M. F. Michel

Efficacy of antibiotic prophylaxis for prevention of native-valve endocarditis

Whether antibiotic prophylaxis can prevent bacterial endocarditis is hotly debated. In an attempt to settle this issue, we have assessed the efficacy of prophylaxis for bacterial endocarditis on native valves in a nationwide, case-control study in the Netherlands. Cases were patients with known cardiac disease in whom endocarditis developed within 180 days of a medical or dental procedure for which prophylaxis was indicated. Of a total of 438 patients with endocarditis diagnosed during 2 years, 48 were eligible for the study. Controls were patients with the same cardiac status in whom endocarditis did not develop within 180 days of a similar procedure; of a total of 889 controls from five hospitals, 200 were eligible. Overall, about 1 in 6 patients in both groups had received prophylaxis. The best estimate of protective efficacy was 49% for first-ever endocarditis occurring within 30 days of a procedure. Endocarditis developed within 30 days of a procedure in only 13% of patients with a previously diagnosed heart lesion which predisposed to the disease. The findings suggest that strict adherence to generally accepted recommendations for prophylaxis might do little to decrease the total number of patients with endocarditis in the community.

Reduction of Surgical-Site Infections in Cardiothoracic Surgery by Elimination of Nasal Carriage of Staphylococcus aureus

OBJECTIVE To test the hypothesis that perioperative elimination of nasal carriage of Staphylococcus aureus using mupirocin nasal ointment reduces the surgical-site infection (SSI) rate in cardiothoracic surgery. DESIGN Unblinded intervention trial with historical controls. SETTING A university hospital, tertiary referral center for cardiothoracic surgery. PATIENTS Consecutive patients undergoing cardiothoracic surgery between August 1, 1989, and February 1, 1991 (historical control group), and between March 1, 1991, and August 1, 1992 (intervention group). RESULTS The historical control group consisted of 928 patients and the intervention group of 868, of whom 752 actually were treated. The 116 patients who were unintentionally not treated were considered as a concurrent control group. In the intention-to-treat analysis, a significant reduction in SSI rate was observed after the intervention (historical-control group 7.3% and intervention group 2.8%; P < .0001). The SSI rate in the concurrent control group was significantly higher than in the treated group (7.8% and 2.0%, respectively; P = .0023). Resistance of S aureus to mupirocin was not observed. CONCLUSION The results of this study indicate that perioperative elimination of nasal carriage using mupirocin nasal ointment significantly reduces the SSI rate in cardiothoracic surgery patients and warrants a prospective, randomized, placebo-controlled efficacy trial. This preventive measure may be beneficial in other categories of surgical patients as well.

Epidemiology of bacterial endocarditis in The Netherlands. I. Patient characteristics.

BACKGROUND Studies of the epidemiology of bacterial endocarditis are usually based on a retrospective review of medical records from referral centers serving diverse patient populations. These studies are therefore likely to suffer from selection bias. We conducted a nationwide prospective epidemiologic study of endocarditis in the Netherlands. METHODS During a 2-year period, all cases of consecutively hospitalized patients with suspected endocarditis in the Netherlands were reported to us. While hospitalized, patients were visited for an in-person interview and a review of the medical record. RESULTS Of 559 episodes, 438 met the criteria for endocarditis; these included 89 episodes of prosthetic valve endocarditis and 349 episodes of native valve endocarditis. Adjusted for age- and sex-specific population figures, the incidence was 19 per million person-years. The incidence increased significantly with age, and men were more often affected than women (266 and 172 cases, respectively). Rheumatic and congenital cardiac lesions formed most of the underlying heart diseases. Mitral valve prolapse was present in only 29 patients with native valve endocarditis (8.3%). A history of intravenous drug abuse was present in 32 patients (7.3%). Viridans streptococci, staphylococci, and enterococci together constituted 86% of the isolated bacterial strains. Only 1.1% of the patients had culture-negative endocarditis. Overall case fatality was 19.7% and varied widely according to causative microorganism. CONCLUSION The distribution of causal microorganisms, the case fatality rate, and the incidence rate of endocarditis are age related. Therefore, a meaningful comparison of data is only possible between population-based cohorts of patients with endocarditis.

Epidemiology of Bacterial Endocarditis in the Netherlands: II. Antecedent Procedures and Use of Prophylaxis

BACKGROUND The reported frequency with which endocarditis is ascribed to an antecedent dental or medical procedure varies from 3% to 62%. METHODS We performed a nationwide prospective study of the epidemiology of bacterial endocarditis in the Netherlands. During a 2-year period, all consecutively hospitalized patients suspected of having endocarditis were visited while still hospitalized for a review of the medical record and an in-person interview that focused on antecedent procedures and administered prophylaxis. All information was checked with pharmacists and dental and medical practitioners. RESULTS Of 427 patients with late prosthetic or native valve endocarditis, 275 were eligible for antibiotic prophylaxis because of a previously known cardiac lesion (n = 197) or a prosthetic valve (n = 78). Of these 275 patients, 64 (23.3%) had undergone a procedure with an indication for prophylaxis within 180 days of onset; in 31 (11.3%) the procedures had been within 30 days of onset. Antibiotic prophylaxis had been administered to 17 (26.6%) of the 64 patients and to eight (25.8%) of the 31 patients. CONCLUSION The results indicate that medical and dental procedures cause only a small fraction of endocarditis. The majority of patients develop the disease along other routes. For an incubation period of 180 days, full compliance with prophylaxis might have prevented endocarditis in 47 (17.1%) of 275 patients with late prosthetic or native valve endocarditis involving a previously known cardiac lesion who underwent a procedure with an indication for prophylaxis. For an incubation period of 30 days, prophylaxis might have prevented endocarditis in 23 (8.4%) of these 275 patients, or 5.3% of all patients with endocarditis (n = 427).

Continuous versus intermittent administration of ceftazidime in experimental Klebsiella pneumoniae pneumonia in normal and leukopenic rats.

Experimental Klebsiella pneumoniae pneumonia was used to study the influence of cyclophosphamide-induced leukopenia on the relative therapeutic efficacy of continuous and intermittent (6-h intervals) administration of ceftazidime. The antimicrobial response was evaluated with respect to the calculated daily dose that protected 50% of the animals from death (PD50) until 16 days after the termination of a 4-day treatment. When ceftazidime was administered intermittently to leukopenic rats, the PD50 was 24.37 mg/kg per day, 70 times (P less than 0.001) the PD50 of 0.35 mg/kg per day for normal rats. Continuous administration of ceftazidime to leukopenic rats resulted in a PD50 of 1.52 mg/kg per day, four times (P less than 0.001) the PD50 of 0.36 mg/kg per day for normal rats. Continuous administration of ceftazidime in daily doses that protected 100% of normal and leukopenic rats from death resulted in serum levels of 0.06 and 0.38 micrograms/ml, respectively, whereas the MIC for the infecting K. pneumoniae strain was 0.2 micrograms of ceftazidime per ml. The effect of the duration of ceftazidime treatment by continuous infusion on the therapeutic efficacy in relation to the persistence of leukopenia was then investigated in leukopenic rats. The administration of 3.75 mg of ceftazidime/kg per day for 4 days protected all leukopenic rats from death, provided the circulating leukocytes returned at the end of antibiotic treatment. When leukopenia persisted for 8 days this ceftazidime treatment schedule resulted in the mortality of rats (P less than 0.05). However, when ceftazidime treatment was continued for 8 days, until the return of the leukocytes, there was no significant mortality (P greater than 0.05).

Pharmacokinetics of ceftazidime in serum and suction blister fluid during continuous and intermittent infusions in healthy volunteers.

The pharmacokinetics of ceftazidime were investigated during intermittent (II) and continuous (CI) infusion in eight healthy male volunteers in a crossover fashion. The total daily dose was 75 mg/kg of body weight per 24 h in both regimens, given in three doses of 25 mg/kg/8 h (II) or 60 mg/kg/24 h with 15 mg/kg as a loading dose (CI). After the third dose (II) and during CI, serum and blister fluid samples were taken. Seven new blisters were raised for each timed sample by a suction blister technique. Blisters took 90 min to form. Samples were then taken from four blisters (A samples) and 1 h later were taken from the remaining three (B samples). The concentration of ceftazidime was determined using a high-performance liquid chromatography method. After II, the concentrations in serum immediately after infusion (t = 30 min) and 8 h after the start of the infusion were 137.9 (standard deviation [SD], 27.5) and 4.0 (SD, 0.7) micrograms/ml, respectively. The half-life at alpha phase (t1/2 alpha) was 9.6 min (SD, 4.6), t1/2 beta was 94.8 min (SD, 5.4), area under the concentration-time curve (AUC) was 285.4 micrograms.h/ml (SD, 22.7), total body clearance was 0.115 liter/h.kg (SD, 0.022), and volume of distribution at steady state was 0.178 liter/kg (SD, 0.023). The blister fluid (A) samples showed a decline in concentration parallel to that of the concentrations in serum during the elimination phase with a ratio of 1:1. The t1/2 of the A samples was 96.4 min (SD, 3.2). The concentration of ceftazidime in the B blister fluid samples was significantly higher (27%) than in the A samples over time. This shows that blisters may behave as a separate compartment and establishes the need to raise new blisters for each timed sample. The mean AUC/h during continuous infusion was 21.3 micrograms . h/ml (SD, 3.0). The total body clearance was 0.113 liter/h . kg (SD, 0.018), the urinary clearance was 0.105 liter/h . kg (SD, 0.012), and the ceftazidime/creatinine clearance ratio was 0.885. The mean AUC of blister fluid per hour was 84.5% (18.0 micrograms . h/liter; SD, 3.6) compared with that of serum. The A samples did not differ significantly from the B samples. The implications of continuous infusion of beta-lactams for treatment of serious infections are discussed.

Distribution, antibiotic susceptibility and tolerance of bacterial isolates in culture-positive cases of endocarditis in The Netherlands

During a two-year period data were collected nationwide in The Netherlands on 438 episodes of bacterial endocarditis (BE) in 432 patients. Of the strains isolated in these patients 419 were available for analysis. Of these, 326 were isolated in native valve endocarditis (NVE) and 93 in prosthetic valve endocarditis (PVE). Viridans streptococci, staphylococci and enterococci together constituted 87 % of the isolates. More than 46 % of the viridans streptococci consisted ofStreptococcus sanguis. Enterococus faecalis andStaphylococcus aureus were the predominant species in the late form of PVE. The majority of the viridans streptococci and haemolytic streptococci were highly susceptible to penicillin. Five of 35 strains of coagulase negative staphylococci were resistant to methicillin. Eleven percent of a random sample of the streptococci collected were tolerant to penicillin. After repeated exposure to a concentration gradient of an appropriate β-lactam antibiotic, this figure increased to 49 %. Of the staphylococci, 5–6 % of the strains were tolerant before induction and 16–20 % after induction. Of theEnterococcus strains (n=40), 12.5 % showed high-level resistance to one or more aminoglycoside.

Impact of the dosage schedule on the efficacy of ceftazidime, gentamicin and ciprofloxacin inKlebsiella pneumoniae pneumonia and septicemia in leukopenic rats

The impact of the dosage schedule on the therapeutic efficacy of antibiotics was investigated in experimentalKlebsiella pneumoniae pneumonia and septicemia in leukopenic rats. The daily doses (mg/kg) that protected 50 % of the animals from death, when calculated for administration at 6 h intervals or by continuous infusion, were as follows: ceftazidime 24.4 and 1.5 (p<0.001), gentamicin 2.8 and 3.8 (p>0.05), and ciprofloxacin 3.3 and 6.5 (p<0.05), respectively. This correlates with the observation that ceftazidime killedKlebsiella pneumoniae slowly but constantly, and relatively independently of concentration, whereas killing by gentamicin or ciprofloxacin was rapid, and markedly dependent on antibiotic concentration. Exposure of bacteria for 1 h to concentrations of fivefold the MBC did not give rise to a postantibiotic effect for any of the drugs. In our model ceftazidime was far more effective when given continuously than when administered at 6 h intervals. On the other hand, the activity of gentamicin was not influenced by the mode of administration, whereas ciprofloxacin was slightly more effective when given intermittently. However, to avoid misleading conclusions regarding the use of antibiotics in humans, the pharmacokinetic differences between rats and man must be considered when interpreting these results.

Role of tolerance in treatment and prophylaxis of experimental Staphylococcus aureus endocarditis with vancomycin, teicoplanin, and daptomycin.

The role of Staphylococcus aureus tolerance in the treatment and prophylaxis of endocarditis in rats was investigated. The efficacies of vancomycin, teicoplanin, and daptomycin, alone and in combination with rifampin, were compared in rats with endocarditis infected with a tolerant strain of S. aureus and in rats with endocarditis infected with its nontolerant variant. In vitro the cloxacillin-tolerant strain was also tolerant to vancomycin and teicoplanin, but not to daptomycin. However, tolerance to these antibiotics did not influence the results of treatment of experimental S. aureus endocarditis. There was no difference in the bacterial densities in the vegetations of rats infected with either the tolerant or the nontolerant strain after 5 days of treatment with any of the antibiotic regimens. Of all antibiotics, daptomycin was the most effective in reducing bacterial numbers in vegetations. Combination of rifampin with vancomycin or teicoplanin improved the results of treatment for the tolerant as well as the nontolerant strains. Daptomycin was as effective alone as in combination with rifampin. In contrast, tolerance influenced the prophylactic effects of vancomycin and teicoplanin. The proportion of rats with sterile vegetations after prophylaxis with vancomycin or teicoplanin at a low dose was lower for those infected with the tolerant strain than for those infected with the nontolerant strain. A low dose of daptomycin was equally effective against the tolerant and the nontolerant strains. However, higher doses of all three antibiotics afforded almost full protection against both strains.

Typing of Acinetobacter calcoaceticus strains isolated from hospital patients by cell envelope protein profiles

The usefulness of sodium dodecyl sulphate-polyacrylamide gel electrophoresis patterns of cell envelope proteins for classifying strains of Acinetobacter calcoaceticus was studied using 129 isolates from 16 in-patients in a teaching hospital. In 11 patients, all of the isolates from each patient exhibited the same pattern irrespective of the body site or time of isolation. The patterns of the isolates from four other patients were indistinguishable, with the exception of one isolate per patient. In the isolates from one patient five patterns were observed. In several cases isolates from different patients exhibited the same pattern. The relative frequency of some of these patterns was low. Epidemiological data were compatible with the assumption that the concurrent presence of bacteria of these patterns in the patients was the result of cross-infection. For one pattern, which was seen in seven patients, cross-infection could not be substantiated. On the basis of analysis of electrophoretic patterns in combination with epidemiological data on a number of strains it is concluded that cell-envelope protein profiles appear to be a useful aid in studying the dissemination of Acinetobacter in the hospital environment.