Extended-spectrum Beta-lactams Research Articles

Synergistic interactions of ciprofloxacin and extended spectrum beta-lactams or aminoglycosides against Acinetobacter calcoaceticus ss. anitratus.

The susceptibility of 54 clinical isolates of Acinetobacter calcoaceticus ss. anitratus to 16 antimicrobial agents was determined in vitro with inoculum of 10(4) and 10(6) cfu by a standard agar dilution method. The most active agents were imipenem, SCH 34343, ciprofloxacin, difloxacin (A-56619), and A-56620. Only imipenem and Abbott quinolones (A-56619 and A-56620) remained active when tested with the heavier inoculum. Except for ticarcillin and ceftazidime, which showed only moderate activity, the extended-spectrum penicillins and cephalosporins, as well as aztreonam and aminoglycosides, were inactive against these highly resistant strains. Nine isolates were selected for combination studies of ciprofloxacin with seven beta-lactams and three aminoglycosides using a checkerboard agar dilution technique. Synergistic or additive interactions at clinically achievable concentrations were more common with amikacin (eight isolates), tobramycin (seven), ceftazidime (six), cefoperazone (six), and aztreonam (six), than with other agents, including mezlocillin (four), piperacillin (three), gentamicin (two), and cefsulodin (two). Antagonism was rare, only occurring with mezlocillin in a single strain. These data suggest that combinations of ciprofloxacin with these agents may be useful for some nosocomial multidrug resistant A. calcoaceticus ss. anitratus infections.

Antimicrobial Prophylaxis in Urologic Surgery

Nosocomial urinary tract infections represent approximately 40 per cent of all nosocomial infections, thereby contributing considerably to secondary bacteremia and sepsis and possibly increased mortality. Urethral catheterization is the single most important predisposing factor in the development of urinary tract infection. Patients at increased risk of nosocomial infectious complications are the elderly, malnourished and debilitated, those with diabetes or prosthetic devices, and those on immunosuppressive therapy. About 75 per cent of nosocomial urinary tract infections are attributable to gram-negative bacteria, a disproportionate number of which when compared with community-acquired infections are caused by Proteus, Klebsiella, and Pseudomonas. There is enough evidence in the literature to support the use of prophylaxis in urologic surgery. Antimicrobial prophylaxis reduces the incidence of postoperative urinary tract infection. It does not seem to reduce the incidence of transient perioperative bacteremia but probably prevents the development of sepsis, thereby reducing the number of serious infective complications, the average hospital stay, and the associated total cost of treatment. To achieve adequate urine, blood, and tissue levels of the antimicrobial agent at the time of surgery, the drug should be given preoperatively. A short perioperative course represents sufficient prophylaxis. Regimens with combinations of beta-lactam and aminoglycoside antibiotics or single use of an extended spectrum beta-lactam antibiotic are acceptable for this purpose.

Mechanisms of resistance to extended-spectrum cephalosporins.

The extended-spectrum beta-lactam antibiotics represent a major advance in antimicrobial therapy, but a newly recognized resistance mechanism may rapidly negate their usefulness. Judicious clinical use will prolong their efficacy.

A review and summary of the pharmacokinetics of cefoperazone: a new, extended-spectrum beta-lactam antibiotic.

Cefoperazone is a new piperazine cephalosporin derivative which has a broad antibacterial activity against aerobic and anaerobic gram-positive and gram-negative cocci and bacilli, including Pseudomonas aeruginosa. In studies of the intramuscular (i.m.) administration of cefoperazone at doses of 0.25, 0.5, and 1 g, mean peak serum concentrations were 22, 33, and 67 micrograms/ml at 1 hr. At 8 hr, serum levels were 2.1, 4.8, and 5.6 micrograms/ml, respectively, for the three doses. The mean half-life after intramuscular injection was 108-154 min. Urinary recovery ranged from 14 to 18% of an administered dose. Intravenous (i.v.) administration of cefoperazone by rapid (3-5 min) infusion produced serum levels at 15 min of 76, 156, and 244 micrograms/ml after doses of 0.5, 1, and 2 g, respectively. Concentrations of cefoperazone at 8 hr were 2.4, 6.5, and 11.8 micrograms/ml after these respective doses. Serum half-life was 115-120 min and urinary recovery, 29-33%. Levels determined at 5 min after bolus injection were 200 micrograms/ml for 1 g, 275 micrograms/ml for 2 g and 518 micrograms/ml for 3 g. Intravenous infusion studies of cefoperazone in which 2 g of the drug has been infused over 15, 30, or 120 min have yielded levels of 250-260 micrograms/ml. At 12 hr, levels of 1-2 micrograms/ml were still present. The half-life found in these studies ranged from 1.6 to 2.38 hr. Urinary recovery was 25-30%. Serum clearances have been 80-90 ml/min and renal clearances, 18-30 ml/min. The apparent volume of distribution of the compound has ranged from 10 to 16 liters. Comparative studies have shown that cefoperazone produced higher serum levels than cefazolin, cefamandole, cefotaxime, and moxalactam. Biliary concentrations exceed 400 micrograms/ml and are two to four times the levels found with cefazolin or cefamandole. In the presence of renal failure there is a minimal increase in serum half-life; but in the presence of biliary obstruction, serum half-life may reach 11 hr, depending on the degree of biliary obstruction. In the presence of biliary obstruction, the drug is 90% removed from the body by renal excretion.