Evaluation of new anti-infective drugs for the treatment of respiratory tract infections. Infectious Diseases Society of America and the Food and Drug Administration.

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.

Randomized comparative study of ceftibuten versus cefaclor in the treatment of acute lower respiratory tract infections.

In a randomized, single-blind trial, ceftibuten in doses of 200 mg and 300 mg administered b.i.d., was compared with cefaclor 500 mg t.i.d. in acute lower respiratory tract infections. A total 545 patients were enrolled, of which 263 were evaluable for efficacy. All patients were adults with a diagnosis of either bacterial pneumonia or bronchitis. The infective organism was eliminated in 83% of the patients in the ceftibuten 200-mg b.i.d. treatment group and in 85% of patients in the 300-mg b.i.d. treatment group. The organisms were eliminated in 79% of cefaclor-treated patients. Satisfactory clinical responses were obtained in 91% of patients in the ceftibuten 200-mg b.i.d. treatment group and in 92% of patients in the ceftibuten 300-mg b.i.d. group. Satisfactory clinical responses were obtained in 91% of cefaclor-treated patients. Predominant pathogens isolated were Streptococcus pneumoniae, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, and strains of Enterobacteriaceae. Adverse experiences reported were similar for the ceftibuten and cefaclor treatment groups. Gastrointestinal side effects occurred in 6% of patients treated with ceftibuten 200 mg BID, 9% in those treated with 300 mg BID, and 7% of cefaclor-treated patients. Ceftibuten 200 and 300 mg twice daily was as effective as cefaclor bacteriologically and clinically in the treatment of lower respiratory tract infections.

Moxalactam: clinical summary of efficacy and safety.

The efficacy and safety of moxalactam disodium were studied by 173 investigators in the United States. Of 3,558 adult and pediatric patients who were treated for various infections, 2,234 met all protocol requirements for evaluation of efficacy of treatment. Effectiveness of moxalactam therapy was defined by a satisfactory bacteriologic response. The pooled data revealed that satisfactory responses were obtained in 80% of urinary tract infections, 91% of intraabdominal infections, 91% of obstetric and gynecologic infections, 92% of lower respiratory tract infections, 92% of skin and skin-structure infections, 90% of bone and joint infections, and 94% of bacteremic infections. The overall rate of efficacy of moxalactam therapy was 89%. The incidence of adverse reactions was low. Hypersensitivity occurred in 2.9% of the 3,558 patients, and gastrointestinal adverse effects, in 2.1%. No renal or hepatic toxicity was related to moxalactam therapy. Hypoprothrombinemia occurred in 25 patients, with clinically apparent bleeding in three. Alcohol intolerance was observed in four patients.

In-vitro activities of cefamandole and cephalothin against 1,881 clinical isolates. A multi-center study.

By use of an agardilution technic, 1,881 clinical isolates were tested against cefamandole and cephalothin. The isolates represented 18 genera, recovered in five geographically separate centers within the United States. The majority of strains were susceptible (MICs less than or equal to 8 micrograms/ml) to both drugs. Cefamandole showed greater activity against most of the bacterial pathogens. Enterococci, Serratia spp., and Acinetobacter spp. were resistant to both drugs. Cephalothin was more active against Staphylococcus aureus, and both cephalosporins were relatively inactive against methicillin-resistant strains of S. aureus. Enterobacter spp. and indole-positive Proteus spp. were susceptible to cefamandole but resistant to cephalothin.

Interpretive criteria for cefamandole and cephalothin disk diffusion susceptibility tests.

A multi-center study of 1,838 clinical isolates established the accuracy of diffusion susceptibility tests with 30-mug cephalothin disks and 30-mug cefamandole disks. The same interpretive zone standards can be applied to tests with either disk but the two drugs cannot be tested interchangeably.

Cefaclor: summary of clinical experience.

Cefaclor, a new semisynthetic cephalosporin antibiotic for oral use, was studied by 62 clinical investigators in six countries in 1493 adult and paediatric patients. The pooled data reveal that satisfactory clinical responses were obtained in 80% of urinary tract infections, 87% of upper respiratory tract infections, 90% of cases of otitis media, 99% of lower respiratory tract infections, and 96% of skin and skin structure infections. Administration of this antibiotic was associated with a low incidence of adverse reactions including gastrointestinal (2.6%) and hypersensitivity (1.5%). Of particular clinical interest were the outstanding results obtained in the treatment of otitis media and lower respiratory tract infections.

Cefaclor--summary of clinical experience.

Cefaclor, a new semisynthetic cephalosporin antibiotic for oral use, was studied by 62 clinical investigators in 6 countries in 1493 adult and paediatric patients. The pooled data reveal that satisfactory clinical responses were obtained in 80% of urinary tract infections, 87% of upper respiratory infections, 90% of cases of otitis media, 99% of lower respiratory tract infections, and 96% of skin and skin structure infections. Administration of this antibiotic was associated with a low incidence of adverse reactions including gastrointestinal (2.6%) and hypersensitivity reactions (1.5%). Of particular clinical interest were the outstanding results obtained in the treatment of otitis media and lower respiratory tract infections.

Rapid detection of ampicillin-resistant Haemophilus influenzae and their susceptibility to sixteen antibiotics.

Ampicillin-resistant and -susceptible strains of Haemophilus influenzae were tested for susceptibility to 16 antibiotics. Chloramphenicol and a new cephalosporin, cefamandole, were most active with minimal inhibitory concentrations (MICs) for all bacteria tested between 0.5 to 2.0 mug/ml. All but two organisms were susceptible to tetracycline. Ampicillin-resistant strains of H. influenzae were less susceptible (MIC, 4 to 32 mug/ml) to carbenicillin and ticarcillin than ampicillin-susceptible organisms (MIC, 0.25 to 1.0 mug/ml). A rapid assay for beta-lactamase, utilizing a chromogenic cephalosporin substrate, detected enzyme production in all 17 ampicillin-resistant strains of H. influenzae.