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PubMed1986

Pain on injection and muscle irritation: a comparison of animal models for assessing parenteral antibiotics.

Pain on injection due to parenteral administration of cephaloridine, cephalothin, and cefoxitin with or without 1% lidocaine was examined in a rat paw-lick model and the results compared with those obtained in a rabbit intramuscular model of irritation. In both animal models, cephaloridine caused similar or a slightly greater response than sterile water. Conversely, cefoxitin and cephalothin caused a much greater reaction than water in both models. The only major difference in the rankings by the two models was with formulations in which an anesthetic agent was incorporated into the diluent. As expected, the presence of a local anesthetic masked pain on injection but not muscle damage. The rat paw-lick model is an alternative to the traditional rabbit muscle irritation model for rapidly assessing both pain on injection and muscle irritation of parenteral formulations.

Animals↗
PubMed1987

An in vitro model for assessing muscle irritation due to parenteral antibiotics.

A rat skeletal muscle cell line (L6) was evaluated for its potential to discriminate the muscle-irritating liability of several parenteral antibiotics. The cells were exposed to clinical as well as diluted concentrations of tetracycline, cefoxitin, cephalothin, carbenicillin, erythromycin, ceforanide, cefazolin, and cephaloridine for 1 hr. Control cells were similarly exposed to culture media for 1 hr. The cells were subsequently assayed for their content of the muscle-associated enzyme creatine kinase (CK). Depletion of CK relative to control cultures was utilized as the index of cellular damage. The results of these analyses revealed the following ranking of antibiotic toxicity to L6 muscle cells: tetracycline, erythromycin, cefoxitin greater than cephalothin, carbenicillin greater than ceforanide, cefazolin greater than cephaloridine. The relative order of toxicity of these antibiotics to L6 cells is in good agreement with their reported muscle-irritating liability in man. The correlation between the results obtained in vitro and the irritancy data in vivo suggests that this model may be a useful adjunct to in vivo testing of parenteral antibiotics for muscle-irritation liability.

Animals↗
PubMed2004

[Modulatory effect of antimicrobial agents or aminoacids on the oxidative burst of polymorphonuclear neutrophils triggered by formylmethionyl-leucyl-phenylalanine (fMLP)].

We have compared the interplay of several antimicrobial agents and aminoacids on the neutrophil respiratory burst in response to formylmethionyl-leucyl-phenylalanine (fMLP), a chemoattractant. Mainly, an inhibitory effect has been observed in the penicillin family of agents and an enhancing effect in the cephalosporin family of agents. The molecules in which the sulfur numbered 1 in the 6-APA or 7-ACA nucleus was replaced by a carbon or an oxygen, had a different effect as compared with the other members of the family. The modulatory effects of ampicillin and cephalothine were not significant at a concentration lower than 10 mg/l and the effect of cephalothine looked maximum at 20-40 mg/l. If studies in cell-free systems demonstrated that the inhibitory effect of some antimicrobials could be due to a direct oxidant-scavenger activity mainly of HOCl, only hypotheses are proposed to explain the enhancing activity of the others. It could be in relation with (i) a synergistic effect upon fMLP receptor leading to an increase in H(2)O(2)/HOCl production or (ii) the generation of new oxydant products originating in cephalosporin lysis under HOCl attack, which would be able to react with luminol. The interplay of antimicrobial agents with the respiratory burst measured outside the cells probably has no therapeutic consequences because the bactericidal activity of neutrophils is achieved inside phagosomes where few agents are known to come into and where chemical conditions are different. On the opposite, in clinical use, this interplay could be interesting to study for a prevention of side effects.

Amino Acids↗
PubMed1984

New rapid method of analysis of cefoxitin in serum and bone, by high-performance liquid chromatography.

A method for the extraction and quantification of cefoxitin in blood and bone samples is described in this paper. The procedure, which prepares biological material for reversed-phase high-performance liquid chromatographic analysis is convenient, rapid and reproducible. It also allows for use of cephalothin as an internal standard in measuring serum cefoxitin levels. Conventional extraction procedures, involving use of organic solvents, generally yield drug recoveries of 60-80%. Use of Baker--10 SPE disposable extraction columns allowed us to consistently obtain greater than 98% recovery of both cefoxitin and cephalothin. Methods for quantification of the extracted drugs include comparison of peak ratios (for serum) or peak heights (for bone) to first-order equations obtained from regression analyses.

Bone and Bones↗
PubMed2002

Biofilm testing of Staphylococcus epidermidis clinical isolates: low performance of vancomycin in relation to other antibiotics.

The in vitro killing effect of widely used antibiotics (cephalothin, clindamycin, erythromycin, ofloxacin, rifampicin, teicoplanin, tetracycline, phosphomycin and vancomycin) was comparatively analyzed in this study on 24-h biofilms of 64 Staphylococcus epidermidis clinical isolates. This effect was assessed at the expected antibiotic concentration reached in serum, using ATP-bioluminescence. Erythromycin, rifampicin, tetracycline and phosphomycin presented generally a higher killing effect than vancomycin, clindamycin, cephalothin, teicoplanin and ofloxacin in these biofilms. Differences in the resistance profiles obtained in classical assays (broth microdilution and diffusion) did not help to predict differences in the killing effect of the antibiotics in biofilms. Only some antibiotics (vancomycin but not rifampicin or tetracycline) highly decreased their killing effect as the biofilm age increased (from 6 to 24 or 48 h). These studies underline the relevance of biofilm susceptibility testing and the potential danger of the indiscriminate use of vancomycin monotherapy as the ultimate resource against infections involving aged biofilms.

Anti-Bacterial Agents↗
PubMed1996

Phenotypic detection of mec A-positive staphylococcal blood stream isolates: high accuracy of simple disk diffusion tests.

Detection of oxacillin-resistance in staphylococci by phenotypic methods remains problematic. Although standardized susceptibility test methods are adequate for Staphylococcus aureus, many are less satisfactory for the coagulase-negative staphylococci (CNS). We have studied 108 consecutive blood culture isolates of staphylococci. The mec A gene was detected by PCR in one S. aureus and 55 CNS isolates. Susceptibility testing was performed as follows: oxacillin (1-microgram), ceftizoxime (30-microgram), and cephalothin (30-microgram) by disk diffusion; oxacillin, ceftizoxime, cephalothin, methicillin, ampicillin, ampicillin/ sulbactam, penicillin, cefazolin, imipenem, and meropenem by the broth microdilution method. In addition, isolates were tested by the oxacillin agar screen plate method. The single oxacillin-resistant S. aureus strain was detected by all oxacillin susceptibility test methods and by the ceftizoxime disk and MIC methods. Two oxacillin-susceptible S. aureus were intermediate (minor error) by ceftizoxime broth microdilution (MIC, 16 micrograms/mL). The most sensitive, simple phenotypic methods for detection of oxacillin-resistant CNS (mec A positive) were as follows: oxacillin disk diffusion at 98%, oxacillin screen plate at 91%, oxacillin broth microdilution at 87%, ceftizoxime disk diffusion at 100%, ceftizoxime broth microdilution at 87%, and methicillin broth microdilution at 83%. These results indicate that oxacillin and ceftizoxime disk diffusion tests are the most accurate phenotypic methods in routine clinical use for detection of oxacillin-resistant CNS. Oxacillin broth microdilution MIC testing (2% NaCl supplement) would perform more satisfactorily (100% sensitivity) with an adjusted interpretive breakpoint at < or = 0.5 microgram/mL, in contrast to the lower accuracy of the "so-called" reference agar screen test.

Anti-Bacterial Agents↗
PubMed1985

Mechanism of inhibition of the PC1 beta-lactamase of Staphylococcus aureus by cephalosporins: importance of the 3'-leaving group.

The hydrolysis of cephalosporins containing good leaving groups at the 3'-position [those used in this study were the chromogenic cephalosporin PADAC [pyridine-2-azo-4'-(N',N'-dimethylaniline) substituted on cephalosporin], cephaloridine, and cephalothin], catalyzed by the Staphylococcus aureus PC1 beta-lactamase, proceeds in two spectrophotometrically observable phases. The first involves formation of an acyl-enzyme intermediate while the second involves partitioning of this intermediate between two pathways. One path yields the normal cephalosporoate (3) from which the 3'-leaving group is spontaneously eliminated in solution to give the 3-methylenedihydrothiazine 2, while the second involves initial elimination of the 3' substituent, thus yielding a second acyl-enzyme intermediate, which then hydrolyzes to give the same final product as from the first pathway. The second acyl-enzyme is relatively inert to hydrolysis (t1/2 congruent to 10 min at 20 degrees C), and its formation thus leads to transient inhibition of the enzyme. The partition ratio between hydrolysis and elimination at the enzyme active site could be determined either spectrophotometrically from burst experiments or from measurements of residual beta-lactamase activity as a function of cephalosporin concentration. This ratio varied with the leaving group ability of the 3' substituent (acetoxy greater than N,N-dimethylaniline-4-azo-2'-pyridinium greater than pyridinium) in the anticipated fashion. The inert acyl-enzyme intermediate was isolated by exclusion chromatography and shown to contain the cephem nucleus, but not the 3' substituent, covalently bound to the enzyme. As would be expected, PADAC, cephaloridine, and cephalothin yielded the same inert intermediate. Cephalosporins with poor or no 3'-leaving groups, e.g., dansylcephalothin and desacetoxycephalothin, neither displayed the branched pathway nor yielded the long-lived acyl-enzyme.

Cephalosporins↗
PubMed1979

Synthesis and antibacterial activity of 2-oxocephalosporins.

The first reported synthesis of 2-oxocephalosporin derivatives has been achieved via ozonolysis of the corresponding 2-methylenecephalosporins. The new cephalosporin derivatives showed some antibacterial activity against Gram-positive bacteria, but the 2-oxo analogue of cephalothin was much less active than cephalothin itself.

Bacteria↗
PubMed1980

Effect of cardiopulmonary bypass on cefazolin disposition.

Cefazolin kinetics was studied in 8 patients the day before (PREOP), during (SURG), and the day after (POSTOP) cardiopulmonary bypass (CPB) surgery. PREOP (48.6 ml/min) and POSTOP (46.6 ml/min) total body clearances were of the same order and both were greater than the SURG (27.4 ml/min) total body clearance. Since cefazolin is almost entirely eliminated by the kidney, the lower SURG clearance is a result of reduced renal elimination, as confirmed by measuring cefazolin SURG (28.7 ml/min) and POSTOP (52.9 ml/min) renal clearance. The reduction in cefazolin renal elimination was the same throughout the surgical procedure, including the period of extracorporeal circulation. Cefazolin distribution was altered by the operative procedure as evidence by a higher SURG steady-state volume of distribution. This increase in apparent cefazolin distribution volume brought about by surgery was not seen with cephalothin, which was investigated by us in a similar group of patients. The different effect of CPB surgery on cefazolin and cephalothin distribution may be due to differences in plasma protein binding.

Aged↗
PubMed1965

Cephalosporinase and penicillinase activities of a beta-lactamase from Pseudomonas pyocyanea.

1. Pseudomonas pyocyanea N.C.T.C. 8203 produces a beta-lactamase that is inducible by high concentrations of benzylpenicillin or cephalosporin C. Methicillin appeared to be a relatively poor inducer, but this could be attributed in part to its ability to mask the enzyme produced. Much of the enzyme is normally cell-bound. 2. No evidence was obtained that the crude enzyme preparation consisted of more than one beta-lactamase and the preparation appeared to contain no significant amount of benzylpenicillin amidase or of an acetyl esterase. 3. The maximum rate of hydrolysis of cephalosporin C and several other derivatives of 7-aminocephalosporanic acid by the crude enzyme was more than five times that of benzylpenicillin. Methicillin, cloxacillin, 6-aminopenicillanic acid and 7-aminocephalosporanic acid were resistant to hydrolysis, and methicillin and cloxacillin were powerful competitive inhibitors of the action of the enzyme on easily hydrolysable substrates. 4. Cephalosporin C, cephalothin and cephaloridine yielded 2 equiv. of acid/mole on enzymic hydrolysis, and deacetylcephalorsporin C yielded 1 equiv./mole. Evidence was obtained that the opening of the beta-lactam ring of cephalosporin C and cephalothin is accompanied by the spontaneous expulsion of an acetoxy group and that of cephaloridine by the expulsion of pyridine. 5. A marked decrease in the minimum inhibitory concentration of benzylpenicillin and several hydrolysable derivatives of 7-aminocephalosporanic acid was observed when the size of the inoculum was decreased. This suggested that the production of a beta-lactamase contributed to the factors responsible for the very high resistance of Ps. pyocyanea to these substances. It was therefore concluded that the latter might show synergism with the enzyme inhibitors, methicillin and cloxacillin, against this organism.

Cephalosporins↗
PubMed1987

Acute pyelonephritis in pregnancy.

There were 107 episodes of pyelonephritis associated with pregnancy or the early puerperium occurring in 103 gravidas investigated retrospectively for information concerning prematurity, low birthweight, and antibiotic susceptibility patterns in the recovered microorganisms. No difference was found in the incidence of prematurity on low birthweight between that group and a control group of gravidas from the same population. Members of the Enterobacteriaceae genus were the most common bacterial isolates from the urine, with a large portion of E. coli being resistant to both ampicillin (33%) and cephalothin (13%). Treated pyelonephritis associated with pregnancy does not appear to predispose to prematurity or low birthweight in this population. Also, initial therapy with a first-generation cephalosporin may no longer be appropriate, because a significant number of isolates (11%) were resistant to cephalothin.

Adolescent↗
PubMed1997

Disc susceptibility testing for thermomphilic campylobacters.

The minimum inhibitory concentrations (MICs) and zone diameters around NCCLS strength discs of 100 clinical isolates of thermophilic Campylobacter species, including 79 strains of Campylobacter jejuni subsp. jejuni, 19 of C. coli and two of C. lari, plus three type strains of these species, were determined for erythromycin, clindamycin, nalidixic acid, norfloxacin, ciprofloxacin, ampicillin, piperacillin, cephalothin, ceftriaxone, chloramphenicol, gentamicin and tetracycline. Using error-rate bounded analysis and adjustment of MIC breakpoints to fit natural populations, tentative interpretive zone diameter criteria were set for each of the antimicrobials. Application of these criteria showed that resistance to quinolones was not detected in species other than C. lari. Two strains of C. jejuni subsp. jejuni were susceptible to cephalothin. The type strain of C. lari was susceptible to erythromycin and resistant to clindamycin. Full resistance to erythromycin, chloramphenicol or gentamicin was not found in any strain, while nine strains were resistant to tetracycline. This disc method should provide a simple approach to resistance detection for surveillance or routine testing of invasive isolates.

Anti-Bacterial Agents↗
PubMed1989

Resistance to antibiotics and inorganic ions in virulent bacterial strains from a hospital.

Virulent strains of Staphylococcus aureus, S. epidermidis, Escherichia coli and Pseudomonas aeruginosa were studied for their resistance to antibiotics and inorganic ions, the correlation with their clinical use and the usefulness as an epidemioliogical tool. Multiresistance was common, the antibiotypes were similar to those previously reported, but characteristic resistotypes endemic of our county were found. A correlation between resistance and metal ion consumption was not detected. Staphylococci strains were susceptible to vancomycin, cephalothin and mercury chloride; S. epidermidis showed higher rates of resistance to antibiotics and lower to cadmium chloride and potassium iodine than S. aureus. E. coli strains were susceptible to new beta-lactamans; resistance to cephalothin, gentamicin, tobramycin and amikacin was less than 10%. P, aeruginosa was the species with the most multiresistance and antibiotype diversity, only ceftazidime, amikacin and imipenem had a resistance rate less than 11%. In both E. coli and P. aeruginosa resistance to all tested metals (except silver nitrate) was found although with different percentages.

Bacteria↗
PubMed2002

Biochemical characterization of a novel extended-spectrum beta-lactamase from Pseudomonas aeruginosa 802.

Pseudomonas aeruginosa 802 was isolated at Rabta hospital in Tunis and was resistant to extended-spectrum cephalosporins and aztreonam. It produced a pI 7.6 extended-spectrum beta-lactamase (ESBL). The ESBL, named LBT 802, was purified to homogeneity by filtration on Sephadex G-75 followed by CM-Sepharose chromatography and high-performance liquid chromatography (HPLC) on a TSK-gel SP-5PW column. The LBT 802 enzyme had a molecular mass of 30 kDa. It showed a broad-substrate profile by hydrolyzing benzylpenicillin, ampicillin, cephalothin, cephaloridine, cefotaxime, ceftriaxone, and cefpirome but not ceftazidime, cefoxitin, imipenem, or aztreonam. The highest hydrolytic efficiency (Vmax/Km) was obtained for ampicillin, cephalothin, cephaloridine, and benzylpenicillin. Among extended-spectrum cephalosporins the best substrate was ceftriaxone followed by cefotaxime and cefpirome. LBT 802 activity was inhibited by clavulanic acid, sulbactam, imipenem, cefoxitin, and aztreonam. It showed its lowest Ki values for clavulanic acid, imipenem and sulbactam.

Anti-Bacterial Agents↗
PubMed2001

Ocular pharmacokinetics of cephalosporins using microdialysis.

The purpose of this study was to delineate the ocular pharmacokinetics of cephalosporins and investigate the presence of peptide transporters in the retina. New Zealand albino rabbits were kept under anesthesia. A concentric microdialysis probe was implanted in the vitreous chamber and linear probe across the cornea in the aqueous humor. Isotonic phosphate buffer saline was perfused through the probes, and samples were collected every 20 min over a period of 10 hr. A 500 microg dose of cephalexin, cephazolin, and cephalothin was administered intravitreally. Inhibition experiments were carried out in vivo, using gly-pro and gly-sar. The vitreal half-lives of cephalexin, cefazolin, and cephalothin were 185.38 +/- 27.25 min, 111.40 +/- 17.17 min, and 146.68 +/- 47.52 min, respectively. Cephalexin generated higher aqueous humor concentrations compared to cefazolin. The pharmacokinetic parameters of cephalexin in the presence of gly-pro, i.e., AUC (44452.06 +/- 3326.55 microg x min/ml), clearance (0.0013 +/- 0.0004 ml/min) and vitreal half-life (825.12 +/- 499.95 min) were different from that of the control (14612.83 +/- 4036.47 microg x min/ml, 0.0036 +/- 0.0011 ml/min, and 187.96 +/- 65.12 min, respectively). Gly-pro did not inhibit cefazolin, and gly-sar showed no effect on the pharmacokinetics of both drugs. These studies indicate the involvement of a peptide carrier in the transport of cephalosporins across the retina. Although gly-pro inhibited the elimination of cephalexin from the vitreous, the effect of an alpha-amino group on peptide carriers was not clearly evident.

Animals↗
PubMed1980

Determination of tolerance to antibiotic bactericidal activity on Kirby-Bauer susceptibility plates.

A rapid method utilizing Kirby-Bauer susceptibility plates was developed to determine bacterial tolerance to antibiotic bactericidal activity. After completion of initial antibiotic disk susceptibility testing, the disks containing cephalothin, cefazolin, nafcillin, oxacillin, and methicillin were removed and replaced with disks containing a potent beta-lactamase. The plates were reincubated for 18-24 hours and examined for regrowth of organisms within the original zone of inhibition. For 15 of 16 patients who had serious Staphylococcus aureus infections, the method correlated with clinical outcome of antibiotic chemotherapy. Broth dilution tests for bactericidal activity only correlated with clinical response for 11 of 16 patients. One hundred consecutive clinical S. aureus isolates tested with the new method demonstrated tolerance in 27% of strains to cephalothin, 15% to cefazolin, 1% to oxacillin, and 2% of nafcillin.

Anti-Bacterial Agents↗
PubMed1978

A comparative study of the activity of cefamandole and other cephalosporins and analysis of the beta-lactamase stability and synergy of cefamandole with aminoglycosides.

The antibacterial activity of cefamandole against 445 clinical isolates was investigated and compared with the activity of other known cephalosporins (cephalothin, cephaloridine, cephalexin, and cefazolin) and of two penicillins (ampicillin and carbenicillin). Cefamandole was the most active antibiotic against isolates of Citrobacter, Enterobacter, and Shigella, and its activity against Staphylococcus aureus, Bacteroides, and some members of the Enterobacteriaceae was comparable to that of the other antibiotics tested. The stability of cefamandole with respect to beta-lactamase was investigated and compared with that of cephalothin, cefazolin, and cephalexin. Cefamandole was stable with respect to the beta-lactamases of Enterobacter and some other members of the Enterobacteriaceae. No significant correlation was found between the antibacterial activity and the beta-lactamase stability of cefamandole, except with Enterobacter. The synergistic activity of cefamandole combined with gentamicin or amikacin was demonstrated by killing-curve techniques, isobolograms, and susceptibility data. Although 12%--46% of the isolates were synergistically inhibited by either combination, antagonism was not observed. No correlation between the hydrolysis of cefamandole by beta-lactamase and the synergistic activity of cefamandole combined with amikacin was demonstrated.

Acinetobacter↗
PubMed1983

Staphylococcal beta-lactamase and efficacy of beta-lactam antibiotics: in vitro and in vivo evaluation.

The susceptibility of five cephalosporins and nafcillin to changes in inoculum size of 26 isolates of Staphylococcus aureus was studied. The spectrum of antibiotic sensitivity to such changes was cefazolin = cephaloridine greater than cefamandole greater than cephalothin greater than cefoxitin = nafcillin. Half of the isolates resulted in large and half in minimal inoculum-induced changes in minimal inhibitory concentrations (MICs). These changes correlated with the amount of beta-lactamase produced by the isolates. The in vivo relevance of these findings was studied in a model of intraperitoneal infection in mice. The effect of beta-lactamase production on mortality was greatest among animals given cefazolin or cephaloridine, intermediate among those given cefamandole, and nonexistent among those given cefoxitin, cephalothin, or nafcillin. The number of organisms in the animals' spleens paralleled survival rates. An increase in the serum level of cefazolin increased the survival rate among mice given that drug. Hence, the survival of mice was influenced by (1) the ability of the infecting organism to increase the MIC of an antibiotic via inoculum increases, (2) the sensitivity of the antibiotic to beta-lactamase, and (3) the peak level of antibiotic attained in serum.

Animals↗