Rates of resistance to 12 antibiotics were determined for 1,289 isolates of Bacteroides fragilis group submitted in 1988-1989 by 22 laboratories in 15 European countries. There was no resistance to metronidazole (breakpoint 8 mg/l) and only one isolate was resistant to chloramphenicol (breakpoint 8 mg/l). Resistance was uncommon for imipenem (0.3% at greater than 4 mg/l), amoxicillin/clavulanate (1% at greater than 8 mg/l), cefoxitin (3% at greater than 32 mg/l), mezlocillin (6% at greater than 64 mg/l) and clindamycin (9% at greater than 4 mg/l). Resistance was the rule for ampicillin (93% at greater than 4 mg/l), ciprofloxacin (56% at greater than 4 mg/l) and tetracycline (64% at greater than 4 mg/l). Bacteroides fragilis, the commonest species, was generally the most sensitive: resistance of this organism was uncommon for cefotetan (4% at greater than 32 mg/l) and ceftazidime (12% at greater than 32 mg/l) to which the other species were more often resistant. There were small but significant differences between laboratories and countries for many of the antibiotics. Regionally the most striking differences were for clindamycin where resistance in Bacteroides fragilis was most common in the South and for tetracycline where resistance in Bacteroides fragilis, Bacteroides thetaiotaomicron and Bacteroides uniformis was least common in the North.
A review of the literature shows that antibiotic concentrations in tissues and tissue fluids are often quoted as being different in profile to concurrent serum levels. To study the relationship between serum and tissue concentrations we analysed published studies where different experimental models were tested simultaneously. In some models serum levels predicted tissue levels while in others they did not. The factors likely to be responsible for the differences were examined. The most important of these factors was tissue geometry (surface area to volume ratio; SA/V). Serum levels predicted tissue levels in models where the SA/V was high (greater than 60) but not where the SA/V's were low (less than 10); here the antibiotic concentrations were lower and more prolonged than serum levels. These observations can be extrapolated to the clinical situation. In most situations involving prophylaxis or treatment of infections in non-specialised tissues (naturally high SA/V), serum levels will closely reflect levels in extracellular tissue fluid where most bacterial infections are located.
The penetration of five cephalosporins into interstitial fluid was investigated by a new method employing cotton threads implanted subcutaneously. Penetration after short bolus injections, calculated as area under interstitial fluid level curve divided by area under serum level curve x 100, was 47.0% for cephradine, 30.6% for cefuroxime, 26.7% for cefotaxime, 24.6% for cefoxitin, and 9.6% for cefoperazone. There was an inverse correlation between the degree of penetration and serum protein binding with r = -0.97. The area under interstitial fluid level curves was the same whether the drugs were administered as short bolus injections or short time infusions.It is generally maintained that only the free, unbound drug is available for antibacterial activity and for distribution to the extravascular compartments. Therefore, for treatment ofinfections outside the vascular compartment, drugs which are minimally bound to serum proteins are regarded as superior to drugs which are highly bound to the serum proteins (11,14,18). Although a number of models have been established to evaluate the influence of serum protein binding on antibiotic pharmacokinetics, especially in animals (4,12,17,18,20), all conclusions are far from certain (15).It is likewise unclear what role the rates of drug delivery play in the penetration of the agent into the extravascular compartment. In one model an infusion for 15 min was preferential over a 1-h infusion or a bolus injection because it yielded higher levels in subcutaneous cage fluid in rabbits (5). In another model the high peak was regarded as important for penetration into extravascular foci (3). In an effort to clarify these issues, we investigated the penetration into the interstitial fluid (IF) of five cephalosporins in humans.(This study was partly presented at the 20th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, La., 1980.) MATERIALS AND METHODS The antimicrobial agents used were cephradine (13), cefuroxime (7), cefotaxime (6), cefoxitin (8), and cefoperazone (19), of which the serum-protein-binding capacities were 10, 33, 40, 70, and 90%, respectively. The serum-protein-binding capacities varied over the concentration range of the drugs, but the figures mentioned are average values over the normal serum concentration range.The investigation was approved by the Ethical Committee of the University of Lund, and the volunteers were verbally informed and gave their verbal consent. Three healthy male and four healthy female volunteers, with no known allergy to penicillin and no history of antimicrobial therapy during the previous month, were treated with each drug. Their mean age was 32.6 years + 7.3 (standard deviation), and their mean weight was 70.4 kg ± 9.3 (standard deviation).All had normal serum creatinines.Each subject received one intravenous injection for 5 min and after at least 1 week an intravenous infusion for 30 min. The doses were 1 g of cephradine, 1.5 g of cefuroxime, and 2 g of cefotaxime, cefoxitin, and cefoperazone.The model use...
Eight patients were treated with ceftazidime, four of whom had impaired renal function with creatinine clearances below 60 ml/min per 1.73 m2. The levels of ceftazidime in serum and extracellular fluid were determined. Half-life in serum and extracellular fluid was 2.5 and 2.2 h respectively for patients with normal renal function. For patients with impaired renal function the half-life of the drug was 7.9 and 115 h, respectively. The penetration of ceftazidime into extracellular fluid was around 50% in both groups. The levels achieved in both serum and extracellular fluid were satisfactorily high and prolonged, suggesting that a dosage regimen of 1 g twice daily is satisfactory.
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