Evaluation of New Anti-Infective Drugs for the Treatment of Respiratory Tract Infections

Abstract

These guidelines deal with the evaluation of anti-infective drugs for the treatment of respiratory tract infections. Five clinical entities are described: streptococcal pharyngitis and tonsillitis, otitis media, sinusitis, bronchitis, and pneumonia. A wide variety of microorganisms are potentially pathogenetic in these diseases; these guidelines focus on the bacterial infections. Inclusion of a patient in a trial of a new drug is based on the clinical entity, with the requirement that a reasonable attempt will be made to establish a specific microbial etiology. Microbiologic evaluation of efficacy requires isolation of the pathogen and testing for in vitro susceptibility. Alternatively, surrogate markers may be used to identify the etiologic agent. The efficacy of new drugs is evaluated with reference to anticipated response rates. Establishment of the microbial etiology of respiratory tract infections is hampered by the presence of "normal flora" of the nose, mouth, and pharynx, which may include asymptomatic carriage of potential pathogens. This issue is addressed for each category of infection described. For example, it is suggested that for initial phase 2 trials of acute otitis media and acute sinusitis tympanocentesis or direct sinus puncture be used to collect exudate for culture. Acute exacerbations of chronic bronchitis also present difficulties in the establishment of microbial etiology. These guidelines suggest that clinical trials employ an active control drug but leave open the possibility of a placebo-controlled trial. For pneumonia, the guidelines suggest the identification and enrollment of patients by the clinical type of pneumonia, e.g., atypical pneumonia or acute bacterial pneumonia, rather than by etiologic organism or according to whether it was community or hospital acquired. For each respiratory infection, the clinical response is judged as cure, failure, or indeterminate. Clinical improvement is not acceptable unless quantitative response measures can be applied.

Emergence of Group A Streptococcus Strains with Different Mechanisms of Macrolide Resistance

“…The efficacy of treatment against streptococcal pharyngitis should be evaluated both clinically and bacteriologically (6). If microbiological treatment failure occurs, persistence or relapse due to the original GAS strain should be distinguished from recurrence due to acquisition of a new strain (6,10).…”

“…GAS isolates were obtained by swabbing of the throat on day 0 (pretreatment isolate [V1]) and day 14 or day 30 (posttreatment isolates [V2]) after the onset of low-dose azithromycin treatment in children. All GAS isolates were associated with bacteriological treatment failure (persistence or relapse) (6,10), and the azithromycin MICs for the posttreatment isolates had increased. The isolates were identified as GAS by colony morphology, betahemolysis on blood agar, and a commercial agglutination technique (Murex Diagnostics, Dartford, United Kingdom).…”

“…RAPD analysis and pulsed-field gel electrophoresis (PFGE) were used to compare pre-and posttreatment GAS isolates in order to distinguish between persistence-relapse and the acquisition of new strains (6,10). RAPD analysis and PFGE were based on previously described methods (2,10).…”

Usefulness of consecutive C-reactive protein measurements in follow-up of severe community-acquired pneumonia

“…Late treatment failure was defined as clinical deterioration or complications including mortality, the need for mechanical ventilation, readministration of i.v. antibiotics after a switch to oral therapy, readmission for pulmonary infection after discharge, or an increase in body temperature after initial improvement in the follow-up period [20]. The per cent decline in CRP levels reflects the relative changes in CRP concentrations in the course of time, calculated in relation to the day 0 CRP concentrations.…”

Resistencias bacterianas y farmacodinámica como bases de la prescripción de antibióticos en infecciones respiratorias

“…Por lo que se refiere a la infección respiratoria, la faringoamigdalitis estreptocócica ha sido la única en la que la erradicación bacteriológica se ha utilizado de forma habitual como variable de eficacia primaria en los estudios 5,6 , fundamentalmente por tres motivos: a) el principal objetivo del tratamiento antibiótico en este proceso infeccioso es la prevención de la fiebre reumática, lo cual se consigue con la erradicación del patógeno de la orofaringe en los primeros 9 días 7 ; b) tanto el diagnóstico etiológico inicial como la confirmación de que S. pyogenes se ha erradicado es sencillo de realizar y muy específico 8 , y c) la dificultad de la evaluación e interpretación de la curación clínica. Si bien es cierto que el tratamiento antibiótico acelera la resolución de la sintomatología de la faringoamigdalitis durante las primeras 48 h 9,10 , también lo es el hecho de que la mayoría de los pacientes presentan una marcada mejoría en las primeras 72 h de haberse iniciado el cuadro, incluso cuando no se instaura tratamiento antimicrobiano 11 .…”