Clinical and bacteriological efficacy of the ketolide telithromycin against isolates of key respiratory pathogens: a pooled analysis of phase III studies.

A pooled analysis of data from 13 phase III studies of telithromycin in the treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute sinusitis or group A beta-haemolytic streptococcal pharyngitis and tonsillitis was undertaken. Causative key respiratory tract pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and Streptococcus pyogenes) were isolated at entry to the studies from cultures of relevant respiratory samples and tested for their susceptibility to telithromycin, penicillin and macrolides (erythromycin A). The combined clinical and bacteriological efficacy of telithromycin at the post-therapy, test-of-cure visit (days 17-24) was assessed in patients from whom a microbiologically evaluable pathogen was isolated at entry. More than 98% of key respiratory pathogens isolated, including penicillin G- and macrolide (erythromycin A)-resistant strains of S. pneumoniae, demonstrated full or intermediate susceptibility to telithromycin in vitro at the breakpoints of < or = 1.0 mg/L (susceptible) and 2.0 mg/L (intermediate) used for the purpose of evaluating the susceptibility of isolates recovered during the clinical trials. Treatment with telithromycin 800 mg once-daily for 5, 7 or 7-10 days resulted in high rates of clinical cure (88.5%) and a satisfactory bacteriological outcome (88.9%), similar to the figures seen with comparator antibacterial agents. Clinical cure and eradication rates were good for all key respiratory pathogens, including penicillin G- and macrolide (erythromycin A)-resistant S. pneumoniae. The results suggest that telithromycin will provide effective empirical therapy for community-acquired upper and lower respiratory tract infections.

Antibacterial resistance among children with community-acquired respiratory tract infections (PROTEKT 1999-2000).

OBJECTIVE: To determine the susceptibility of bacterial respiratory tract pathogens, isolated from children (0-12 years) as part of the global PROTEKT surveillance study (1999-2000), to a range of antibacterials, including the ketolide telithromycin. METHODS: Minimum inhibitory concentrations of the antibacterials studied were determined at a central laboratory using the NCCLS microdilution broth method. Macrolide resistance mechanisms were detected by PCR. RESULTS: Of 779 Streptococcus pneumoniae isolates worldwide, 43% were non-susceptible to penicillin (18% intermediate; 25% resistant) and 37% were resistant to erythromycin, with considerable intercountry variation. Eighteen per cent of 653 Haemophilus influenzae and >90% of 316 Moraxella catarrhalis isolates produced beta-lactamase. Of 640 Streptococcus pyogenes isolates, 10% were resistant to erythromycin, with considerable intercountry variation. All S. pneumoniae and 99.8% of H. influenzae isolates were susceptible to telithromycin using breakpoints proposed to the NCCLS (

Antibacterial resistance of community-acquired respiratory tract pathogens recovered from patients in Latin America: results from the PROTEKT surveillance study (1999-2000).

PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a global surveillance study established in 1999 to monitor antibacterial resistance of respiratory tract organisms. Thirteen centers from Argentina, Brazil and Mexico participated during 1999-2000; they collected 1806 isolates (Streptococcus pneumoniae 518, Haemophilus influenzae 520, Moraxella catarrhalis 140, Staphylococcus aureus 351, S. pyogenes 277). Overall, 218 (42.1%) of the S. pneumoniae isolates had reduced susceptibility to penicillin, 79 (15.3%) were penicillin-resistant and 79 (15.3%) were erythromycin-resistant. Mexico had the highest prevalence of penicillin (76.5%) and erythromycin (31.2%) resistance. Of 77 erythromycin-resistant S. pneumoniae tested for resistance genotype, 43 possessed mef(A), 33 possessed erm(B) and 1 possessed both erm(B) and mef(A) mechanism. All S. pneumoniae isolates were fully susceptible to telithromycin, linezolid, teicoplanin and vancomycin. Among H. influenzae isolates, 88 (16.9%) produced beta-lactamase, ranging from 11% (Brazil) to 24.5% (Mexico). Among M. catarrhalis isolates, 138 (98.6%) produced beta-lactamase. Twenty-four (8.7%) of the S. pyogenes isolates were erythromycin-resistant; resistance being attributable to mefA (n=18), ermTR (n=5) and ermB (n=1). All H. influenzae, M. catarrhalis and S. pyogenes were fully susceptible to telithromycin. Methicillin resistance was found in 26.5% of the S. aureus isolates (Argentina 15%; Mexico 20%; Brazil 31.3%). Telithromycin was effective against 97.7% of methicillin-susceptible isolates. PROTEKT confirms that antibacterial resistance is an emerging problem in Latin America. The previously reported high levels of pneumococcal resistance to the beta-lactam and macrolides were exceeded. New agents that do not induce resistance or that exert low selective pressure, e.g. telithromycin, are essential to safeguard future antibacterial efficacy.

Antibacterial resistance of community-acquired respiratory tract pathogens recovered from patients in Latin America: results from the PROTEKT surveillance study (1999-2000)

PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a global surveillance study established in 1999 to monitor antibacterial resistance of respiratory tract organisms. Thirteen centers from Argentina, Brazil and Mexico participat ed during 1999-2000; they collected 1,806 isolates (Streptococcus pneumoniae 518, Haemophilus influenzae 520, Moraxella catarrhalis 140, Staphylococcus aureus 351, S. pyogenes 277). Overall, 218 (42.1 percent) of the S. pneumoniae isolates had reduced susceptibility to penicillin, 79 (15.3 percent) were penicillin-resistant and 79 (15.3 percent) were erythromycin-resistant. Mexico had the highest prevalence of penicillin (76.5 percent) and erythromycin (31.2 percent) resistance. Of 77 erythromycin-resistant S. pneumoniae tested for resistance genotype, 43 possessed mef(A), 33 possessed erm(B) and 1 possessed both erm(B) and mef(A) mechanism. All S. pneumoniae isolates were fully susceptible to telithromycin, linezolid, teicoplanin and vancomycin. Among H. influenzae isolates, 88 (16.9 percent) produced b-lactamase, ranging from 11 percent (Brazil) to 24.5 percent (Mexico). Among M. catarrhalis isolates, 138 (98.6 percent) produced b-lactamase. Twenty-four (8.7 percent) of the S. pyogenes isolates were erythromycin-resistant; resistance being attributable to mefA (n=18), ermTR (n=5) and ermB (n=1). All H. influenzae, M. catarrhalis and S. pyogenes were fully susceptible to telithromycin. Methicillin resistance was found in 26.5 percent of the S. aureus isolates (Argentina 15 percent; Mexico 20 percent; Brazil 31.3 percent). Telithromycin was effective against 97.7 percent of methicillin-susceptible isolates. PROTEKT confirms that antibacterial resistance is an emerging problem in Latin America. The previously reported high levels of pneumococcal resistance to the b-lactam and macrolides were exceeded. New agents that do not induce resistance or that exert low selective pressure, e.g. telithromycin, are essential to safeguard future antibacterial efficacy

Evolving resistance patterns in community-acquired respiratory tract pathogens: first results from the PROTEKT global surveillance study. Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin.

In recent years, antibacterial resistance among respiratory pathogens implicated in community-acquired respiratory tract infections (RTIs) has spread worldwide at an alarming rate. Thus, there is a pressing need for new antibacterials that retain activity against resistant organisms, have a low potential to select for resistance and do not induce cross-resistance. Telithromycin is the first of a new class of antibacterials - the ketolides - that have been designed specifically to overcome resistance among respiratory tract pathogens. This paper presents the first results of the PROTEKT study (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin), a worldwide surveillance study initiated to chart the prevalence of important resistance phenotypes and genotypes and the comparative activity of telithromycin against such strains. Analysis of over 7,000 bacterial isolates by April 2001 has confirmed the notable prevalence of strains resistant to commonly prescribed RTI antibacterials for all the pathogens studied. Telithromycin demonstrates high activity against isolates of Streptococcus pneumoniae, irrespective of penicillin G, macrolide or fluoroquinolone resistance. Telithromycin is also highly active against other respiratory tract pathogens, including Streptococcus pyogenes and beta-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis. These data justify the assertion that telithromycin is a promising new candidate for the empirical treatment of community-acquired RTIs, particularly in the face of increasing antibacterial resistance.

Respiratory pathogens: assessing resistance patterns in Europe and the potential role of grepafloxacin as treatment of patients with infections caused by these organisms.

Although most respiratory tract infections (RTI) are caused by viruses, various bacteria, particularly Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, are common causes of community-acquired pneumonia, acute exacerbations of chronic bronchitis, otitis media and sinusitis. Empirical antibiotic therapy of patients with RTI must take account of the increasing prevalence of resistance among the predominant pathogens. Europe-wide susceptibility surveillance studies have revealed that resistance to penicillin and macrolides is highly prevalent among isolates of S. pneumoniae from France and Spain. Uniquely, in Italy, macrolide resistance is highly prevalent while the prevalence of penicillin resistance is low. Resistance to other antibiotic classes, including chloramphenicol, doxycycline and, in particular, co-trimoxazole, is associated with penicillin resistance in pneumococci, but resistance to the fluoroquinolones is rare. beta-Lactamase production is the principal mechanism of resistance in isolates of H. influenzae and M. catarrhalis, with fluoroquinolone resistance being detected rarely in these pathogens. In 1998 a surveillance study involving 15 European countries determined the susceptibilities of many respiratory pathogens to a range of antimicrobials, including grepafloxacin. The MIC(90) of grepafloxacin for 1251 isolates of S. pneumoniae was 0.25 mg/L, the MICs for only five strains being >2 mg/L, and 99.4% of all of the isolates tested were inhibited by concentrations

The treatment of neonatal meningitis due to gram-negative bacilli with ciprofloxacin: evidence of satisfactory penetration into the cerebrospinal fluid.

We describe two cases of neonatal meningitis due to Gram-negative bacilli treated successfully with ciprofloxacin. Examination of serial samples of cerebrospinal fluid indicated the effect of meningeal inflammation on penetration of this drug into the CSF.

Contamination of blood during cardiopulmonary bypass: the effect of antibiotic prophylaxis.

Despite antibiotic prophylaxis in cardiac surgery, gram-positive bacteria can be isolated in up to 10% of intraoperative blood cultures. During a prospective randomized trial, blood was collected from the oxygenator at the end of bypass in 58 patients given teicoplanin and in 60 others given flucloxacillin and tobramycin. Coagulase-negative staphylococci were cultured from 16 patients given teicoplanin but in only four cases after flucloxacillin and tobramycin (Fisher's exact test, P = 0.005). In contrast, Propionibacterium spp. or coryneforms were isolated from 22 patients given flucloxacillin and tobramycin and from only one patient in the teicoplanin group. There were no cases of prosthetic valve endocarditis. After 3 h exposure to 4 x MIC of teicoplanin there was only a 10-60 fold reduction in cfus of Staphylococcus epidermidis, which may partly explain the excess of these organisms.

The comparative activity of twelve 4-quinolone antimicrobials and sulphadiazine against Neisseria meningitidis.

The minimal inhibitory concentrations (MICs) of twelve 4-quinolone antimicrobials and sulphadiazine were determined for 160 clinical isolates of Neisseria meningitidis. The bacteria were recovered from nasopharyngeal carriers and cases of meningitis examined in The Gambia, West Africa, during the 1982-83 dry season. MICs were determined using an agar dilution technique in Mueller-Hinton agar supplemented with 10% lysed horse blood. The inoculum used was approximately 10(4) colony-forming units of each organism, contained in 10 microliters of Mueller-Hinton broth, which was applied to the agar plates using a multipoint inoculator. Following inoculation, plates were incubated for 18 h at 37 degrees C in an atmosphere enriched to 5% carbon dioxide. The MIC of each antimicrobial for each isolate examined was determined as the lowest concentration of the antimicrobial which completely inhibited growth of the inoculum. The minimum concentrations of each antimicrobial required to inhibit 50% (MIC50) and 90% (MIC90) of the isolates examined were also determined. The more recently synthesised 4-quinolones were very active against the isolates of Neisseria meningitidis, ciprofloxacin being marginally the most active (MIC90 0.008 micrograms/ml). The activity of the 4-quinolone antimicrobials was unaffected by the MICs of sulphadiazine required by the organisms, which ranged from 0.5- greater than 64 micrograms/ml.

Treatment of Neisseria gonorrhoeae infections in men with single-dose thiamphenicol.

A group of 50 men with uncomplicated gonococcal infections were treated with single, oral doses of 2.5 g of thiamphenicol. Reexamination, which included culture for Neisseria gonorrhoeae, was performed three to four days and seven days after treatment. Thirty-two (91%) of 35 men with urethral infections, 13 (87%) of 15 with rectal infections, and four (57%) of seven with pharyngeal infections were cured. None of the men from whom N. gonorrhoeae was reisolated admitted further sexual exposure. Treatment failure did not correlate with decreased sensitivity of the isolates to thiamphenicol in vitro. Three men had urethral infections with Chlamydia trachomatis before therapy, and the organism was reisolated after therapy in every case. No hematologic abnormalities occurred in any of the 50 patients treated with thiamphenicol, but 13 (26%) developed adverse gastrointestinal symptoms.