. Antibodies to cephalothin-coated red blood cells were removed partially by incubating her serum with either benzylpenicillin or cefazolin. Complement-fixing IgG antibodies which reacted with red blood cells coated by cefazolin, cephalothin, and benzylpenicillin were considered to be responsible for hemolysis during the administration of cefazolin and, subsequently, cephalothin. The patient recovered completely following discontinuation of antibiotics, transfusion of red blood cells, and treatment with glucocorticoids. It is concluded that hemolysis may occur during therapy with cefazolin, as well as cephalothin, and may develop rapidly in a patient with penicillin sensitivity.

Adult↗

Treatment of experimental Staphylococcus aureus endocarditis: comparison of cephalothin, cefazolin, and methicillin.

The effectiveness of cefazolin in Staphylococcus aureus endocarditis has been questioned because of in vitro inactivation by staphylococcal beta-lactamase. Cefazolin, although inactivated in vitro by S. aureus beta-lactamase, was as effective as cephalothin in the treatment of left-sided S. aureus endocarditis in rabbits. Cefazolin (20 mg/kg every 6 or 8 h), cephalothin (40 mg/kg every 6 h), and methicillin (40 mg/kg every 6 h), administered intramuscularly, were compared in the treatment of left-sided endocarditis caused in rabbits by a highly penicillin-resistant strain of S. aureus. The three antibiotics were all effective in reducing titers in vegetations. However, at the dose used, methicillin reduced the titers more rapidly than cephalothin or cefazolin. Cefazolin concentrations in serum were about double those achieved with cephalothin or methicillin. However, cefazolin was only half as active as methicillin and one-eighth as active as cephalothin in vitro in a serum assay. The half life in serum of cefazolin, cephalothin, and methicillin were each about 30 min. Serum bactericidal activities of the three antibiotics were very similar.

Animals↗

Randomized prospective study of ceftazidime versus ceftazidime plus cephalothin in empiric treatment of febrile episodes in severely neutropenic patients.

In a prospective randomized study, ceftazidime monotherapy was compared with a combination of ceftazidime plus cephalothin in 102 febrile neutropenic patients. Thirty bacteriologically documented infections, of which 23 were bacteremias, in 48 clinically assessable patients were treated with ceftazidime alone. Twenty-four bacteriologically proven infections, of which 18 were bacteremias, in 42 clinically assessable patients were treated with a combination of ceftazidime and cephalothin. The clinical response rates in assessable patients were 77% for ceftazidime monotherapy and 88% for the combination. The bacteriological clearance rate was 70% for ceftazidime monotherapy and 79% for the combination. Efficacy against gram-negative pathogens appeared to be excellent, with 93% clearance for ceftazidime monotherapy and 100% clearance for the combination. The bacteriological clearance of gram-positive infections was only 60% for both regimens, with failures mainly due to Streptococcus faecalis and Streptococcus sanguis, which are primarily resistant to both ceftazidime and cephalothin. After addition of vancomycin to those infections which did not respond to empiric therapy, bacteriological clearance rates of 94% (ceftazidime plus vancomycin) and 90% (ceftazidime and cephalothin plus vancomycin) were achieved. Three superinfections were registered in the ceftazidime group and two were seen in the combination group. Other adverse effects of ceftazidime were minimal and were not enhanced by combination with cephalothin. It is concluded that ceftazidime is an effective drug for the empiric treatment of febrile neutropenic patients, especially if one is prepared to modify therapy if resistant gram-positive strains or mycotic infections are encountered. Neither the clinical nor bacteriological cure rates could be substantially improved by adding cephalothin to ceftazidime in initial empiric treatment of febrile neutropenic patients.

Adolescent↗

Double-blind comparison of cephacetrile with cephalothin-cephaloridine.

Under double-blind protocol, a controlled comparison was made between a new cephalosporin, cephacetrile, and cephalothin or cephaloridine. The patient's primary physician determined the indications for treatment, and the dosage was uniform for each route of administration. Infecting strains of staphylococci and Proteus mirabilis had a lower median inhibitory concentration for cephalothin than cephacetrile; the opposite was true for Escherichia coli and Klebsiella species. The average peak serum level 1 h after a dose of 2 g intravenously was 74.9 +/- 21 and 21.5 +/- 8.7 mug/ml for cephacetrile and cephalothin, respectively; 6 h after the dose, the respective levels were 12.4 +/- 4.3 and 3.7 +/- 0.9 mug/ml. Renal clearances were similar and the plasma clearance was proportional to the serum levels. In the urine, the concentration of cephacetrile was three times higher than that of cephalothin. Based on a percentage of therapeutic potential, success in the treatment of infections with susceptible organisms was 42 and 44% for the two different drug regimens. Initial bacterial resistance was found in about one-fifth of infections, and concomitant therapy with other drugs was practiced in one-half of the treatment courses. Intravenous use of cephacetrile was discontinued prematurely more often than was use of cephalothin, suggesting less tolerance. Although there was no overt toxicity, more than 75% of patients on either regimen had some form of unwanted response to treatment, the most common being superinfection. From this limited but controlled experience, cephacetrile can be considered comparable to cephalothin in antimicrobial treatment and overall side reactions.

Acetamides↗

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.

Adult↗