Development of revised quality control limits for disk diffusion susceptibility tests of selected cephem antibiotics with Haemophilus influenzae and description of a new control strain.
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Inconsistent quality control results in disk diffusion testing of cefaclor, cefamandole, cefonicid, and cefuroxime with Haemophilus influenzae ATCC 49247 and Haemophilus test medium (HTM) prompted a search for an alternative control strain that would provide more reliable results. A five-laboratory study was conducted to evaluate two candidate H. influenzae strains as possible alternatives to the aforementioned strain. Repetitive testing of the candidate strains and H. influenzae ATCC 49247 over several days with a total of six different lots of HTM documented consistent performance of the two candidate strains and confirmed inconsistent results for some of the antibiotics with H. influenzae ATCC 49247. In particular, certain lots of HTM failed to yield cefaclor and cefamandole zone sizes within the quality control range advocated by the National Committee for Clinical Laboratory Standards. Because of the greater consistency offered by the new strains, one was selected (now designated H. influenzae ATCC 49766) to be recommended for routine quality control testing of cefaclor, cefamandole, cefonicid, cefuroxime, and the related carbacephem loracarbef. The new control strain and zone size ranges proposed here have been approved by the National Committee for Clinical Laboratory Standards in place of the previously recommended strain and zone size limits for testing of these five cephem antibiotics. (+info)
Influence of angiotensin II-induced alterations in renal flow on excretion of cefonicid in isolated perfused rat kidneys.
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The effects of variations in renal perfusate flow on the excretion of cefonicid was examined in isolated perfused rat kidneys. Cefonicid, an expanded-spectrum cephalosporin, is primarily eliminated by active tubular secretion and is neither metabolized nor reabsorbed in the isolated kidney. We used angiotensin II (AII), a strong vasoconstrictor hormone of the afferent and the efferent arterioles in the kidney, to determine whether the renal and secretion clearances, as well as the excretion ratio (ER = CLR/[fu x GFR], where CLR is renal clearance, fu is the unbound fraction, and GFR is glomerular filtration rate), of this low-extraction compound can be altered by a decreased perfusion flow. Control studies were performed in the absence (n = 5) and presence (n = 4) of AII; cefonicid studies were performed in the absence (n = 4) and presence (n = 5) of AII. AII (1 to 4 ng/min) and cefonicid (5 to 10 micrograms/min) were infused into the perfusate. Cefonicid was assayed by high-performance liquid chromatography, and its protein binding was determined by ultrafiltration. AII decreased the perfusate flow rate and increased the renal vascular resistance and filtration fraction of the isolated kidney in the presence and absence of cefonicid. The glomerular filtration rate remained unchanged among the groups. The fractional excretion of glucose was low and steady, indicating a well-preserved tubular function. Although the unbound fraction was unchanged between treatments, the renal and secretion clearances and the excretion ratio of cefonicid were reduced by about 40% in the presence of AII (excretion ratios, 10.3 without AII versus 6.03 with AII). These results suggest that the altered clearance parameters of cefonicid are the result of a flow-induced change in the intrinsic secretory transport of the drug. (+info)
Influence of the unbound concentration of cefonicid on its renal elimination in isolated perfused rat kidneys.
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The effect of variations in plasma protein binding on the renal excretion of cefonicid was assessed by using isolated perfused rat kidneys. Cefonicid exhibits preferential binding ex vivo to human serum albumin (HSA), as opposed to bovine serum albumin (BSA), and is eliminated mainly by tubular secretion, a process that was reported to be dependent on the total drug concentration. This contradicts previous studies with antimicrobial compounds and other drugs of low renal extraction in which the unbound drug concentration was shown to be the driving force for carrier-mediated tubular transport. To clarify this discrepancy, we performed perfusion studies by using 6% BSA at initial concentrations of 200 micrograms/ml (n = 6) and 20 micrograms/ml (n = 9) and in a combination of 4% BSA plus 2% HSA at initial concentrations of 200 micrograms/ml (n = 4). The excretion ratio [ER = CLR/(fu x GFR)] of cefonicid decreased with increasing unbound concentrations, whereas no apparent relationship with the total concentration was evident. At similar total concentrations of cefonicid, the renal clearance remained unchanged; the secretion clearance increased significantly in the 4% BSA-2% HSA experiments, reflecting the reduced unbound fraction and unbound drug concentration of cefonicid. The excretion ratio data were compatible with a model in which Michaelis-Menten kinetics were required to describe active transport and secretion was dependent on the unbound cefonicid concentration. As a result, changes in plasma protein binding as a result of drug interactions or disease states could significantly influence the tubular transport capability of compounds with low renal extraction. (+info)
Cefonicid versus clindamycin prophylaxis for head and neck surgery in a randomized, double-blind trial, with pharmacokinetic implications.
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Perioperative single-dose antibiotic prophylaxis of cefonicid was compared with clindamycin in a prospective, randomized, double-blind trial of patients undergoing oncologic head and neck surgery. Antibiotics were administered intravenously beginning 1 to 2 h preoperatively. Cefonicid, 1 g, was given as a single dose. Clindamycin, 600 mg, was administered every 8 h for a total of four doses. Blood and wound drainage samples were collected for 24 h following the dose of cefonicid and assayed for total and free cefonicid concentrations, using reverse-phase high-performance liquid chromatography. Although total concentrations of cefonicid in both serum and wound drainage exceeded the MIC for 90% of the isolates of common bacterial pathogens for 24 h, free concentrations in serum and wound drainage (11.0 and 14.9% of total concentrations) were subinhibitory within 6 h following administration. Free concentrations of cefonicid in the postoperative wound drainage were subinhibitory for the entire study period, both perioperatively and postoperatively. Postoperative wound infection occurred significantly (P less than 0.05) more frequently in patients receiving cefonicid (24%) as compared with those receiving clindamycin (8.2%). The relatively low free levels of cefonicid achieved in serum and wound drainage were attributed to the high degree of protein binding (89% in serum) and may be related to the poor clinical outcome. (+info)
Randomized, double-blind trial of cefonicid and nafcillin in the treatment of skin and skin structure infections.
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We compared treatment with one daily intravenous dose of cefonicid and multidose nafcillin in 65 patients with severe infections of the skin or skin structure. Clinical cure or improvement was achieved in 91% of the patients given cefonicid and in 87% of the patients given nafcillin (P = 0.97). The use of cefonicid may allow outpatient therapy of some severe infections. (+info)
Perioperative antibiotic prophylaxis for herniorrhaphy and breast surgery.
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We assessed the efficacy of perioperative antibiotic prophylaxis for surgery in a randomized, double-blind trial of 1218 patients undergoing herniorrhaphy or surgery involving the breast, including excision of a breast mass, mastectomy, reduction mammoplasty, and axillary-node dissection. The prophylactic regimen was a single dose of cefonicid (1 g intravenously) administered approximately half an hour before surgery. The patients were followed up for four to six weeks after surgery. Blinding was maintained until the last patient completed the follow-up and all diagnoses of infection had been made. The patients who received prophylaxis had 48 percent fewer probable or definite infections than those who did not (Mantel-Haenszel risk ratio, 0.52; 95 percent confidence interval, 0.32 to 0.84; P = 0.01). For patients undergoing a procedure involving the breast, infection occurred in 6.6 percent of the cefonicid recipients (20 of 303) and 12.2 percent of the placebo recipients (37 of 303); for those undergoing herniorrhaphy, infection occurred in 2.3 percent of the cefonicid recipients (7 of 301) and 4.2 percent of the placebo recipients (13 of 311). There were comparable reductions in the numbers of definite wound infections (Mantel-Haenszel risk ratio, 0.49), wounds that drained pus (risk ratio, 0.43), Staphylococcus aureus wound isolates (risk ratio, 0.49), and urinary tract infections (risk ratio, 0.40). There were also comparable reductions in the need for postoperative antibiotic therapy, non-routine visits to a physician for problems involving wound healing, incision and drainage procedures, and readmission because of problems with wound healing. We conclude that perioperative antibiotic prophylaxis with cefonicid is useful for herniorrhaphy and certain types of breast surgery. (+info)
Effect of age and renal function on cefonicid pharmacokinetics.
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Cefonicid (15 mg/kg) was administered intravenously at a constant rate of infusion over 15 min to 10 geriatric patients (mean age, 77 years) and to 4 young subjects (mean age, 35 years). Model-dependent and noncompartmental pharmacokinetic parameters were calculated and found to be congruous; noncompartmental data are reported. Significant differences in the values for area under the curve, mean residence time, total body clearance, and renal clearance were observed between the geriatric and young groups. Mean elimination half-life values were 9.59 and 4.88 h for the geriatric and young groups, respectively. Total body and renal clearances were inversely correlated to age and directly correlated to creatinine clearance. Free fraction was not correlated to albumin concentration but was correlated exponentially to total cefonicid concentration. Despite the prolonged half-life values observed in our geriatric patients, the difference in mean trough concentrations was slight. Daily administration of a 15-mg/kg dose should provide adequate concentrations in serum and should not produce appreciable accumulation in geriatric patients. (+info)
Evaluation of the bactericidal activity of beta-lactam antibiotics on slowly growing bacteria cultured in the chemostat.
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The bactericidal activity of 23 beta-lactam antibiotics was compared in slowly growing bacteria cultured in a chemostat. In an attempt to mimic possible in vivo conditions, slowly growing cultures were produced by limitation of iron, glucose, phosphate, or magnesium. Only select antibiotics remained effectively bactericidal against slowly growing cells. For these compounds, the rate of antibiotic-induced loss of viability was a constant when killing was expressed per generation (in contrast to absolute time) in that slowly growing bacteria were killed proportionately more slowly. Individual antibiotics differed greatly, however, in their specific bactericidal activities against slowly growing cells, i.e., in the absolute degree of killing elicited during exposure of the bacteria to MIC equivalents of the drugs. Specific bactericidal activities varied not only with drug structure but also with the bacterial strains and, to a lesser extent, with the nature of the growth-limiting nutrient. In slowly growing cultures exposure to the low drug concentrations studied here (near MIC) caused killing without detectable lysis. Antibiotics with high specific bactericidal activities were capable of rapidly killing cultures of slowly growing pathogens despite extremely long generation times approaching those reported for in vivo growth rates. (+info)