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PubMed1987

Beta-lactam antibiotics and human lymphocyte function: the in vitro effect on blastogenesis, lymphokine production and suppressor cell functions.

The effects of penicillin, cephalothin and cefoxitin on lymphokine production and mitogen stimulation of human peripheral blood lymphocytes and suppressor cell functions in man were studied with concentrations achievable in serum. Penicillin (50 and 100 micrograms/ml) and cephalosporins (50 and 100 micrograms/ml) directly stimulated production of the lymphokine leukocyte aggregating factor (LAgF) by unstimulated lymphocytes and enhanced mitogen-stimulated production of this lymphokine. Neither beta-lactam derivative interfered directly with neutrophil aggregation. Using the same concentration, penicillin did not suppress but had either no effect on or slightly increased the unstimulated and mitogen-stimulated lymphocyte transformation responses, whereas cephalosporins significantly suppressed both responses. Suppression of blastogenesis by the latter could be mediated through suppressor cell enhancement as indicated by the significant suppressed lymphocyte transformation observed while using the supernatant of cephalosporin-stimulated and cultured lymphocytes. This suppressive activity was more pronounced with cephalothin than with cefoxitin while it was not observed with penicillin which rather stimulated thymidine uptake. These findings suggest that enhancement of lymphokine production and suppression of lymphocyte transformation by cephalosporins are not contradictory and reflect a stimulating effect on two different lymphocyte subsets. The enhancement of suppressor function might account for the lower incidence of late hypersensitivity reactions observed in patients treated with the cephalosporins compared with those treated with penicillins.

Cefoxitin↗
PubMed1986

Prevalence of antimicrobial resistance among clinical isolates of Haemophilus influenzae: a collaborative study.

The prevalence of antimicrobial resistance was assessed among a total of 3,356 clinical isolates of Haemophilus influenzae obtained from 22 medical centers distributed throughout the United States during the period July, 1983 through June, 1984. All strains were examined for beta-lactamase production with a rapid acidometric assay and for resistance to ampicillin, chloramphenicol, cephalothin, cefamandole, cefaclor, tetracycline, and erythromycin with a standardized disk diffusion procedure. The overall rate of beta-lactamase production was 15.2%, although results of disk diffusion tests suggested that the overall rate of ampicillin resistance was 19.5%. Twenty-one percent of encapsulated type b strains produced beta-lactamase; 12.1% of non-type b strains were beta-lactamase positive. Specific rates of beta-lactamase production obtained at individual study centers varied widely with no evidence of geographic clustering. The highest rates of beta-lactamase production were observed with isolates of H. influenzae recovered from infants and young children, and from blood and cerebrospinal fluid specimens. The overall rate of chloramphenicol resistance was 0.6%. The prevalence of cephalothin, cefamandole, cefaclor, tetracycline, and erythromycin resistance was 9.9%, 2.4%, 2.8%, 6.4%, and 64.2%, respectively. beta-Lactamase positive isolates of H. influenzae had higher rates of resistance to all of the cephalosporins than did strains that lacked beta-lactamase.

Adolescent↗
PubMed2004

Resistance of uropathogens in symptomatic urinary tract infections in León, Nicaragua.

Management of urinary tract infections (UTI) in Central America and especially Nicaragua, is complicated by the lack of knowledge about the antibiotic resistance of uropathogens. We conducted a prevalence study to gain more insight into the aetiology, bacterial resistance and risk factors for symptomatic UTI in the region of León, Nicaragua. In 2002, all consecutive patients with UTI symptoms and pyuria >/=10 WBC/hpf were admitted to the study. Positive cultures from midstream urine specimens were defined as >/=10(5) cfu/ml of a single uropathogen. Susceptibility tests were performed with disc diffusion tests using the Kirby-Bauer method and broth microdilution using National Committee for Clinical Laboratory Standards criteria both in León and a reference laboratory in Utrecht. A positive culture was present in 62 of 208 study subjects (30%). Escherichia coli (56%), Klebsiella spp. (18%) and Enterobacter spp. (11%) were the most frequent pathogens isolated. Presence of cystocele, incontinence and increasing age were risk factors for bacterial UTI. E. coli was least resistant to ceftriaxone, amikacin and nitrofurantoin (>90% susceptible). We observed high resistance rates in E. coli to amoxicillin (82%, MIC(90) 128 mg/l), trimethoprim-sulphamethoxazole (TMP-SMX) (64%, MIC(90) 32 mg/l), cephalothin (58%, MIC(90), 32 mg/l), ciprofloxacin (30%; MIC(90), 32 mg/l), amoxicillin/clavulanate (21%, MIC(90) 8 mg/l) and gentamicin (12%, MIC(90) 2 mg/l). Our results suggests that community acquired uropathogens in Nicaragua are highly resistant to many antimicrobial agents. The use of amoxicillin, trimethoprim-sulphamethoxazole and cephalothin against uropathogens needs to be reconsidered. High quinolone resistance rates among E. coli in Nicaragua gives cause for great concern.

Adult↗
PubMed2002

Interaction of human organic anion transporters with various cephalosporin antibiotics.

Cephalosporin antibiotics are thought to be excreted into the urine via organic anion transporters (OATs). The purpose of this study was to elucidate the interaction of human-OATs with various cephalosporin antibiotics, using proximal tubule cells stably expressing human-OAT1, human-OAT3 and human-OAT4. Human-OAT1 and human-OAT3 are localized to the basolateral side of the proximal tubule, whereas human-OAT4 is localized to the apical side. The cephalosporin antibiotics tested were cephalothin, cefoperazone, cefazolin, ceftriaxone, cephaloridine, cefotaxime, cefadroxil and cefamandole. All of these cephalosporin antibiotics significantly inhibited organic anion uptake mediated by human-OAT1, human-OAT3 and human-OAT4. Kinetic analysis revealed that these inhibitions were competitive. The inhibition constant (K(i)) values of cefoperazone, cefazolin, ceftriaxone and cephaloridine for human-OAT1 were much lower than those for human-OAT3 and human-OAT4, whereas the K(i) values of cephalothin and cefotaxime for human-OAT3 were much lower than those for human-OAT1 and human-OAT4. Human-OAT4 mediated the bidirectional transport of estrone sulfate, an optimal substrate for human-OAT4. These results suggest that human-OAT1, human-OAT3 and human-OAT4 interact with various cephalosporin antibiotics, and that human-OAT1 and human-OAT3 play a distinct role in the basolateral uptake of cephalosporin antibiotics. Since the K(i) value of cephaloridine for human-OAT4-mediated organic uptake was much higher than that for human-OAT1, the results indicate the possibility that human-OAT4 limits the efflux of cephaloridine, leading to the accumulation of cephaloridine and the induction of nephrotoxicity.

Animals↗
PubMedDate not supplied

In vitro susceptibility of Yersinia kristensenii strains to beta-lactam antibiotics.

The beta-lactam antibiotic susceptibility and beta-lactamase activity of 22 Yersinia kristensenii strains were determined in order to compare these properties with those reported for Y. enterocolitica. Carbenicillin, cephaloridine, cefoxitin and cefotaxime were the most active antimicrobial agents tested against Y. kristensenii. All strains were resistant to penicillin G, cephalothin, cephapirin and cephalexin. On the other hand, ampicillin and cefazolin activity could be considerated as intermediate. The influence of incubation temperature was also evaluated. All Y. kristensenii strains were more resistant at 22 degrees C than at 37 degrees C to beta-lactam antibiotics. Susceptibility to cefazolin was not affected by the incubation temperature. All Y. kristensenii strains produce beta-lactamase. The substrate profile of this enzyme is that of a cephalosporinase: its activity was highest on cephalothin, cephapirin, cephaloridine and cefazolin, while hydrolysis of ampicillin and carbenicillin was not detected. beta-Lactamase-resistant cefoxitin and cefotaxime were not hydrolysed. A correlation between beta-lactam antibiotic susceptibility and the hydrolysis rate of these antibiotics by beta-lactamase was observed, except for cephaloridine and cefazolin; these antibiotics were very good beta-lactamase substrates, but their MIC values were low.

Ampicillin↗
PubMed1974

Elimination of bacteria from dogs with antibiotics.

The effect of oral administration of neomycin cephalothin or kanamycin cephalothin on the aerobic intestinal bacterial flora, was studied in dogs maintained under isolation conditions in a conventional animal room. The dogs were successfully freed of aerobic bacteria with both combinations within two to seven days after the start of antibiotic treatment, and were maintained bacteria free for up to 21 days. Decontamination was attained more rapidly in dogs that were bathed in hexachlorophene surgical soap before and during the first and third days of antibiotic treatment. There was no evidence of toxicity from either of the antibiotic combinations. These results indicate that, as with mice and monkeys, decontamination of dogs with oral antibiotics is feasible. The technique is of potential value in preventing endogenous bacterial infections in canine experimental studies involving use of immunosuppressive agents.

Administration, Oral↗
PubMed1998

Spectrofluorimetric study of the degradation of alpha-amino beta-lactam antibiotics catalysed by metal ions in methanol.

The alpha-aminopenicillins ampicillin and amoxicillin and a cephalosporin, cephalothin, give rise to a fluorescent product when their methanolic solutions are incubated for prolonged time periods. The process also occurs in the presence of the metal ions Cd2+, Co2+ and Zn2+. The effects of the different ions on the emission and excitation wavelengths and the appearance rate of the fluorophore were studied. The appearance of the fluorescent product was zero order for ampicillin and amoxicillin in metal ion-free solution and solutions with Cd2+ and Zn2+, whereas in the presence of Co2+ ion it was first order under the experimental conditions used; for cephalothin it was first order in all cases. Apparent fluorescent compound formation rates were calculated in the zero-order reactions and rate constants in the first-order reactions. The activation energy of the formation reaction of the fluorescent products of amoxicillin and ampicillin was calculated from a study of the reactions at four temperatures; all the values recorded were between 34 and 118 kJ mol-1. As a possible mechanism for the formation of these products, cyclization of the penamaldic derivative of the antibiotic, which is formed in the first stage of the methanolytic reaction, is proposed.

Amoxicillin↗
PubMed1987

Nucleophilic re-activation of the PC1 beta-lactamase of Staphylococcus aureus and of the DD-peptidase of Streptomyces R61 after their inactivation by cephalosporins and cephamycins.

It has been shown previously [Faraci & Pratt (1985) Biochemistry 24, 903-910; (1986) Biochemistry 25, 2934-2941; (1986) Biochem. J. 238, 309-312] that certain beta-lactam-processing enzymes form inert acyl-enzymes with cephems that possess good leaving groups at the C-3' position. These inert species arise by elimination of the leaving group from the initially formed and more rapidly hydrolysing acyl-enzyme, which has the 'normal' cephalosporoate structure. The present paper shows that a strong nucleophile, thiophenoxide, can catalyse the re-activation of three examples of these inert acyl-enzymes, generated on reaction of cephalothin and cefoxitin with the PC1 beta-lactamase of Staphylococcus aureus and of cephalothin with D-alanyl-D-alanine transpeptidase/carboxypeptidase of Streptomyces R61. In view of the reversibility of the elimination reaction, demonstrated in model systems [Pratt & Faraci (1986) J. Am. Chem. Soc. 108, 5328-5333], this catalysis is proposed to arise through nucleophilic addition to the exo-methylene carbon atom of the inert acyl-enzyme to regenerate a more rapidly hydrolysing normal cephalosporoate. Strong support for this scenario was obtained through comparison of the kinetics of the catalysed re-activation reaction with those of turnover of the relevant 3'-thiophenoxycephems, thiophenoxycephalothin and thiophenoxycefoxitin. The enzymes appear to stabilize the products of the elimination reaction with respect to the normal cephalosporoate, but more strongly to destabilize the transition states. The effects of other nucleophiles, including cysteine, glycine amide and imidazole, on the above enzymes and on other beta-lactamases can be understood in terms of the model reaction kinetics and thermodynamics.

Carboxypeptidases↗
PubMed2000

Antibiotic-resistant gram-negative bacteria in a virtually closed water reticulation system.

The effect of the effluent from a chicken meat-processing plant on the antibiotic-resistant bacterial profile was investigated in an almost closed water reticulation system. Of the 273 faecal coliform isolates 256 (93%) were resistant to one or more of the eight antibiotics tested. The most prevalent isolates were for the beta-lactam antibiotics ampicillin and cephalothin followed by the sulphonamides sulphatriad and cotrimoxazole. Eleven different resistance patterns were identified with a single pattern, comprising of ampicillin-, cephalothin-, streptomycin-, sulphatriad-, cotrimoxazole- and tetracyclin-resistant isolates, dominating the meat-processing effluent. An apparent correlation was observed between the specific use of certain antibiotics and the prevalence of the corresponding resistant bacterial isolates. The drugs used to treat the occasional infections, belonging to the beta-lactam and sulphonamide group of antibiotics, seemed to have a more pronounced effect on the antibiotic-resistant bacterial profile in the primary water source than those drugs used as feed additives, oxytetracyclin and the aminoglycoside flavomycin.

Ampicillin↗
PubMed2003

Antibiotics induce apoptosis of human peritoneal mesothelial cells.

The peritoneal mesothelial cell is a critical component of the peritoneal membrane. The intraperitoneal use of several antibiotics to treat bacterial peritonitis is current clinical practice. Our previous study showed that cephalothin (CPL) and cefotaxime (CFT) have cytotoxic effects on human peritoneal mesothelial cells (HPMC), however, the exact mechanism of cytotoxicity has not been elucidated. In the present study, flow cytometry, TdT-mediated dUTP nick-end labelling (TUNEL) staining and electron microscopy were used to detect the apoptosis of HPMCs. Immunofluorescent staining was used to evaluate the cytochrome c distribution pattern. Western blotting was used to assess apoptotic signalling proteins. We found that CPL (0.5 mg/mL) and CFT (1 mg/mL) induced apoptosis of HPMCs, whereas cefazolin (0.5 mg/mL) and ceftriaxone (0.5 mg/mL) failed to induce apoptosis of HPMCs. While the DNA content of CFT- or CPL-treated cells was reduced, as determined by flow cytometry, cefazolin and ceftriaxone had no such effect. The CFT- or CPL-treated cells displayed the features of apoptosis both under the electron microscope and by using TUNEL staining. However, cefazolin and ceftriaxone produced the same result as the medium controls. Furthermore, CFT and CPL increased the expression of Bax and p53, and caused the translocation of cytochrome c from the mitochondria to the cytoplasm. The HPMC treated by CFT but not by CPL induced the cleavage of procaspase-3 to form active caspase-3. In conclusion, cefotaxime and cephalothin induce apoptosis of HPMCs in vitro. Signal transduction may be through the mitochondrial pathway.

Anti-Bacterial Agents↗
PubMed2006

Reduced ability of penicillin to eradicate ingested group A streptococci from epithelial cells: clinical and pathogenetic implications.

BACKGROUND: Group A streptococci (Streptococcus pyogenes; GAS) invades human epithelial cell lines. Failure of penicillin to eradicate GAS from the throats of patients, especially those who are GAS "carriers," has been increasingly reported. However, there has been no comprehensive evaluation of how effectively antibiotics that are used to treat GAS enter upper respiratory tract epithelial cells and kill internalized GAS. We examined the viability of ingested, intracellular GAS after epithelial cell exposure to antibiotics commonly recommended for therapy of GAS infections. METHODS: A human laryngeal epithelial cell line (HEp-2) was used. Three techniques were used to study antibiotic (penicillin V, erythromycin, azithromycin, cephalothin, and clindamycin) killing of ingested GAS: examination by electron microscopy of ultrathin sections of ingested GAS, qualitative determination of intra-epithelial cell antibiotic, and special stain evaluation of intracellular GAS viability after epithelial cell exposure to antibiotics. RESULTS: GAS survived intracellularly despite exposure of the GAS-containing epithelial cells to penicillin. In contrast, there was killing of ingested GAS after exposure of epithelial cells to either erythromycin or azithromycin. Electron microscopy confirmed a lack of intracellular GAS fragmentation (cell death) after exposure of epithelial cells to penicillin in contrast to obvious GAS fragmentation after epithelial cell exposure to erythromycin or azithromycin. Cephalothin, a cephalosporin, and clindamycin were more effective in killing ingested GAS than was penicillin, but they were less effective than erythromycin or azithromycin. CONCLUSIONS: These observations strongly suggest that if the GAS upper respiratory tract carrier state results from intra-epithelial cell GAS survival, the failure of penicillin to kill ingested GAS may be related to a lack of effective penicillin entry into epithelial cells. These unique observations may have clinical implications for understanding GAS respiratory tract carriers and managing GAS infections.

Anti-Bacterial Agents↗
PubMedDate not supplied

Efficacy of parenteral antibiotics in the treatment of experimentally induced intraabdominal sepsis.

An experimental model of intraabdominal sepsis closely approximating the disease in humans was used to evaluate the efficacy of clindamycin, tobramycin, cephalothin, and cefamandole, alone and in combination, in reducing both early mortality due to peritonitis and the subsequent development of abscesses. Sepsis was induced in rats by intraperitoneal placement of gelation capsules containing various amounts of human stool inoculum. Ninety percent of the untreated animals given a high inoculum died of peritonitis within 24 hr, and the survivors showed significant intraabdominal abscesses at the time of sacrifice. Animals treated with clindamycin-tobramycin, cephalothin-tobramycin, cefamandole-tobramycin, or cefamandole alone in the high-inoculum group showed a significant decrease in early mortality. Only animals treated with clindamycin-tobramycin, however, had a significantly increased cure rate (survival with no abscess present at time of sacrifice). In low-inoculum groups, several antibiotics alone or in combination significantly decreased mortality and increased cure rates. The selective use of antibiotics is critical in the treatment of severe forms of intraabdominal sepsis.

Abdomen↗
PubMedDate not supplied

Efficacy of antibiotic combinations including rifampin against methicillin-resistant Staphylococcus epidermidis: in vitro and in vivo studies.

Rifampin in combination with other antibiotics has been used successfully in the treatment of serious infections due to Staphylococcus epidermidis. The authors evaluated the efficacy of rifampin in combination with either cephalothin, nafcillin, gentamicin, or vancomycin to determine in vitro synergistic or antagonistic interactions of the combinations and to determine the role of the second antibiotic in preventing the emergence of rifampin-resistant mutants. The authors found that among 10 isolates of methicillin-resistant S. epidermidis, synergy was found in checkerboard studies (inoculum, 10(5) colony-forming units/ml) for only two isolates and only with nafcillin and rifampin; antagonism was present with one combination for each of four different isolates. Time-kill studies showed each antibiotic capable of preventing the emergence of rifampin-resistant mutants for all 10 isolates, but no synergy or antagonism was present. In experimental endocarditis, however, the addition of cephalothin did not prevent the emergence of rifampin-resistant mutants, and rifampin-resistant mutants were as capable of causing endocarditis as were their rifampin-sensitive parents. Thus, rifampin was a bactericidal antibiotic against methicillin-resistant S. epidermidis. The benefit of a second antibiotic in vitro was the prevention of the emergence of rifampin-resistant mutants. However, in vivo results with a beta-lactam antibiotic did not confirm in vitro observations. More animal and human studies should be performed with antibiotic combinations including rifampin against methicillin-resistant S. epidermidis.

Animals↗
PubMedDate not supplied

Cross-allergenicity and immunogenicity of aztreonam.

The immunochemistry of aztreonam, the prototype of the new monobactam class of beta-lactam antibiotics, was studied in a series of experimental and clinical investigations. Rabbit antibodies to aztreonam and naturally occurring human antibodies that recognize aztreonam were found to have negligible cross-reactivity with benzylpenicillin, cephalothin, and cefotaxime. Aztreonam likewise displayed negligible cross-reactivity (less than or equal to 0.001%) with antibodies to penicillin (including human IgE antibodies to major and minor penicillin determinants) and to cephalothin. These studies suggest that aztreonam may be well tolerated by penicillin-allergic individuals, and this possibly is now being evaluated in clinical trials. Seven (6.25%) of 112 healthy persons tested had preexisting IgG antibodies to aztreonam in low titer, presumably as a result of exposure to naturally occurring cross-reacting moieties. Only two of seven patients with preexisting IgG antibodies to aztreonam had a rise in titer following aztreonam treatment. No IgE antibody to aztreonam was detected in serum specimens obtained on day 10 during any of the 112 courses of therapy. These clinical observations suggest but do not prove that aztreonam has only weak potential to elicit a drug-specific immunologic response.

Allergens↗
PubMed1975

Susceptibility of Anaerobic bacteria to carbenicillin, cefoxitin, and related drugs.

The agar dilution technique was used for determination of the bacteriostatic activity of carbenicillin, penicillin G, cefazolin, cephaloridine, cefoxitin, and cephalothin agaomst a variety of anaerobic bacteria. Carbenicillin showed a high level of activity at a concentration of smaller than or equal to 100 mug/ml; only five of 123 strains of Bacteroides fragilis, one strain of Bifidobacterium eriksonii, and one strain of Clostridium bifermentans were resistant to a concentration of larger than or equal to 100 mug/ml. Cefoxitin, a beta-lactamase-resistant drug, was highly active against B. fragilis and most other anaerobes at a concentration of smaller than or equal to 32 mug/ml; the exceptions were one strain of Bacteroides species and 13 of 28 strains of Clostridium species. The other cephalosporins were less active against B. fragilis but exhibited good activity against most of the other strains tested. Bactericidal concentrations of cefoxitin and cephalothin were determined for 51 selected strains by the broth dilution technique, and the activities of these drugs were compared with those of two other drugs (clindamycin and metronidazole) known to be very active against anaerobes. Metronidazole wasthe most consistently bactericidal of the four drugs tested for this activity.

Anaerobiosis↗
PubMed1975

Resistance categories of enterobacteria to beta-lactam antibiotics.

The activities of cephaloridine, cephalothin, and ampicillin against dense cultures of 103 ampicillin-resistant gram-negative bacilli were compared in a turbidimetric system. The organisms were divided into two groups according to their behavior in conventional minimal inhibitory concentration titrations: those fully resistant to ampicillin at a concentration of 500 mug/ml and those inhibited by 32-500 mug of ampicillin/ml. Of the 83 strains in the first group, most were more sensitive to cephalothin than to cephaloridine, whereas the 20 strains in the second group exhibited a number of interesting properties peculiar to them. On the basis of these and previous results, six distinct categories of resistance to beta-lactam antibiotics have been detected among enterobacteria.

Ampicillin↗
PubMed1977

Standardization of a preparative ultracentrifuge method for quantitative determination or protein binding of seven antibiotics.

A preparative ultracentrifuge method was standardized for determination of quantitative binding of cephalothin, cefamandole, cefazolin, cefaclor, erythromycin, gentamicin, and chloramphenicol to human serum proteins. At achievable in vivo concentrations, serum binding was 78.5% for cephalothin, 79.9% for cefamandole, 88.5% for cefazolin, 23.5% for cefaclor, 41.9% for erythromycin, 22.7% for gentamicin, and 59.5% for chloramphenicol. Techniques that use semipermeable cellophane or diaflow membranes, cross-linked dextran, inhibition of bacterial growth, protein precipitation, or liquid partitioning all have inherent problems with either the ligand or the antibiotic adversely interacting with the experimental apparatus. Ultracentrifugation provides a rapid, reproducible technique for protein-binding determinations of the classes of antibiotics described.

Anti-Bacterial Agents↗
PubMed1986

Comparative efficacy of pefloxacin and six other antimicrobial agents on Staphylococcus aureus experimental abscesses.

Pefloxacin (Pef) is a new quinolone which has been shown to have good in-vitro activity against Staphylococcus aureus, and to reach high tissue concentrations. Its efficacy was compared to that of 2 quinolone derivatives, norfloxacin (Nor) and ciprofloxacin (Cip) and to that of methicillin (Meth), cephalothin (Cep), pristinamycin (Pri) and vancomycin (Van), in an experimental model of S. aureus abscesses. Mice challenged with an intramuscular thigh injection of a calibrated inoculum developed local abscesses. Three S. aureus strains (with different antibiotic resistance profiles (Pase-, Pase+, MethR)) were used. In this model, the antibiotics showing the best ED50 following oral administration, against all three strains were Pef greater than Cip greater than Pri greater than Nor, by subcutaneous administration for the Pase- strain Pef = Cip greater than Cep greater than Van; for the Pase+ strain Pef = Cip greater than Van greater than Meth and for the Pase+ MethR strain: Pef = Cip greater than Van greater than Cep. These data indicate that pefloxacin and ciprofloxacin are highly active in vivo against various strains of S. aureus, and appear to be more potent than norfloxacin, vancomycin, cephalothin and methicillin.

Abscess↗