[Pharmacologic innovations, the fluoroquinolone model]. / Innovations pharmacologiques, le modèle des fluoroquinolones.

OBJECTIVES: Like all the disciplines involved in infectious diseases and antibiotic therapy, pharmacokinetics and pharmacodynamics (PK/PD) of antibiotics have evolved significantly. They include new investigation procedures like in vitro models and new animal models. There is a current trend towards better methods, newer definitions and improved quality of research in this particular field. DEFINITIONS: The current evolution of pharmacology of antibiotics is mainly characterized by the development of pharmacodynamics (PD) which offers the advantage of including microbiology data. New PD parameters have been defined. It is recommended to working groups involved in PK/PD research to compare their results and tend to a consensus on the methods to be used. CONCLUSION: Benefiting from such progress, preclinical phases of PK/PD studies of new molecules as well as revision of older antibiotics permit a rigorous and clinical approach to the use of antibiotics.

[Latest news on fluoroquinolones]. / Dernières nouvelles des fluoroquinolones.

THE AIMS OF NEW FLUOROQUINOLONES: Are to widen the antimicrobial spectrum and eventually reach anaerobic bacteria, to increase the activity on resistant Gram positive bacteria and to enhance the affinity of the molecule for the target enzymes of the bacteria THE EXPECTATIONS WITH THE NEW QUINOLONES: Globally, the tests conducted show far superior activity than that of the agents used for comparison. CONCERNING THE OLDER FLUOROQUINOLONES: Despite the threat of emergence of resistance in pneumococci, questions are raised on the clinical correspondence of the microbiological data obtained, notably with the rates of therapeutic failure, observed in patients exhibiting strains with supposedly high MICs.

[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.

[Epidemiology and management of suspected pneumonia in nursing home residents]. / Epidémiologie et prise en charge des pneumopathies suspectées en maison de retraite.

OBJECTIVE: We conducted a descriptive epidemiology study to examine the conditions of management of infectious lung disease in institutionalized elderly populations (population profile, diagnostic and therapeutic modalities) and to analyze the general and mental consequences in terms of independence (impact of the infectious event on the subject's life style). PATIENTS AND METHODS: A pragmatic survey was conducted by a multicentric observatory composed of 573 general practitioners, practicing in nursing homes. The series included 1790 patients aged over 70 years and residing in nursing homes who developed infectious lung disease over a 10-month period. The MMSE score was used to assess mental status and the Barthel index to assess functional handicap. Each patient was evaluated at the time of the final diagnosis (prescription of an antibiotic or decision for hospitalization) and at most 3 days after the end of this treatment or at discharge from hospital. RESULTS: The elderly population (84 +/- 7 years) was predominantly composed of women. The patients were treated for an acute respiratory infection considered in 30% of the cases to be acute lobar pneumonia. Subgroups of patients were identified for analysis: death (3.7%), x-ray confirmation of the diagnosis (11.5%), hospitalized patients (10.2%). In addition to major deterioration of the general health status, a consequence of the infection more than of the severity of the respiratory symptoms, the development of an acute episode coincided with reduced intellectual functions and onset of a state of confusion. In 70% of the cases, this resulted in a loss of independence of variable importance--simple difficulty for moving around to major functional handicap. The infectious episode was cured or improved (persistence of minor signs not requiring specific treatment) in 94.3% of the cases with appropriate antibiotics: single-drug regimen in 93.7% give per os (75%) or intravenously (25%) using aminopenicillin (with or without a beta lactamase inhibitor) in 80% of the cases. Antibiotic treatment was associated with physical therapy in more than half the cases, and with general conticosteroids in 40%. The treatment scheme was modified in 9.4% of the cases (change of antibiotic in 6%). CONCLUSION: This survey confirms the high risk related to general conditions in elderly institutionalized patients who develop respiratory infection. More than the infection itself, the rapid degradation of the general health status, or decompensation of comorbid states can create life-threatening situations or favor the development of irreversible handicaps.

Guidelines on antimicrobial chemotherapy for prevention and treatment of infections in the intensive care unit.

Severe infections (SIs) in Intensive Care Units (ICUs) constitute difficult therapeutic problems confronting clinicians who deal with severely ill patients. Some SIs are opportunistic infections acquired either in the community or in hospitals, particularly in immunodepressed patients. The great majority of ICU infections are of nosocomial origin. Resistant organisms have led to changing antibiotic therapy in ICU infections. Before microbiology is available, empiric therapy is based on: (i) proper identification of bacterial risks in each infection site; (ii) local surveillance of frequent nosocomial organisms/susceptibility patterns in the ICU; (iii) identification of environmental risk factors and the patient's underlying condition. In documented infection, antibiotic therapy must take into account gram-positive vs gram-negative bacteria or mixed infections, pharmacokinetics/pharmacodynamic parameters of chosen antibiotic(s) and concentrations at the infection site, in order to prevent selection of resistant mutants and to provide the most efficient antibiotic therapy. With increasingly sophisticated intensive care measures, invasive exploratory procedures, and surgical procedures, evolving profiles of hospital infections require updated Guidelines for treatment of severe infections in ICUs. Preventive and therapeutic strategies include control of antibiotic use, and suitable antibacterial treatments which result in shortened hospital stay, improved outcome of hospital infections and significant cost savings.

Treatment and prevention of antibiotic associated diarrhea.

Mild or severe episodes of antibiotic-associated diarrhea (AAD) are common side effects of antibiotic therapy. The incidence of AAD differs with the antibiotic and varies from 5 to 25%. The major form of intestinal disorders is the pseudomembranous colitis associated with Clostridium difficile which occurs in 10-20% of all AAD. In most cases of AAD discontinuation or replacement of the inciting antibiotic by another drug with lower AAD risk can be effective. For more severe cases involving C. difficile, the treatment of diarrhea requires an antibiotic treatment, with glycopeptides (vancomycin) or metronidazole. Another approach to AAD treatment or prevention is based on the use of non-pathogenic living organisms, capable of re-establishing the equilibrium of the intestinal ecosystem. Several organisms have been used in treatment or prophylaxis of AAD such as selected strains of Lactobacillus acidophilus, L. bulgaricus, Bifidobacterium longum, and Enterococcus faecium. Another biotherapeutic agent, a non-pathogenic yeast, Saccharomyces boulardii has been used. In animal models of C. difficile colitis initiated by clindamycin, animals treated with S. boulardii (at end of vancomycin therapy) had a significant decrease in C. difficile colony-forming units, and of toxin B production. In several clinical randomised trials (versus placebo), S. boulardii has demonstrated its effectiveness by decreasing significantly the occurrence of C. difficile colitis and preventing the pathogenic effects of toxins A and B of C. difficile. It has been shown to be a safe and effective therapy in relapses of C. difficile colitis. A good response has been seen in children with AAD, treated by S. boulardii only. In ICUs prevention of AAD remains based on limitation of antibiotic overuse and spread of C. difficile or other agents of AAD should be prevented by improved hygiene measures (single rooms, private bathrooms for patients, use of gloves and hand washing for personnel). In addition the increasing use of biotherapeutic agents such as S. boulardii should permit the prevention of the major side effect of antibiotics, i.e. AAD in at risk patients.

[Resistance and new antibiotic strategies. New antistaphylococcal antibiotics]. / Résistances et nouvelles stratégies antibiotiques. Nouveaux antibiotiques antistaphylococciques.

INJECTABLE SPECTROGRAMIN: Combination regimens using quinupristin/dafopristin with either gentamicin or vancomycin have powerful bactericidal activities (even against quinupristin-resistant strains) against methicillin-resistant Staphylococcus aureus (MRSA) in a model of experimental endocarditis in the rabbit. In clinical trials, quinupristin/dalfopristin is becoming a therapeutic alternative to consider after failure of conventional antistaphylococcal treatments. NEW GENERATION CEPHALOSPORINS: These new cephalosporins, particularly C-3 pyridinium-thiomethyl-cephalosporins, new (3-dithiocarbamoyl) cephalosporins, and a series of new compounds with high affinity for MRSA PLP2a, are particularly active against MRSA and are unaffected by beta-lactamases. A NEW CARBAPENEM: This new antibiotic has a wide bactericidal effect against Gram-positive organisms and is active against MRSA as well as penicillin-resistant S. pneumoniae. NEW FLUOROQUINOLONE DERIVATIVES: In vitro, these new derivatives have been found to be active against MRSA, pneumococci non-sensitive to ciprofloxacin, and Bacteroides fragilis, Mycobacterium tuberculosis, Chlamydia pneumoniae.

[Resistance and new antibiotic strategies. The other new molecules]. / Résistances et nouvelles stratégies antibiotiques. Les autres molécules nouvelles.

ANTI-PNEUMOCOCCAL DRUGS: New fluoroquinolones with different targets than earlier compounds have been found to be active in certain cases of respiratory tract pneumococcal infections. Moxifloxacin, levofloxacin and gatifloxacin have been particularly effective. These new antibiotics can be classed in a new category of "respiratory quinolones". EFFLUX PUMP INHIBITORS: The bacterial efflux systems are complex resistance mechanisms allowing the bacteria to expulse certain antibiotics belonging to several drug families and thus to develop multiple resistance capacities. A new series of efflux pump inhibitors has been recently synthesized. Associated with an antibiotic (levofloxacin, macrolide) these inhibitors significantly increase antibacterial activity. BACTERIAL WALL INHIBITORS: These compounds target the biosynthesis units of the bacterial walls, inhibiting for example bacterial enzyme Mur A. CYCLIC LIPOPEPTIDES: These include daptomycin which acts on peptidoglycan synthesis in the bacterial wall via a mechanism different from that of glycopeptides. NEW BETA-LACTAMS: Faropenem is a new member of the penem family. Ceftidoren is an oral cephalosporin that gives 64 to 70% cure after 7 to 10 days in cases of acute maxillary sinusitis and 81 to 83% in exacerbations of acute bronchial infections. In streptococcal pharyngitis in adults, ceftidoren produces better eradication (90%) of S. pyogenes than penicillin V (83%) at treatment end.

[Resistance and new antibiotic strategies. Consequences of the use of antibiotics: how to preserve they efficacy]. / Résistances et nouvelles stratégies antibiotiques. Les dérives de l'emploi des antibiotiques: comment préserver leur efficacité?

FACTORS CONTRIBUTING TO RESISTANCE: Several factors contribute to the spread of resistance (international travel, grouping together severely ill patients, etc.) and others contribute to the emergence of resistance (e.g., catheters for S. epidermidis). The effect of these different factors on the spread and expression of resistance cannot be predicted. How can antibiotic efficacy be preserved? Less overuse of antibiotics, for example for bronchial infections, would be helpful. Educational programs, for patients and physicians alike, is also a crucial point, although its impact has been somewhat disappointing. OTHER ATTITUDES COULD ALSO BE IMPLEMENTED: Use of the most powerful member of a given antibiotic family, overall restriction on antibiotic use, improved diagnostic and laboratory methods. All of these propositions must be examined in light of real experience.

[West Nile virus (WNV) encephalitis]. / L'encéphalite à West Nile Virus (WNV).

A DISEASE ON THE COME BACK: West Nile encephalitis has been known since the thirties. It generally occurs in Africa and Western Asia, rarely in Europe. The disease has disappeared from France since 1960, but has reappeared in the United States and in Israel. A SEVERE VIRAL INFECTION: West Nile encephalitis is caused by a flavivirus. After 2 to 15 days incubation, the patient experiences fever, headache, diffuse pain, and sometimes skin rash. Disorientation, stiff neck, convulsions and paralysis then develop and lead to death in 10 to 15% of the cases. No antiviral agent is active against the West Nile virus. TRANSMISSION AND PREVENTION: The disease is transmitted to man by mosquitos that became contaminated from infected birds. The most effective preventive measure is the fight against mosquitos.

[ICAA 1999: news in antibiotic therapy]. / ICAAC 1999: nouveautés en antibiothérapie.

NEW DERIVATIVES OF OLDER COMPOUNDS: Beta-lactamine derivatives include ne penems and carbapenems as well as beta-lactamase inhibitors and a few cephalosporins. Non-fluoroquinolones without a fluoride atom on position 6 have an antibacterial activity at least equivalent to the most active fluorated products available, suggesting that the contribution of the fluroide atom actually is of limited impact in fluoroquinolones. The clinical importance of these new derivatives remains to be documented. New tetracyclin analogs include glycycyclins. These compounds appear to be active against species resistant to this family of drugs. NEW ANTIBIOTIC CLASSES: A few coumarins have interesting antibacterial activities, essentially against Gram-positive resistant germs. Daptomycin, a glycopeptide-like molecule, gives favorable results for the treatment of Gram-positive infections and yet is comparatively less toxic for the kidney and the auditory system. Oxazolidinones, particularly linezolide, are currently indicated for penicillin and glycopeptide resistant Gram-positive strains. PHARMACOLOGY STUDIES: Recent studies have been conducted on ketolides (14-chain derivatives obtained from erythromycin A) and new fluoroquinolones, gemifloxacin and gatifloxacin, which are active against Gram positive germs (S. pneumoniae) and bactericidal against multiresistant Gram negative.

Current guidelines for the treatment and prevention of nosocomial infections.

Nosocomial infections (NIs) are among the most difficult problems confronting clinicians who deal with severely ill patients. The incidence of these hospital-acquired infections varies with the size of hospitals, with specialities of wards, and with many other factors such as length of hospital stay, local trends in antibiotic usage, nursing and hygiene conditions, hospital design and geographical distribution of patients at risk. An average incidence of NI can be estimated at 5 to 10%, with higher rates in large university hospitals, reaching up to 28% in the intensive care unit (ICU). Changing epidemiology of NI and emerging resistance problems have resulted in evolving strategies of antibiotic usage in patients at risk. Several recent antibiotic resistance problems have been identified, for instance in Gram-positive organisms, and have been surveyed, in addition to those previously well known in Gram-negative bacilli. The choice of empiric antibiotic therapy for the treatment of any NI before microbiology is available has become a difficult challenge, requiring: (i) surveillance data on a regular basis of predominant organisms in units at risk; (ii) surveillance of the current resistance patterns of these organisms; (iii) identification of outbreaks involving the prevalent organisms, using modern molecular techniques for typing the strain and assess cross-contamination. In documented infection, monotherapy vs combination therapy has been often discussed in the treatment of serious Gram-negative hospital infections, but these concepts vary with the site of infection, the nature of organism involved and its pattern of resistance, the kind of antibiotic which may more or less quickly select resistant mutants. Antibiotic therapy concepts vary significantly between countries, and combinations either empirical or based on laboratory data are often preferred in European countries than in the US. Frequent collaborative studies and an increasing communication between experts of different countries, make guidelines and consensus conferences, established in a particular country, useful elsewhere and may contribute to improvement in the management of NI. Guidelines for the prevention and the control of NI are well established in many developed countries and they may have resulted in the improvement of the prevention and the treatment of NI. However, there is still potential progress that should be made, including individual preventive practices, improvement in nursing practices, control of antibiotic use, trend to shorten the hospital stay and early discharge from hospital, which results in significant cost savings.

The suppository form of antibiotic administration: pharmacokinetics and clinical application.

The rectal route of antibiotic administration might be used effectively when other routes of administration are inadequate or unsuitable. With the use of various adjuvants, the rectal route can provide satisfactory pharmacokinetics and acceptable local tolerance. Experiments in animals have demonstrated the influence of the pharmaceutical formulation of suppositories on the rectal absorption and systemic distribution of beta-lactams and aminoglycosides. In healthy volunteers and in children under treatment, similar adjuvants--mainly glyceride mixtures or non-ionic surface agents--have increased the rectal absorption of aminopenicillins, cephalosporins and macrolides. Other antibiotics, including metronidazole and cotrimoxazole, have been investigated in respect of their potential rectal administration.

[Forum on bacterial resistance]. / Forum sur les résistances bactériennes.

Recently, in daily newspapers and on television, attention of the audience has been focused on the overuse of antibiotics and on the role it plays in the emergence and dissemination of resistance mechanisms in the human environment. The role of food from animal origin in relation to the use of antibiotic resistance, infectious diseases, medical practice and ENT infections have accepted to answer a series of questions concerning risks versus usefulness of antibiotic usage. From the answers, we may note convergent views and discrepancies: (i) there was agreement concerning the unnecessary prescription of antibiotics in rhinopharyngitis and few other common viral infections; (ii) the risk of misuse of antibiotics in patients with poor compliance and further risk of erroneous self prescription of the remaining tablets has been cited; (iii) in the problem of resistance resulting from growth promoting antibiotics in animals, it has been experimentally shown that from 2 bacteria of the same species introduced in the animal gut, one susceptible, the other resistant, the latter will be eliminated by means of the "barrier effect"; similarly in case of transfer of resistance from an exogenous bacteria to a "resident" organism of the gut, the latter will be eliminated by the homologous susceptible ones; only an antibiotic therapy may confer importance to the resistant bacteria. In this respect, care should be taken for resistance spread such as that concerning penicillin-resistant pneumococci and surveillance and control of resistance mechanisms has become necessary. However we should look with reluctance at the diffusion of inevitably simplified and truncated information from Media, showing the negative aspects of antibiotics only. Moreover, as underlined by the expert from the Institut Pasteur, there are new perspectives in the development of effective new agents based on the modern "genomic" research.

Clinical and bacteriologic epidemiology of extended-spectrum beta-lactamase-producing strains of Klebsiella pneumoniae in a medical intensive care unit.

The epidemiology of extended-spectrum beta-lactamase (ESBL)-producing strains of Klebsiella pneumoniae was studied over a 16-month period in a medical intensive care unit (ICU). A control program involving enhanced isolation procedures, surveillance cultures at admission and then at 1-week intervals, and selective digestive decontamination (SDD) was instituted. Phenotypic and genotypic markers (plasmid content and DNA macrorestriction polymorphism determined by pulsed-field gel electrophoresis) were used to compare 138 strains of ESBL-producing K. pneumoniae. The incidence of colonization and/or infection with ESBL producers was 11.9%. ESBL-producing K. pneumoniae strains were isolated from 64 of 65 patients. Fifty-five cases were considered acquired in the ICU, while nine cases were imported. Forty-five infections occurred in 32 patients; 20 infections involved the urinary tract. SDD failed to reduce the incidence of acquisition of ESBL-producing K. pneumoniae. Combined use of markers was necessary to achieve accurate differentiation of strains. A single epidemic clone (SHV-4 beta-lactamase-producing K. pneumoniae) was the cause of 85% of the ICU-acquired cases. Sporadic occurrence of SHV-5, TEM-3, SHV-2, and SHV-3 producers accounted only for a few cases.