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 doripenem against anaerobic bacteria]. / Activité du doripénème sur les bactéries anaérobies strictes.

AIMS OF THE STUDY: This study examines the activity of doripenem, a new carbapenem compound compared with amoxicillin-clavulanic acid, piperacillin+tazobactam, imipenem, clindamycin and metronidazole against 316 anaerobes. METHODS: Inoculum preparation and agar dilution method were performed according to the CLSI method for anaerobes (M11A7). RESULTS: At a concentration of 4µg/ml doripenem and imipenem (IMP) inhibited 122 (96 %) and 126 (99 %) strains of the Bacteroides fragilis group, respectively. In contrast, doripenem appeared more potent than IMP against Gram-positive anaerobes inhibiting at the same concentration of 4µg/ml 145/145 strains (100 %) versus 115/145 for IMP (79.3 %). Against 316 anaerobic strains, the carbapenem doripenem had an MIC(50) of 0.25µg/ml and an MIC(90) of 2µg/ml. Results were similar to those for imipenem (MIC(50) of 0.125µg/ml and MIC(90) of 4µg/ml). If we consider the resistant breakpoints of the two carbapenems as defined by EUCAST, the resistance rate for doripenem (MIC>4µg/ml) 1.6 % is similar to that of imipenem (MIC>8µg/ml) 1.3 %. CONCLUSION: Thus independently of the PK/PD parameters the two carbapenems demonstrated very close activity; doripenem was more potent on Gram-positive anaerobes and slightly less potent against Gram-negative anaerobes mainly the B. fragilis group. Further clinical studies are needed to assess its usefulness in patients.

Penetration of lomefloxacin into bronchial secretions following single and multiple oral administration.

The bronchial penetration of lomefloxacin, a new difluorinated quinolone, was evaluated in 36 patients who underwent bronchoscopies for diagnostic purposes. Patients were randomized into two groups, with 18 patients (Group I) receiving a single oral dose of 400 mg lomefloxacin and 18 patients (Group II) receiving 400 mg twice daily. Samples of serum and bronchial secretions were collected simultaneously in both groups at 1, 2, or 4 hours after lomefloxacin administration. The results of this study showed that bronchial penetration of lomefloxacin was rapid and yielded high concentrations; the mean bronchial levels of the drug reached 2.78 +/- 3.64 micrograms/mL in Group I 1 hour after the dose, and 2.84 +/- 1.73 micrograms/mL in Group II at the fourth hour. The ratio between bronchial and simultaneous serum concentrations was 89% at the first and second hours after the dose for Group I, and it was 77% 4 hours after oral administration in Group II. In comparing these results to previous reports of lomefloxacin penetration into bronchial mucosa or of concentrations of other new fluoroquinolones into bronchial secretions, it is to be noted that the local concentrations of the newer quinolones are of very similar values, ranging from 2.7 micrograms/mL (ofloxacin) to 4.46 micrograms/mL (pefloxacin). This study confirms that lomefloxacin achieves high tissue concentrations in the respiratory tree; this characteristic, together with lomefloxacin's antibacterial spectrum, indicates promise in the treatment of many respiratory infections.

An outbreak of imipenem-resistant Acinetobacter baumannii in critically ill surgical patients.

OBJECTIVE: To describe an outbreak of imipenem-resistant Acinetobacter baumannii (IR-Ab) and the measures for its control, and to investigate risk factors for IR-Ab acquisition. DESIGN: An observational and a case-control study. SETTING: A surgical intensive care unit (ICU) in a university tertiary care hospital. METHODS: After admission to the ICU of an IR-Ab-positive patient, patients were prospectively screened for IR-Ab carriage upon admission and then once a week. Environmental cleaning and barrier safety measures were used for IR-Ab carriers. A case-control study was performed to identify factors associated with IR-Ab acquisition. Cases were patients who acquired IR-Ab. Controls were patients who were hospitalized in the ICU at the same time as cases and were exposed to IR-Ab for a similar duration as cases. The following variables were investigated as potential risk factors: baseline characteristics, scores for severity of illness and therapeutic intervention, presence and duration of invasive procedures, and antimicrobial administration. RESULTS: Beginning in May 1996, the outbreak involved 17 patients over 9 months, of whom 12 acquired IR-Ab (cases), 4 had IR-Ab isolates on admission to the ICU, and 1 could not be classified. Genotypic analysis identified two different IR-Ab isolates, responsible for three clusters. Ten of the 12 nosocomial cases developed infection. Control measures included reinforcement of barrier safety measures, limitation of the number of admissions, and thorough environmental cleaning. No new case was identified after January 1997. Eleven of the 12 cases could be compared to 19 controls. After adjustment for severity of illness, a high individual therapeutic intervention score appeared to be a risk factor for IR-Ab acquisition. CONCLUSION: The outbreak ended after strict application of control measures. Our results suggest that high work load contributes to IR-Ab acquisition.

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.

[Role of cefuroxime-axetil in the treatment of respiratory tract infections. Bacteriological and pharmacological data]. / Place du céfuroxime-axetil dans le traitement des infections respiratoires. Bases bactérologiques et pharmacologiques.

Cefuroxime-axetil, the 1-acetoxyethyl ester of cefuroxime, is a prodrug for oral administration. The indication of this new formulation in the treatment of community acquired RTI required an updating of its activity against respiratory pathogens. A total of 260 isolates were included in a study using MIC determination (agar dilution technique): the mode MICs for Haemophilus spp., Branhamella catarrhalis, streptococci, S. pneumoniae ranged from 0.016 to 0.5 mg/l; no difference was noted between beta-lactamase producers and non producers in Haemophilus and B. catarrhalis; coagulase positive staphylococci, E. coli, K. pneumoniae isolated from RTI exhibited mode MICs not exceeding 4 mg/l (except for methicillin-R staphylococci mode MIC greater than 128 mg/l). Simultaneously the pharmacokinetic parameters were determined in healthy volunteers after a loading dose (500 mg) of the drug: 7 consecutive samples collected after a light meal provided the following data: Cmax = 7.77 +/- 2.2 mg/l; Tmax = 2.33 +/- 0.23 hrs; t1/2 beta = 1.18 +/- 0.19 hrs; AUC = 22.17 +/- 6.4 h.mg/l. Cmax and AUC were half of these values after administration of 250 mg. These results, together with the known intrinsic beta-lactamase stability of cefuroxime, should ensure sufficient in vivo concentrations and effective in vivo antibacterial activity against most respiratory pathogens after oral administration of cefuroxime-axetil.

[Streptpcoccus pneumoniae: current status of its resistance to antibiotics]. / Streptococcus pneumoniae: état actuel de la résistance aux antibiotiques.

A WORLDWIDE ISSUE: Streptococcus pneumoniae is an important pathogen implicated in many illnesses. The susceptibility of this bacteria has greatly changed since 1967 when it was the leading strain resistant to penicillin G. Since that time, the resistance of S. pneumoniae has become a worldwide problem leading to the development of schemes to monitor resistance in different countries. The analysis of these "observation" studies points out the wide variability of resistance to antibiotics depending on the concerned country and region. Amoxicillin, cefotaxim, the new fluoroquinolones and vancomycin have exhibited the best preservation of efficacy worldwide. RESISTANCE IN FRANCE: Pneumococcal resistance is high in France against penicillin, third-generation cephalosporins, and erythromycin. Resistance has however appeared to stabilize since 1997, with the exception of invasive strains which have shown a rising level of penicillin G resistance. A NEW THREAT: Several authors have reported that vancomycin-tolerant strains have a significant clinical importance and must be carefully monitored. Reasonable prescription of antibiotics appears to be more than ever necessary to reduce the selection pressure of antibiotics.

[Ketolides and oxazolidinones. Mechanisms of action and antibacterial spectrum]. / Kétolides et oxazolidinones. Mécanisme d'action et spectre antibactérien.

CHANGING RESISTANCE OF GRAM-POSITIVE COCCI: Several new families of antibiotics are under development in response to the changing resistance of Gram-positive cocci. Linezolide, the leading member of the oxazolidinone family and telithromycin and ABT-773, leading members of the ketolide family have reached an advanced stage of development. INHIBITION OF PROTEIN SYNTHESIS: Oxazolidinones and ketolides inhibit protein synthesis at different levels. Oxazolidinones inhibit formation of the 70S initiation complex and ketolides block the protein elongation step by inhibiting peptidyl transferase. MECHANISMS OF RESISTANCE: To date, no cross resistance of linezolide with other antibiotic families used for the treatment of Gram-positive bacteria has been observed. It is quite difficult to obtain resistant mutants in the laboratory but two point mutations on the 23S ribosome fraction have been described in vivo. Resistance of Gram-positive cocci to macrolides occur via mechanisms altering the target (methylation of 23S rRNA or ribosome protein mutations) or via mechanisms involving active efflux. LINEZOLIDE: Linezolide is highly active in vitro against meticillin-resistant Staphylococcus aureus (MRSA), against Streptococcus including resistant pneumococcal strains, and against glycopeptide-resistant E. faecium and E. faecalis strains. TELITHROMYCIN AND ABT-773: These ketolides are active against Streptococcus and Pneumococcus strains exhibiting erythromycin-inducible resistance and resistance by active efflux. In addition, these antibiotics are highly active against other bacteria causing respiratory tract infections (Moraxella and Haemophilus), anaerobic germs and intracellular germs (Legionella).

[Epidemiology of resistance to antibiotics in respiratory tract infections]. / Epidémiologie de la résistance aux antibiotiques dans les infections respiratoires.

AN EVOLVING PROBLEM: Antibiotic resistance currently concerns H. influenzae, S. pneumoniae, S. pyogenes, M. catarrhalis, all species which are particularly susceptible to beta-lactamines, fluoroquinolones and macrolides. Incidence of resistance has reached high levels in many countries, including France in certain instances. BETA-LACTAMINE RESISTANCE: Penicillin-resistant pneumococci (partial and total resistance) are unequally distributed over the globe. In France the frequency is high, particularly in children. S. pyogenes strains remain sensitive to peni-G. Amino-penicillin resistance of H. influenzae and M. catarrhalis results from enzymatic processes (penicillinase production) and concerns an important proportion of the strains, particularly for M. catarrhalis. FLUOROQUINOLONE-RESISTANCE: Fluoroquinolone resistance is now described for H. influenzae. Though rare, this is a serious problem as it proves that this bacterial species can adapt to new antibiotics used for the treatment of respiratory tract infections. Resistance is acquired by modifying the antibiotic target, DNA gyrase and/or topo-isomerases, enzyme implicated in bacterial DNA. The presence of multiple mutations in the genes coding for these enzymes raises the MIC for fluoroquinolones, including those for the most recent compounds. Streptococci resistance to fluoroquinolones is increasing but no new mechanisms of resistance have been described. MACROLIDE-RESISTANT STREPTOCOCCI: Acquired resistance results either from the presence of erm genes causing a modification in the bacterial ribosome by methylation or by the presence of mef genes coding for efflux proteins. Incidence of macrolide resistance and the distribution of these different mechanisms vary greatly from one country to another. EMPIRICAL TREATMENT OF RESPIRATORY TRACT INFECTIONS: Epidemiological data and the locoregional bacterial ecology must be considered when prescribing an empirical treatment for respiratory tract infections.

[Bacterial resistance and new therapeutic perspectives]. / Résistance bactérienne et nouvelles perspectives thérapeutiques.

A PROGRESSING PHENOMENON: Concern about bacterial resistance to antibiotics is growing steadily as new mechanisms of resistance are regularly detected. Cocci have generally remained very antibiotic-sensitive, but resistance is developing. MACROLIDE-RESISTANT STREPTOCOCCI: Streptococci resistance to macrolides is related either to a change in the target, the bacterial ribosome (usually the case), or to an efflux mechanism pushing the antibiotic out of the bacteria before it reaches the target (a mechanism which has been confirmed in different parts of the world). QUINOLONE RESISTANCE: Resistance to quinolones results from a modification of the target, bacterial topo-isomerases, or via an efflux mechanism described in several Gram positive and Gram negative bacteria. HOPES FOR THE FUTURE: New families of antibiotics are currently under evaluation, particularly compounds directed against bacteria resistant to classically used antibiotics. Likewise, several fluoroquinolones are under development. Most have a wide spectrum including Gram positive cocci, particularly enterococci and strict anaerobic bacteria. A rigorously applied antibiotic prescription policy is however required to control bacterial resistance to antibiotics.

[From the parenchyma to the mucosa biopsy: significance and importance of local assays of antibiotics. A critical study]. / Du parenchyme à la biopsie de muqueuse: signification et portée des dosages locaux d'antibiotiques. Etude critique.

The authors discussed the relevance of antibiotic concentrations as measured in tissues and fluids of the respiratory tract. They analysed theoretical factors which influence tissue distribution of antibiotics as well as the results of studies carried out in animal and in human tissues. Various factors may interfere with the results of antibiotic assays: but the data published by various groups were usually convergent: this confirms the significance of "tissue pharmacokinetics". New protocols based on more refined and reliable techniques were proposed recently, which underlines the attention payed to these studies.

[Blood culture update]. / Actualités sur l'hémoculture.

BACKGROUND: Blood culture is one of the most important bacteriological examinations with important clinical and therapeutic consequences. Blood cultures should be ordered in all patients with signs suggesting septicemia, endocarditis or severe infection (pneumococcal pneumonia, bacterial meningitis with bloodstream dissemination). Blood culture methods have evolved considerably over the last twenty years. After using manual methods for many years, read by non-standardized visual methods, the development of media with defined compositions and supplemented to allow growth of bacteria difficult to culture has been associated with the development of automatic blood culture devices. AUTOMATIC DEVICES: These devices have undergone rapid improvement. Semi-automatic devices (Bactec NR-660) were rapidly followed by completely automatic techniques, including four devices currently available: since 1989 Bio-Argos (Rio-Rad) and Bact/Alert (Organon-Teknika) and in 1993, Bactec 9240 (Becton-Dickinson) and Vital (BioMérieux). All these devices allow automatic detection of CO2 produced during bacterial growth. Automatic reading systems provide continuous output avoiding the need for invasive methods and thus the risk of contamination in addition to saving time. Potential application to achieve quantitative blood cultures for intensive care units is in the development stage. CONSEQUENCES: The reliability of these devices is well recognized and their contribution to severe bacterial infection is undeniable. There are certain limitations however related to material cost and the non-identification of the pathogen involved. Molecular biology techniques open new perspectives in this field. The evolution of techniques, definitions, and pathogenic approach to septicemia must be revisited as new infectious situations have been identified at the same time as new investigation tools resulting from considerable technological progress. New methods of blood culture have largely contributed to this progress.

[Nosocomial infections caused by Acinetobacter. Epidemiology and therapeutic difficulties]. / Infections nosocomiales à acinetobacter. Epidémiologie et difficultés thérapeutiques.

Nosocomial infections due to Acinetobacter calcoaceticus are not easy to treat particularly in intensive-care and surgical units. Our study included 33 cases of nosocomial infections which developed during 1987 in the surgical intensive care unit and in the urology department. Acinetobacter was isolated from various types of nosocomial infections: urinary tract infections (43 per cent); septicaemia (15 per cent); surgical infections (27 per cent) and respiratory tract infections (15 per cent). Forty eight per cent of the patients received an antibiotic therapy and 52 per cent had no specific treatment. The following beta-lactam antibiotics were studied: ticarcilline, mezlocilline, cefotaxime and ceftazidime, and 83 per cent of the strains were TICRMEZRCTXR (phenotype IV). All the strains except one were imipenem susceptible. The study of aminoglycoside resistance in Acinetobacter showed that 91 per cent of the strains were gentamicin resistant (GENR); 25.5 per cent were gentamicin, and amikacin resistant and tobramycin susceptible (GENR AMKR TOBS, phenotype IV), and 45 per cent were GENR TOBR AMKR (phenotype V). Acinetobacter strains were resistant and 63 per cent pefloxacin resistant. Co-trimoxazole resistant strains represented 65 per cent of the strains. Should major antibiotics be used to treat nosocomial infections due to multiresistant Acinetobacter strains? Are prophylaxis, aseptic and surgical procedures sufficient to control these infections?

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.

[Present status of nitroxoline]. / Actualité de la nitroxoline.

Nitroxoline (8-hydroxy-5-nitroquinoline) has been used since 1962 in the treatment of urinary tract infections especially those due to gram negative bacilli (E. coli). The current renewal of the drug is in relation to the recently shown activity of nitroxoline against fungi (Candida, Torulopsis), Mycoplasma and U. urealyticum, as well as Trichomonas. In order to update the knowledge of the drug, the aim of this study was a pharmacokinetic study in serum and urines collected after administration of one single dose (2 X 100 mg) and after multiple doses (200 mg X 3). Eight healthy volunteers were included in the study. The assays were carried out by means of the microbiological procedure and HPLC comparatively in the same samples. From the results several comments should be made: 1) In all subjects, serum levels were measurable 15 to 30 min. after administration, suggesting a rapid absorption. 2) Despite individual variations due to oral administration, pharmacokinetic parameters could be calculated: Tmax: 1.75 +/- 1.04 h; Cmax: 5.59 +/- 3.15 mg/l; t 1/2 beta: 2.63 +/- 2.66 h. 3) The hepatic metabolization of the drug into conjugated derivatives occurs early as shown by early levels of conjugated nitroxoline as measured by means of HPLC; the metabolization seems to be variable according to the subjects quantitatively and as for its kinetics. 4) The urinary elimination of nitroxoline is extremely rapid, and high levels of free drug and conjugated derivatives were measured at the 1st hour after the administration. Persistent high levels were measured at the 10th and 24th hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue kinetics of telithromycin, the first ketolide antibacterial.

The potential efficacy of an antibacterial depends not only on its spectrum of activity but also on its concentration at the site of infection. The tissue kinetics of telithromycin-the first ketolide antibacterial-are reviewed here. Telithromycin accumulates rapidly in white blood cells, inflammatory fluid, and cells and tissues of the upper and lower respiratory tract, with mean concentrations above the MICs of key respiratory pathogens. Tissue kinetics of telithromycin support facilitated delivery to the site of infection, good efficacy against intracellular respiratory pathogens and respiratory pathogens at extracellular sites in the airways, and effectiveness in the treatment of upper and lower respiratory tract infections (RTIs). The tissue kinetics profile of telithromycin, together with its microbiological profile, makes it a promising new antibacterial for the treatment of community-acquired RTIs.

Concentration of meropenem in serum and in bronchial secretions in patients undergoing fibreoptic bronchoscopy.

The objective of the study was to evaluate the ability of meropenem to reach the bronchial lumen. 24 patients undergoing fibreoptic bronchoscopy for exploratory purposes were given a single dose of meropenem 1 g as an (i.v., infusion over 30 min. Plasma (P) sampling times were: 0, 0.5, 1, 2 and 3 h. Bronchial secretions (BS) were collected by fibreoptic bronchoscopy at the same sampling times (except for 0 and 0.5 h) in three groups of 8 patients. Meropenem was measured by bioassay using E. coli ATCC 39118 as the test-organism. The results showed that meropenem had reached a high plasma concentration at the first sampling time (59.8 mg.l-1) and then the plasma level decreased rapidly to 10.6 mg.l-1 and 2.7 mg.l-1 at 2 and 3 h respectively. The highest concentration achieved in bronchial secretion was 0.53 mg.l-1 in the third hour, ie 20% of the serum level. The data indicate significant penetration of meropenem into bronchial secretions and achievement of a local level sufficiently high to eradicate most respiratory pathogens.

Penetration of piperacillin-tazobactam into bronchial secretions after multiple doses to intensive care patients.

The penetration of piperacillin-tazobactam in eight mechanically ventilated intensive care patients (age, 56.0 +/- 12.2 years, and weight, 76.5 +/- 15.2 kg [means +/- standard deviations]) with bacterial pneumonia was investigated. They were given intravenous doses of piperacillin (4 g) and tazobactam (0.5 g) as 30-min infusions every 6 h. The kinetic study was performed after the fourth dose on day 2 of treatment. Samples of blood and bronchial secretions (BS) were collected before the fourth dosing and 0.5, 1, 2, 4, and 6 h after the end of infusion. Drug concentrations in both sera and BS were measured by high-performance liquid chromatography. Concentrations (in micrograms per milliliter) in serum were 184.80 +/- 63.03 and 40.03 +/- 30.79 for piperacillin and 23.05 +/- 7.53 and 4.86 +/- 4.54 for tazobactam at 0.5 and 6 h, respectively, after the end of infusion. The corresponding concentrations (in micrograms per milliliter) in BS were 29.33 +/- 25.08 and 20.25 +/- 19.11 for piperacillin and 6.86 +/- 4.25 and 4.25 +/- 2.78 for tazobactam. The percentages for the extent of penetration of piperacillin and tazobactam, as defined by the BS/serum area under the curve ratio, were 35.70 and 78.42%, respectively. These data indicate good penetration of both piperacillin and tazobactam into BS. The concentrations of tazobactam in BS are persistent and high enough to exceed the values found to be effective in vitro against the tazobactam-susceptible beta-lactamases produced by the most important pathogens responsible for nosocomial pneumonia.

Trometamol-fosfomycin (Monuril) bioavailability and food-drug interaction.

A new water-soluble monobasic salt of fosfomycin with trometamol has recently been developed for oral administration. The objective of this study was to evaluate the pharmacokinetics of trometamol-fosfomycin (Monuril) in serum and in urine in 10 healthy volunteers after oral administration of one single dose (50 mg/kg). In the same volunteers the concentrations of fosfomycin were measured before and after food absorption, in serum and urine samples taken at t = 0, 2, 4, 6, 8 and 24 h after the dose (plus 0.5 and 1 h for serum samples). The measurement of fosfomycin levels was carried out by means of a microbiological procedure using Proteus mirabilis ATCC 21100 as test organism. The results indicated at 2 or 4 h serum peak levels ranging from 9 to 28 micrograms/ml, with mean values of about 17-21 micrograms/ml. The urine concentrations reached 2,000-2,500 micrograms/ml at 2 h, with high levels maintained till the 8th hour (1,200-2,750 micrograms/ml) and persistence of noticeable concentrations at 24 h (100-700 micrograms/ml). The influence of food absorption, even variable, decreased significantly the rate of absorption, with lower serum and urine levels, as measured in the same volunteers. Taking into account this factor influencing the bioavailability and the distribution of the drug, the results of the study confirm that a high proportion of the oral dose of trometamine salt of fosfomycin is absorbed; the extremely high urinary recovery of the drug even after food administration could certainly allow short-course therapy or even single-dose therapy in the treatment of uncomplicated urinary tract infection.