Biomedical subjects
Publications and source records attributed to H Drugeon.
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Marbofloxacin is a new fluoroquinolone developed exclusively for veterinary use. Minimum inhibitory concentrations of marbofloxacin were assessed for 816 recent isolates associated with canine or feline diseases. Marbofloxacin showed a broad spectrum of activity against gram-negative and gram-positive bacteria. In vitro rates of killing of marbofloxacin and enrofloxacin were compared against strains of Staphylococcus intermedius and Pasteurella multocida, and the results showed no marked difference between the two antibiotics. The duration of bactericidal activity was evaluated ex vivo in the urine of dogs and cats treated with marbofloxacin and lasted from 2 to 5 days after a single administration according to the dosages. Post-antibiotic effect durations were determined with Escherichia coli, Pasteurella multocida, Staphylococcus aureus and Staphylococcus intermedius and were found almost equal to those of enrofloxacin or ciprofloxacin. These results predict a great potential for marbofloxacin in the treatment of a wide range of diseases in dogs and cats.
The in vivo efficacy of ciprofloxacin or pefloxacin alone or in combination with fosfomycin was evaluated in experimental aortic valve endocarditis induced in 133 rabbits by a multidrug-susceptible or multidrug-resistant strain of Pseudomonas aeruginosa. Therapy was initiated early (12 h after infection), when bacterial counts in aortic valve vegetations were relatively low, or late (48 h after infection), when vegetations contained a larger inoculum. Antibodies were administered as a continuous 24-h intravenous infusion. Mean steady-state levels of ciprofloxacin (64 mg/kg), pefloxacin (64 mg/kg), and fosfomycin (300 mg/kg) in serum were 2.5, 4.2, and 63.9 mg/liter, respectively. For the multidrug-susceptible strain, all regimens except pefloxacin alone significantly reduced the number of CFU per gram of vegetation versus controls, whether treatment was performed early or late. For the multidrug-resistant strain, none of the regimens showed differences from untreated controls, except ciprofloxacin-fosfomycin, which significantly reduced bacterial counts in vegetations compared with controls when therapy was begun early (4.1 +/- 1.1 log10 CFU/g of vegetation; P < 0.001 versus the control). These data suggest that combination of fosfomycin with ciprofloxacin or pefloxacin is more effective than ciprofloxacin or pefloxacin alone for the therapy of severe infections caused by multidrug-susceptible P. aeruginosa.
RP 59500 is a new injectable streptogramin composed of two synergistic components (quinupristin and dalfopristin) which are active against erythromycin-susceptible and -resistant gram-positive pathogens. The present experiments compared the therapeutic efficacy of RP 59500 with that of vancomycin against experimental endocarditis due to either of two erythromycin-susceptible or two constitutively erythromycin-resistant isolates of methicillin-resistant Staphylococcus aureus. RP 59500 had low MICs for the four test organisms as well as for 24 additional isolates (the MIC at which 90% of the isolates were inhibited was < 1 mg/liter) which were mostly inducibly (47%) or constitutively (39%) erythromycin resistant. Aortic endocarditis in rats was produced with catheter-induced vegetations. Three-day therapy was initiated 12 h after infection, and the drugs were delivered via a computerized pump, which permitted the mimicking of the drug kinetics produced in human serum by twice-daily intravenous injections of 7 mg of RP 59500 per kg of body weight or 1 g of vancomycin. Both antibiotics reduced vegetation bacterial titers to below detection levels in ca. 70% of animals infected with the erythromycin-susceptible isolates (P < 0.05 compared with titers in controls). Vancomycin was also effective against the constitutively resistant strains, but RP 59500 failed against these isolates. Further experiments proved that RP 59500 failures were related to the very short life span of dalfopristin in serum (< or = 2 h, compared with > or = 6 h for quinupristin), since successful treatment was restored by artificially prolonging the dalfopristin levels for 6 h. Thus, RP 59500 is a promising alternative to vancomycin against methicillin-resistant S. aureus infections, provided that pharmacokinetic parameters are adjusted to afford prolonged levels of both of its constituents in serum. This observation is also relevant to humans, in whom the life span of dalfopristin in serum is also shorter than that of quinupristin.
Aminoglycoside bactericidal activity during the first 24 h of treatment probably is a determining parameter in the prognosis of severe gram-negative infections in immunocompromised patients. To identify the predictive factors involved in the definition of the best therapeutic regimen for Enterobacter cloacae and Serratia marcescens infections, we studied different gentamicin, tobramycin, and amikacin regimens by using an experimental model of rabbit endocarditis. Two factors appear to play an important role in predicting in vivo efficacy: (i) the level of in vivo bactericidal activity, which can differ widely from one aminoglycoside to another for the same bacterial strain and from one strain to another of the same species, and (ii) the critical serum drug concentration (CSC, in milligrams per liter), defined as the lowest serum antibiotic concentration capable of producing a significant CFU reduction (P less than 0.05) in endocarditis vegetations 24 h after the beginning of a continuous infusion. Stepwise regression analysis showed that for gentamicin and S. marcescens, the area under the concentration-time curve above the CSC and then the time above the CSC are the determining parameters for efficacy (R = 0.69; F = 13.5; P = 0.001), whereas for amikacin and S. marcescens, the time above the CSC and then the area under the concentration-time curve above the CSC predict efficacy (R = 0.74; F = 24.0; P = 0.0001). The lowest CSC is that of amikacin (about 8 mg/liter); those of gentamicin and tobramycin are about 15 mg/liter. In severe S. marcescens infections, intermittent amikacin dosing offers excellent bactericidal activity within the first 24 h.
9 elderly and 9 younger adult patients, with proven post-operative lower urinary tract infection were treated with 400 mg of norfloxacin twice daily for 5 days. Pharmacokinetics of norfloxacin were measured on days 1 and 5. Compared to the younger adult patients, the elderly showed a decreased creatinine clearance and, following the last dose on day 5, an increased maximum plasma concentration of norfloxacin, an increased area under the concentration-time curve and a decreased total body clearance of norfloxacin. These results confirm that in elderly, as in younger adult patients, the pharmacokinetics of norfloxacin can be described by a linear model and accumulation of the drug during repetitive multiple doses is predictable. The differences between the two groups cannot be considered as clinically significant so that no dose change would be required in elderly patients within the range of creatinine clearance studied.
Aminoglycosides are usually considered to be concentration-dependent antibiotics and to have similar pharmacodynamic and pharmacokinetic properties. To verify the equivalent activity of the aminoglycosides on a susceptible strain, we tested the killing rate of three aminoglycosides (gentamicin, tobramycin, and amikacin) on one strain of Serratia marcescens both in vitro and in vivo by using a rabbit model of left-ventricle endocarditis. Despite, similar MICs, the time-kill curve of gentamicin was consistently better than those of amikacin and tobramycin, whatever the concentration of each antibiotic used (1, 2, 4, 8, 16, or 32 mg/liter), after a 5-h incubation. The in vivo bacterial reduction in the vegetations was measured 24 h after administration of an intravenous 48-mg/kg bolus of each antibiotic or at the end of a 24-h continuous intravenous infusion of the same dose. Gentamicin was significantly more effective when administered as a bolus than when administered as a continuous infusion (2.8 +/- 0.2 versus 6.4 +/- 1.5 log10 CFU/g of vegetation, respectively; P less than 0.01), whereas amikacin was more effective as a continuous infusion than as a bolus injection (3.6 +/- 2.0 versus 7.5 +/- 1.3 log10 CFU/g of vegetation, respectively; P less than 0.01). Tobramycin was not very effective, whatever the dosage tested (approximately 6.5 to 7 log10 CFU/g). These results suggest that concentration-dependent bactericidal activities, both in vitro and in vivo, may vary greatly among aminoglycosides despite similar MICs.
The in vitro antimicrobial activity of ticarcillin (TICAR), mezlocillin (MEZLO), piperacillin (PIPER), cefoperazone (CPZ), cefotaxime (CTX) and ceftazidime (CAZ), alone and in combination with 8 micrograms/ml of sulbactam (SULB), was studied by agar dilution against TICAR resistant strains isolated in 8 hospitals over a period of 3 months in 1989 (747 enterobacteria, 110 Ps. aeruginosa and 48 Acinetobacter sp.). SULB did not modify the activity of beta-lactam antibiotics against Ps. aeruginosa. The 6 beta-lactam antibiotics SULB combinations were only active for 27% of Acinetobacter SULB sensitive. SULB restored the activity of: MEZLO, PIPER, CPZ in Enterobacteria producing a penicillinase; PIPER, CTX and CAZ in Enterobacteria producing a broad-spectrum beta-lactamase; MEZLO, PIPER, CTX and CAZ in M. morganii producing a derepressed cephalosporinase.
Minimal inhibitory concentrations (MICs) of lomefloxacin (LOM) was determined by agar dilution for 2,819 bacterial strains isolated in 1988 in 9 university hospitals. Activity of LOM against nalidixic acid (NAL) susceptible (S) Enterobacteriaceae was close to that of pefloxacin (PEF) (mode MIC: 0.12-0.25 micrograms/ml); like for PEF, this activity was reduced against NAL resistant (R) Enterobacteriaceae (mode MIC: 4). MICs of LOM against P. aeruginosa were between 0.5 and 16 (mode: 2). LOM had also a good activity against NAL S A. baumannii (mode MIC: 0.5) but this activity is reduced against NAL R Acinetobacter (MICs : 4 to 128). LOM was highly active against Haemophilus (mode MIC: 0.06), Gonococci (mode MIC: 0.008), Meningococci (mode MIC: 0.03), Branhamella (mode MIC: 0.12-0.25). LOM showed activity similar to PEF against methicillin susceptible Staphylococci (mode MIC: 0.5-1); the resistant strains are usually methicillin resistant. Similar to the currently available quinolones, LOM is less effective against L. monocytogenes (mode MIC: 8), Enterococci (mode MIC: 4), Streptococci (mode MIC: 4) and Pneumococci (mode MIC: 8). Finally, for the anaerobic bacteria, LOM is more active against Clostridium perfringens (mode MIC: 1) than against Bacteroides fragilis (mode MIC: 32).
Identification of Mycobacterium species is currently a long and fastidious procedure. We have developed a rapid (5-h) standard method using the API-ZYM system and rapid nitratase, urease and catalase tests. Pigmentation and growth rate were noted (but were only necessary for complete identification of 6% of strains). The tests were assigned numerical values from which a profile number was derived. A total of 716 strains were studied: 434 belonging to the M. tuberculosis complex and 282 other mycobacteria including 21 from M. avium complex. All M. tuberculosis complex strains were differentiated from all other mycobacteria and M. bovis was clearly separated from M. tuberculosis. All M. avium complex strains were differentiated from other mycobacteria. Among mycobacteria other than tubercle bacilli, 97% of the strains studied were identified. The method has proven to be simple, rapid and standardizable. It is suggested that the use of a code list could permit identification of most mycobacteria.
Three hundred fifty-two patients from 20 intensive care units, suffering from pneumonia or nosocomial septicemia were treated at random with either ceftazidime + pefloxacin (CP) or ceftazidime + amikacin (CA). After exclusion of patients who did not comply with the protocol and of cases where no organism was isolated, 108 assessable patients received CP and 114 received CA. The cure rates achieved in infections due to a single organism were 82 per cent in the CA group and 62 per cent in the CP group. In infections due to multiple organisms, the cure rate was 67 per cent with both antibiotic regimens.
The preliminary results obtained in 212 patients from 20 intensive care units, suffering from pneumonia or nosocomial septicemia and treated at random with either ceftazidime + pefloxacin (CP) or ceftazidime + amikacin (CA) were analyzed. After exclusion of patients who did not comply with the protocol and of cases where no organism was isolated, 57 assessable patients received CP and 72 received CA. The cure rates achieved in infections due to a single organism were 85 per cent in the CA group and 63 per cent in the CP group. In infections due to multiple organisms, the cure rate was 74 +/- 2 per cent with both antibiotic regimens.
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In this study measurements were made of the minimal inhibitory concentrations of 6 cephalosporins (cefamandole, cefuroxime, cefadroxil, cefoxatin and cefotaxime in comparison with cefalothin) against 532 bacterial strains isolated at the Regional Hospital Centre, Nantes, France, between 15.12.1977 and 15.3.1978. There were 163 Gram-positive bacteria of 2 species and 369 Gram-negative bacilli of 11 species and different genera. The results have been produced in the form of cumulative curves, in percentage for the most numerous genera or species. Cefalothin remained the most active on S. aureus and Listeria. Cefamandole came second. The action of the four other cephalosporins was very closely related to that in relation to S. aureus. For all the Gram-negative bacilli, Cefotaxime was the most active. Its MIC's can be up to more than 100 times lower than those of the other cephalosporins. Of the others, cefamandole appeared the best. It was difficult to classify the last four, as the MIC's may vary from one bacterial species to another. The bacterial activity (MBC) in a liquid medium was found for 178 of the strains (10 genera or species) of which one was Gram-positive (S. aureus). The ratio MBC/MIC (the measurements were taken in a liquid medium in all cases) confirmed the fact that all the cephalosporins are clearly bactericidal (the ratio was most often equal to 1 and sometimes to 2) for all the Gram-negative bacilli. Cefalothin and cefotaxime appeared the most bactericidal and cefamandole the least.
Development of a strategy for the investigation of pulmonary infectious disease is aimed at identifying the organism responsible for the infection in order to prescribe the appropriate antibiotic therapy. Factors involved in the choice of a method are the underlying condition (healthy, high risk or immunodepressed subject), the type of infection (primary, secondary), the technical abilities of the medical and bacteriological team and finally the value of the different techniques of isolation. The latter must provide a specimen which is not contaminated by the oropharyngeal flora. Their reliability involves definition of a reference method which can be used to test the other techniques in comparison, and requires comparison of the bacteriological results obtained with clinical and radiological data as well as the results of the resultant therapeutic decision. Indirect methods of investigation (blood cultures, serological studies) are relatively unfruitful. Criteria of value of direct methods of investigation are defined and applied to each method (expectoration, transtracheal aspiration, bronchial fibroscopy, transparietal puncture). On the basis of data in the literature and their own results, the authors undertake an analytical then comparative (in a given patient) study of the different methods, and identify their indications.
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The authors studied comparatively the sensitivity of 3 bacterial strains (P. Aeruginosa and two E. coli) with regard to antibiotics using an automatic method (ABAC) compared with a gel diffusion technic with impregnated disks. Each strain was tested by both methods 50 to 55 times. The diffusion method was easily reproducible with an average standard deviation of 2.23 mm. Its results were in agreement compared with the average diameter of measurements in 93.3% of cases. The automatic method gave results which agreed together in 95.7% of cases. It is thus reproducible. If one compares it with the results of the diffusion method, considered here as the reference method, we obtained the same response in 86.3% of cases. In 13.7% there was disagreement in interpretation (in most cases, the strain found intermediate in gel diffusion was considered sensitive on autoanalysis).
The authors compared for routine use, the results obtained on 399 strains of Gram negative bacilli by two technics of antibiotic sensitivity: the technic of gel diffusion with imprenated discs and an automatic method (ABAC apparatus). Among the antibiotics used as a routine in our laboratory by the diffusion method and the 16 studied with the ABAC apparatus, 11 are common to both methods and were compared. The concordance of the results was greater than 90% for colistine (94.5%), oxolinic acid (93.5%), tobramycin (91.7%). It lies between 80 and 90% in the case of carbenicillin (89.1%), nalidixic acid (87.5%), kanamycin (87.2%). It is less in the case of gentamicin (77.9%), ampicillin (77.3%, chloramphenicol (76%), streptomycin (70.3%), minocycline with 55.9% gave the lowest results. The percentage of uninterpretable responses by ABAC was 0.7% for all 11 antibiotics. The correlations were good for the Enterobacteriaceae: Serratia (75.4%), Eschericia coli (87.5%). They are less in the case of Pseudomonas aeruginosa (71.6%). The ABAC makes sensitivity test automatic and appears a reliable method.