Claude Carbon

Reduction of Antibiotic Use in the Community Reduces the Rate of Colonization with Penicillin G—Nonsusceptible Streptococcus pneumoniae

BACKGROUNDnThere is a lack of evidence documenting the impact of optimized antibiotic use on the rates of colonization with penicillin G-nonsusceptible Streptococcus pneumoniae (PNSP) in children. This study evaluates the effect of community-based intervention strategies on the prevalence of pnsp colonization.nnnMETHODSnA controlled, population-based pharmacoepidemiological trial was conducted from January through May 2000. Three French geographic areas were selected on the basis of demographic similarities. Two intervention strategies were implemented: (1) reduced antibiotic use, which was achieved by not prescribing antibiotics for presumed viral respiratory tract infections (the prescription-reduction group); and (2) better adaptation of dose and duration (the dose/duration group). A control group received no intervention. The target population was children aged 3-6 years who were attending kindergarten. Oropharyngeal pneumococcus colonization and antibiotic use were monitored throughout the 5-month study.nnnRESULTSnThe prescription-reduction, dose/duration, and control groups included 601, 483, and 405 children, respectively. The interventions induced significantly larger decreases in antibiotic use in the prescription-reduction group (-18.8%) and dose/duration group (-17.1%) than in the control group (-3.8%), and the rates of PNSP colonization were initially similar for the 3 groups (52.5%, 55.1%, and 50.0%, respectively). At the end of the 5-month study, the rates of PNSP colonization were 34.5% for the prescription-reduction group (P=.05) and 44.3% for the dose/duration group (P=.8), compared with 46.2% for the control group.nnnCONCLUSIONSnIntensive educational strategies aimed at optimizing antibiotic use can significantly reduce the rate of PNSP colonization in areas with high resistance rates.

Trends in Antimicrobial Drug Use in the Community—France, 1981–1992

Trends in the use of antimicrobials in France between 1980-1981 and 1991-1992 were analyzed. Data were obtained from surveys of health and ambulatory care, which were based on national probability samples. In a 3-month period in 1980, 17% of the population of France was treated with an antibiotic, compared with 25% in 1991 (P < .001). The frequency of respiratory tract infections with a presumed viral etiology that were diagnosed and treated with antibiotics increased by 86% for adults and 115% for children in the 11-year period. The proper use of cephalosporins must be encouraged, and vigilance is required in view of the increased improper use of fluoroquinolones, mainly for respiratory tract infections with a presumed viral etiology.

Inappropriateness and variability of antibiotic prescription among French office-based physicians.

OBJECTIVEnTo describe oral antibiotic prescription in the community.nnnDESIGNnAudit of anti-infective prescribing in office-based medical practice.nnnSETTINGnCenter of France, in the Loiret, a 600,000 inhabitant administrative division.nnnMAIN OUTCOME MEASURESnClinical hypothesis and antimicrobial drugs used as well as daily doses and durations of treatment.nnnRESULTSnRespiratory tract infections with a presumed viral etiology accounted for 36% of prescriptions. In children, a high percentage of antibiotic prescriptions were underdosed as compared to clinical recommendations, particularly in acute otitis media. The variability of the daily dose was high, with coefficients of variation over 40% in acute otitis media or acute tracheobronchitis. Whatever the clinical hypothesis, the duration of treatment was close to 8 days. In acute otitis media, the coefficient of variation was 14%, the lowest for all diagnoses.nnnCONCLUSIONnOur investigation identified two main areas for improving antimicrobial drug prescribing: (1) reduction of useless prescriptions in respiratory tract infections with a presumed viral etiology, and (2) increasing the prescribed daily dose of antimicrobials to the recommended levels.

Complex Relationship between Acquisition of β-Lactam Resistance and Loss of Virulence in Streptococcus pneumoniae

In a previous study of a murine peritonitis model, no Streptococcus pneumoniae strains were found that were both clinically penicillin resistant and virulent. This study assessed the relationship between acquired resistance and virulence in single- and double-isogenic penicillin-resistant (Peni-R) mutants obtained by transformation of a virulent penicillin-susceptible recipient strain with pbp2b and pbpX polymerase chain reaction fragments from a Peni-R donor strain. Sequence analysis results of the pbp2b and pbpX alleles from these strains were in keeping with acquired penicillin resistance. The virulence of these strains was significantly reduced, which shows a relationship between beta-lactam resistance and loss of virulence. The phenotype of the 23.2x mutant remained stable after in vivo passage, which suggests that the pbpX gene is involved in growth, whereas virulent revertants of the 23.2b and 23.2b.2x mutants had no change in MIC. Compensatory mutations are implicated in the revival of virulence.

Effects of diclofenac on experimental streptococcal necrotizing fasciitis (NF) in rabbit

Abstract Aggravation of necrotizing fasciitis (NF) by the administration of non-steroidal antiinflammatory drugs (NSAIDs) has recently been suggested. A rabbit model of streptococcal NF was used to study the effects of parenteral administration of an NSAID on NF evolution and outcome. Of 16 rabbits inoculated with a Streptococcus pyogenes suspension together with staphylococcal alpha toxin, 8 were treated with two doses of 4 mg/kg diclofenac on day 1 after inoculation. Clinical, bacteriological and histological studies were performed until day 10. Under our experimental conditions, NSAID treatment significantly limited NF extension. A specific inverse relationship between the extent of inflammation and bacterial density in NF lesions was observed on day 1 after inoculation in the treated group suggesting that the greater severity of NF in humans treated with an NSAID could be due to the therapeutic delay induced by the misleading clinical effects of the NSAID, and not to inhibition of antibacterial defence.

Narrow Versus Broad Spectrum Antibacterials

Streptococus pneumoniae represents an interesting model to discuss the relative impact of broad versus narrow spectrum antibacterials as potential selectors for resistance. Indeed, this pathogen is responsible for potentially severe infections in the community, and has a great capacity for acquisition of resistance to antibacterial agents. It has been the focus of many studies to elucidate some unique aspects of molecular biology, including the adaptive mechanisms responsible for emergence and spread of multiresistance.In the past, the use of narrow spectrum agents was recommended in order to try to reduce the risk of selection of resistance. This concept is nowadays somewhat obsolete for several reasons. S. pneumoniae is able to acquire resistance to antibacterials belonging to different families of drugs through different molecular mechanisms. Thus, selection of multiresistant pneumococci can result from exposure to very different agents, including narrow spectrum as well as broad spectrum agents. In vitro studies have shown a different potential for selection of resistance among the β-lactam agents. Furthermore, several studies have more or less directly established a close relationship between the level of antibacterial use and the rate of selection of resistance. In addition to the overall amount of antibacterials prescribed in the community, several other factors have been shown to influence the rate of selection of resistance, including the use of doses that are too low, the length of therapy and the duration of bacterial exposure to long-acting agents compared to drugs with short half-lives.Therefore, there are three main ways to control selection and spread of resistant strains: by (i) reducing the amount of antibacterials used; (ii) using optimal dosages (avoiding underdosing) and treatments of short duration; and (iii) reducing the risk of transmission among young children attending daycare centres or kindergartens. In order to help physicians reduce the number of unnecessary prescriptions, it is important to develop rapid tests to recognise the bacterial origin of a febrile illness and even more important to detect resistance to antibacterials. However, apart from rapid diagnostic tests for streptococcal pharyngitis, those tests are not currently available.As a consequence, currently, the debate around narrow versus broad spectrum antibacterials remains a false debate. Physicians should use broad spectrum agents in many instances of upper or lower respiratory tract infection, taking into consideration the probable pathogens and the risk of (multi)resistance to antibacterials. Once rapid diagnostic are available in community practice, allowing a precise diagnosis of the offending agent and its susceptibility profile, physicians will be able to add to their current criteria the selective potential for resistance of the antibacterials that appear to be active in vitro.

What is the Place of Fluoroquinolones in the Treatment of Community-Acquired Respiratory Tract Infections?

The newest (third generation) fluoroquinolones are potentially useful agents in the management of community-acquired respiratory tract infections. This is mainly due to their increased activity against Streptococcus pneumoniae, a pathogen poorly susceptible to the second-generation compounds, and playing a major role in upper and lower respiratory tract infections. Also, their spectrum includes the other main pathogens involved in those infections, comprising Haemophilus influenzae and intracellular agents, against which the newest fluoroquinolones exhibit a similar activity to that of the previous compounds. The pharmacokinetic and pharmacodynamic properties of the newest quinolones make them suitable for effective therapy of lower respiratory tract infections. However, careful attention should be paid to the dose and dosing regimen of each compound in clinical usage in order to select the most adapted drug. In clinical trials, the fluoroquinolones have been shown to be at least as effective as the comparators in the treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis (AECB) or sinusitis, including documented pneumococcal infections. Their tolerance is generally considered to be good. The main question regarding the fluoroquinolones in the treatment of community-acquired respiratory tract infections is their role as first-line agents used in single drug therapy. Cost-effectiveness studies are needed to define this role further. Identification of subpopulations of patients at risk of being infected by penicillin-resistant pneumococci or Gram-negative bacilli who could benefit from a fluoroquinolone could be useful. Also, it must be considered that a large use of fluoroquinolones as first-line agents in very common infections such as AECB or sinusitis could contribute to the selection of bacteria, including S. pneumoniae, resistant to this class of antibiotics. Careful control of fluoroquinolone usage and development of bacterial resistance is of great importance.

Ceftriaxone diffusion into cardiac fibrin vegetation. Qualitative and quantitative evaluation by autoradiography

Summary— Heterogeneous diffusion of some antibiotics into fibrin rich infectious processes is one explanation of the difficulty to cure infections such as endocarditis. Ceftriaxone is a β lactam antibiotic, potentially useful due to a broad spectrum of activity and its long elimination half‐life. We investigated by means of autoradiography the diffusion of labelled ceftriaxone into large infected cardiac vegetations obtained in a rabbit model of endocarditis. Ten d after infection 250 μCi 14C ceftriaxone was injected over 30 min. Thirty min after the end of infusion (T30) vegetation/blood radioactivity ratio was 0.58 ± 0.4 (n = 3). At T200, radioactivity decreased approximatively 3‐fold, in blood and in vegetations simultaneously. Autoradiography showed that at T30, ceftriaxone was 20–30 times more concentrated at the periphery of vegetation than in the core. Autoradiography obtained at T200 showed a progressive diffusion toward the core. The diffusion gradient may explain the fact that high local concentrations are necessary to sterilize vegetations. The pattern of diffusion of antibiotics in fibrin is an important pharmacokinetic parameter for predicting in vivo activity.

Quinolones in the Treatment of Lower Respiratory Tract Infections in Adult Patients

SummaryThe potential role of quinolones is discussed on the basis of data obtained during the past 2 years from epidemiological studies, in vitro investigations, animal experiments and clinical trials.Although the newest compounds exhibit good activity against Streptococcus pneumoniae and intracellular pathogens in animal models, the role of quinolones as first line therapy in community-acquired pneumonia is still debatable and may be modified according to clinical presentation and the rate of resistance of pneumococci to β-lactams and macrolides.Cost-utility and cost-benefit studies are required to delineate precisely the role of quinolones in the treatment of acute exacerbations of chronic bronchitis.In addition, promising results indicating a possible future for the clinical use of quinolones in the therapy of mycobacterial infections have been obtained.

Animal models of endocarditis

Bacterial endocarditis is a difficult infection to cure, due to poor penetration of antibiotics into infected vegetations, altered metabolic state of bacteria within the lesion, and absence of adequate host-defense cellular response which could cooperate with antibiotic action. The contribution of animal models to a better understanding of the pathophysiology of the infection and to definition and improvement of therapeutic regimens of endocarditis in humans remains of great importance due to the difficulties encountered in clinical trials. The advantage of the experimental model is that besides the fact that it closely simulates the characteristics of the infection in humans, it provides clear endpoints which allow statistical comparisons among different therapeutic regimens: number of bacteria per gram of tissue, frequency of emergence of resistance, positivity of blood cultures, death vs. survival rates, and percentage of relapses after treatment has been stopped. All these parameters are more sensitive and more easy to study than in humans. The animal model has definitively established that bactericidal therapy is warranted and that in vitro susceptibility tests, especially those evaluating the killing rate, have a good predictive value on the therapeutic outcome. Two main aspects are discussed for their relevance to human therapy: (i) the kinetics of antibiotic diffusion into vegetations, with special reference to data obtained with autoradiography; and (ii) the specificity of some pharmacodynamic aspects of antibiotics in endocarditis, including the clinical consequences of these two parameters with respect to antibiotic dosing regimens and length of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)