In vitro antibacterial activity of doripenem against clinical isolates from French teaching hospitals: proposition of zone diameter breakpoints.

The aims of the study were to determine the in vitro activity of doripenem, a new carbapenem, against a large number of bacterial pathogens and to propose zone diameter breakpoints for clinical categorization in France according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) minimum inhibitory concentration (MIC) breakpoints. The MICs of doripenem were determined by the broth microdilution method against 1,547 clinical isolates from eight French hospitals. The disk diffusion test was performed (10-µg discs) according to the Comité de l'Antibiogramme de la Société Française de Microbiologie (CASFM) method. The MIC(50/90) (mg/L) values were as follows: methicillin-susceptible Staphylococcus aureus (MSSA) (0.03/0.25), methicillin-resistant Staphylococcus aureus (MRSA) (1/2), methicillin-susceptible coagulase-negative staphylococci (MSCoNS) (0.03/0.12), methicillin-resistant coagulase-negative staphylococci (MRCoNS) (2/8), Streptococcus pneumoniae (0.016/0.25), viridans group streptococci (0.016/2), ß-hemolytic streptococci (≤0.008/≤0.008), Enterococcus faecalis (2/4), Enterococcus faecium (128/>128), Enterobacteriaceae (0.06/0.25), Pseudomonas aeruginosa (0.5/8), Acinetobacter baumannii (0.25/2), Haemophilus influenzae (0.12/0.25), and Moraxella catarrhalis (0.03/0.06). According to the regression curve, the zone diameter breakpoints were 24 and 19 mm for MICs of 1 and 4 mg/L, respectively. This study confirms the potent in vitro activity of doripenem against Pseudomonas aeruginosa, Acinetobacter, Enterobacteriaceae, MSSA, MSCoNS, and respiratory pathogens. According to the EUCAST MIC breakpoints (mg/L) ≤1/>4 for Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter, and ≤1/>1 for streptococci, pneumococci, and Haemophilus, the zone diameter breakpoints could be (mm) ≥24/<19 and ≥24/<24, respectively.

Activity of linezolid against Gram-positive cocci isolated in French hospitals as determined by three in-vitro susceptibility testing methods.

In total, 844 strains of Gram-positive cocci were collected from six university hospitals in France between September 1999 and January 2000. MICs of linezolid were determined: (i) for all strains by agar dilution (method A); (ii) by broth microdilution (method B) for staphylococci and enterococci; (iii) by Etest (method E) for beta-haemolytic streptococci and Streptococcus pneumoniae. Susceptibility to other antibiotics was determined by the disk diffusion method. MIC50 and MIC90 values were identical (2 mg/L) for methicillin-susceptible Staphylococcus aureus (n = 179) by methods A and B. Linezolid was active against methicillin-resistant S. aureus (n = 117), with an MIC90 of 2 mg/L (methods A and B), but with a lower MIC50 of 1 mg/L by method A. Of the 200 coagulase-negative staphylococci, 56.5% were methicillin-resistant and 43.5% were methicillin-susceptible. Linezolid had similar in-vitro activity by methods A and B (MIC50 and MIC90 values of 1-2 mg/L), irrespective of methicillin susceptibility. The MIC90 of linezolid for all enterococci (150 Enterococcus faecalis and 50 Enterococcus faecium) was 2 mg/L by both methods. MICs of linezolid for beta-haemolytic streptococci had a narrow range of 0.5-2 mg/L (method A) and 0.125-2 mg/L (method E). Pneumococci (n = 118), including 67 penicillin G-intermediate and -resistant strains, were all inhibited by linezolid 2 mg/L (MIC90 of 2 mg/L by methods A and E). No strain had an MIC of > 2 mg/L by agar dilution or Etest, or of > 4 mg/L by broth microdilution. Overall, the study confirmed the good in-vitro activity of linezolid and the very narrow range of MICs for Gram-positive cocci susceptible or resistant to other antibiotics, irrespective of the method used.

Pharmacokinetics and pharmacodynamics of two oral forms of cefuroxime axetil.

Cefuroxime axetil is a cefuroxime ester that can be administered by mouth. Two dosage forms (tablets and granules) have been developed for oral administration. We evaluated the pharmacokinetics and pharmacodynamics of these forms in an open cross-over study involving 12 healthy volunteers receiving single doses of 250 mg. The bioavailability of the two forms was different, the observed peak concentration and time-concentration curve values of the tablet form being, respectively, 39 and 27% higher than those of the granule form. However, ex vivo studies of serum bactericidal activity against Streptococcus pneumoniae showed no significant differences between the two formulations. This is in keeping with the fact that the bactericidal activity of samples from only six subjects gave evaluable data for Haemophilus influenzae; although small differences were found between the two formulations, further investigations are required. The pharmacodynamic approach is becoming an essential element in determining the equivalence of antibiotic dosage forms.

Actinomycosis of the gallbladder due to Actinomyces naeslundii.

We report two cases of actinomycosis of the gallbladder due to Actinomyces naeslundii. Both patients presented with acute cholecystitis. After cholecystectomy with the removal of gallstones each patient made an uneventful recovery. The literature on cholecystitis due to Actinomyces is reviewed.

A new approach to optimal antibiotic dosage regimen by coupling pharmacokinetics and killing curve parameters.

Antibiotic therapy is directed against bacteria responsible for infectious pathology which are able to resist treatment mainly when the dosage is misadapted. The choice of the initial dosage regimen actually takes into account toxicological, bacteriological and pharmacokinetic parameters. The determination of the classical bacteriological data is performed in vitro using fixed drug concentrations that are far from human therapy conditions, and moreover the efficiency is not well defined. The estimation of the pharmacokinetic parameters is realized in animals, healthy subjects or ill patients but takes into account only the drug disposition without correspondence with the kinetics of the antibiotic effect on the bacteria. Thus, each type of evaluation is made independently from the others without any correlation between the observed phenomena. It appears, therefore, interesting to propose a new approach including pharmacokinetic and bacteriological data to enable approximation of drug efficacy. The coupled evaluation of individual pharmacokinetic estimation and the killing curve determinations of an antibiotic will allow this type of development. On the basis of these data, a preliminary profile of the optimal dosage would be possible. This methodology has been applied to three antibiotics: teicoplanin, amikacin and ofloxacin and demonstrates a time- or dose-dependent activity, with interesting possibilities for optimization of dosage.

[Detection of anaerobes by direct immunofluorescence on clinical samples : evaluation of fluoretec F and M (author's transl)]. / Détection des anaérobies par immunofluorescence directe sur les prélèvements cliniques : évaluation des fluoretec F et M.

Immunofluorescence is a method allowing rapid identification of bacteria. The authors study two reagents. Fluoretec F and M, respectively detecting bacteroidis fragilis and bacteroidis melaninogenicus. These reactions were carried out directly on the clinical specimens. After a study carried out with 132 clinical specimens, by comparison with the usual techniques for isolation and identification, the following results were seen : Fluoretec F showed 89 p. cent concordance, 0.8 p. cent false negatives and 3 p. cent false positives. In 7.2 p. cent of cases, the type of discordance could not be determined. Fluoretec M showed 87.8 p, cent concordance, 6.1 p. cent false negatives, 0.8 p. cent false positives and in 5.3. p. cent of cases, the discordance could not be specified. Application of direct immunofluorescence for these two specific tests allowed rapid orientation of diagnosis and allowed evaluation of reliability of culture techniques.

[Microbiologic criteria of the choice of antibiotic for antibiotic prophylaxis in surgery]. / Critères microbiologiques du choix d'un antibiotique pour l'antibioprophylaxie en chirurgie.

The choice of an antibiotic for antimicrobial prophylaxis is based on microbiological, pharmacokinetic, chemical and pharmacodynamic parameters. The knowledge of the bacterial flora allows the identification of bacteria which could be responsible for postsurgical infections. These floras are complex and their equilibrium can be modified by various factors, such as hospitalization, co-existing disease, medico-surgical procedure, administration of antibiotics, which cause the selection of the so-called hospital-bacteria feared by therapists. The infection will develop according to the quantity of bacteria that have been introduced and to their virulence, which is often altered by local factors, especially the biomaterials. The knowledge of pharmacodynamic parameters such as bactericidal activity, postantibiotic effect, activity on virulence factors (bacterial adhesion), allows the refinement of the choice of the antibiotic and the optimization of its posology.

[Pharmacokinetics of azlocillin in the burn patient]. / Pharmacocinétique de l'azlocilline chez le brûlé.

Pharmacokinetic values of azlocillin were determined in burned patients during the exudation and repair periods. A single dose of 80 mg/kg was administered intravenously over 30 min. Pharmacokinetic constants were calculated using an open two-compartment model. During the exudation period the ultimate serum half-lives (t 1/2 beta) were 1.17 to 1.4 h, 1.73 to 1.78 h and 3.3 h respectively with creatinine clearances of 111-131, 60-94 and 14 ml/min/1.73 m2. Renal clearances varied from 30.9 to 128 ml/min/1.73 m2. During the repair period little change was observed in t 1/2 beta, but renal clearance increased from 36.6 to 116 ml/min/1.73 m2 in one patient. It is concluded that azlocillin behaves in burned patients as in patients with impaired renal function.

[Theoretical bases for the combination of ceftazidime with other antibiotics. Synergism research]. / Bases théoriques de l'association de la ceftazidime avec les autres antibiotiques. Recherche de synergie.

Combinations of antibiotics have always been difficult to study, and the available methods often give discordant results making interpretation uneasy in the absence of in vitro-in vivo correlations. By studying the bactericidal effects of combinations a better definition of interactions between two antibiotics can be obtained if the concept of dominance is taken into account. Ceftazidime, a time-dependent antibiotic, acts synergistically with aminoglycosides, notably against moderately sensitive strains. This synergistic effect results from acceleration of the early bacterial kill and from blockage of the late regrowths. With quinolones, the synergistic effect does not result from blockage of late regrowths. However, the significance of these results needs to be confirmed by clinical trials.

[Antibacterial effects of the combinations of azlocillin with other antibiotics]. / Effets antibactériens des associations d'azlocilline avec d'autres antibiotiques.

Evaluating the synergistic effects of antibiotic associations is by no means an easy task owing to the diversity of the test methods utilized for this purpose. Data extracted from 11 reports published between 1975 and 1982 and concerning associations of azlocillin with various aminoglycosides (gentamicin, sisomycin, netilmicin, amikacin, tobramycin and dibekacin) and with two beta-lactam antibiotics (cloxacillin and cefotaxime) are reviewed in this article. On the whole, a synergistic effect against Staphylococcus aureus, Pseudomonas aeruginosa and Enterobacteriaceae was most frequently observed with the azlocillin-aminoglycoside association. This effect was usually more pronounced with organisms showing low sensitivity to azlocillin and less pronounced with organisms resistant to aminoglycosides. As often pointed out, there is no general rule that would help predict with certainty from the sensitivity of a strain whether or not any given antibiotic association will act synergistically on that strain.

[Bactericidal effect of piperacillin alone and combined]. / Activité bactéricide de la pipéracilline seule et associée.

The bactericidal activity of piperacillin was evaluated by the kill rate kinetics method. Piperacillin compared with amoxicillin, amdinocillin, mezlocillin, cefotaxime, ceftazidime and latamoxef. Against E. coli, piperacillin and antibiotics electively bound to penicillin-binding protein (PBP) 3 had the same, mainly time-dependent, bactericidal activity. Antibiotics bound to PBP 1 and 2 mainly have a dose-dependent activity. The bactericidal activity of piperacillin against E. coli was enhanced when the drug was combined with amoxicillin and amdinocillin; in contrast, the kill rate remained unmodified when piperacillin was combined with latamoxef. When the piperacillin-amikacin combination was tested against Pseudomonas aeruginosa, Enterobacter cloacae, Escherichia coli and Serratia marcescens, early synergism (5th hour), was weak, but after 24 hours piperacillin reduced the regrowth observed with the aminoglycoside, and synergism was much more pronounced irrespective of the species investigated.

[Treatment of exacerbations of chronic obstructive pulmonary disease with pristinamycin]. / Traitement des exacerbations de broncho-pneumopathie chronique obstructive (BPCO) par la pristinamycine.

BACKGROUND: Pristinamycin is a bactericidal antibiotic whose spectrum covers the main respiratory pathogens including S. pneumoniae poorly sensitive to penicillin. It has not yet been evaluated in short course treatment of acute exacerbations of chronic obstructive bronchitis (AECB). METHODS: 476 patients suffering from an AECB were randomised to either a short course of pristinamycin, 3 G daily for 4 days, or conventional treatment with co-amoxiclav (AAC) 2G daily for 8 days. The duration of follow-up was 6 months. RESULTS: The clinical success rate at 21 days was the same in both groups at 87.2% and 87.9%, CI95% [-7.0%, 6.0%], in the protocol population (FEV1<80%). Among the 120 patients in whom a bacterial pathogen was isolated at the time of inclusion a satisfactory bacteriological response was obtained in 84.6% of the PRI patients against 78.2% of the AAC patients. The time to relapse was comparable with a relapse rate of 25% reached in 128 days in the PRI group and 125 days in the AAC group. Treatment related side effects occurred in 9.2% of the PRI group and in 10.6% of the AAC group. CONCLUSION: Pristinamycin 3 G daily for 4 days is as effective and well tolerated as co-amoxiclav 2G daily for 8 days in the treatment of AECB.

[Critical serum concentration of antibiotics. A therapeutic tool and means of comparative evaluation]. / La concentration sérique critique des antibiotiques. Outil thérapeutique et moyen d'évaluation comparative.

It is difficult to predict the clinical activity of antibiotics solely on the basis of in vitro data. Experimental models measuring the relationship between serum concentration and in vivo activity are essential for comparing the activity of different compounds currently available. The critical serum concentration can be used to compare the intrinsic activity of antibiotics on a given bacterial strain. When compared with the minimal inhibiting concentration measured in vitro, "activity loss" can be determined for each antibiotic placed in contact with bacteria in an infected tissue. The relevance of this therapeutic tool in comparison with other methods is discussed.

[Triclocarban antibacterial activity on resistant staphylococci, streptococci, and enterococci]. / Activité antibactérienne du triclocarban sur les staphylocoques, entérocoques et streptocoques résistant.

Triclocarban is an antiseptic of the anilide family. Its antibacterial activity was re-assessed in vitro against various susceptible and antibiotic resistant staphylococcus, streptococcus, and enterococcus strains. The results of this study show that, in vitro, the effectiveness of triclocarban antibacterial is maintained at very low MICs ranging from 0.5 to 8 mg/L for the various resistant strains studied. Triclocarban remains still very effective for the treatment of either initially bacterial skin and mucosal infections, or skin and mucosal at risk of super infection.

In vitro antibacterial activity of ceftobiprole against clinical isolates from French teaching hospitals: proposition of zone diameter breakpoints.

The aims of this study were to determine the in vitro activity profile of ceftobiprole, a pyrrolidinone cephalosporin, against a large number of bacterial pathogens and to propose zone diameter breakpoints for clinical categorisation according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) minimum inhibitory concentration (MIC) breakpoints. MICs of ceftobiprole were determined by broth microdilution against 1548 clinical isolates collected in eight French hospitals. Disk diffusion testing was performed using 30 µg disks according to the method of the Comité de l'Antibiogramme de la Société Française de Microbiologie (CA-SFM). The in vitro activity of ceftobiprole, expressed by MIC(50/90) (MICs for 50% and 90% of the organisms, respectively) (mg/L), was as follows: meticillin-susceptible Staphylococcus aureus, 0.25/0.5; meticillin-resistant S. aureus (MRSA), 1/2; meticillin-susceptible coagulase-negative staphylococci (CoNS), 0.12/0.5; meticillin-resistant CoNS, 1/2; penicillin-susceptible Streptococcus pneumoniae, ≤ 0.008/0.03; penicillin-resistant S. pneumoniae, 0.12/0.5; viridans group streptococci, 0.03/0.12; ß-haemolytic streptococci, ≤ 0.008/0.016; Enterococcus faecalis, 0.25/1; Enterococcus faecium, 64/128; Enterobacteriaceae, 0.06/32; Pseudomonas aeruginosa, 4/16; Acinetobacter baumannii, 0.5/64; Haemophilus influenzae, 0.03/0.12; and Moraxella catarrhalis, 0.25/0.5. According to the regression curve, zone diameter breakpoints could be 28, 26, 24 and 22 mm for MICs of 0.5, 1, 2 and 4 mg/L respectively. In conclusion, this study confirms the potent in vitro activity of ceftobiprole against many Gram-positive bacteria, including MRSA but not E. faecium, whilst maintaining a Gram-negative spectrum similar to the advanced-generation cephalosporins such as cefepime. Thus ceftobiprole appears to be well suited for the empirical treatment of a variety of healthcare-associated infections.