In Vitro Susceptibility of Haemophilus influenzae and Neisseria gonorrhoeae to Ro 13-9904 in Comparison with Other β-Lactam Antibiotics

Abstract

Ro 13-9904 has high in vitro activity, as does cefotaxime, against 57 Haemophilus influenzae and 60 Neisseria gonorrhoeae strains, including 5 and 11 filactamase-producing strains in each group, respectively.The appearance of 8i-lactamase-producing Haemophilus influenzae (2, 9) and Neisseria gonorrhoeae strains (1, 7) resistant to ampicillin and penicillin has prompted the search for alternative safe and effective drugs which are not affected by the enzyme. The second-and thirdgeneration cephalosporins, including cefamandole, cefuroxime, cefoxitin, and cefotaxime, have shown promising results in this respect. Recently, a new semisynthetic cephalosporin, Ro 13-9904 (W.H.O. approved generic name, ceftriaxone), has also been shown to have high in vitro activities against many gram-negative bacteria (8, 10). We therefore determined, by the agar dilution technique, the in vitro susceptibility of 57 H. influenzae and 60 N. gonorrhoeae strains to Ro 13-9904, and the results were compared with those of penicillin, ampicillin, and six other cephalosporins.H. influenzae strains were identified by their morphology, growth characteristics, and X-and V-factor requirements. All strains except two were isolated from sputum specimens of patients with respiratory tract infections, mostly exacerbation of chronic bronchitis. A total of five ,Blactamase-producing Haemophilus strains, identified by the filter-paper chromogenic cephalosporin test (6), were found among the sputum isolates, and two type B H. influenzae strains isolated from cerebrospinal fluid were non-,B-lactamase producers. The strains were kept at -20°C in tryptic soy broth (Difco) containing 0.5% yeast extract, 0.5% soluble hemoglobin (Oxoid), and 20% glycerol (vol/vol) until ready for susceptibility testing. The 60 N. gonorrhoeae strains, including 11 ,B-lactamase-producing strains, the sources of the antibiotics, and the agar dilution technique have been described in a previous report (5). Ro 13-9904 was supplied by F. Hoffmann-La Roche Co. A standardized inoculum of 103 colony-forming units per ml was used for all bacterial strains throughout this study. The test medium was Mueller-Hinton agar (Difco) supplemented with 1% hemoglobin (Oxoid) and 1% supplement B (Difco) for both Haemophilus and gonococcal strains.The activity of Ro 13-9904 and eight other ,Blactam antibiotics against H. influenzae and N. gonorrhoeae strains is shown in Table 1. Ro 13-9904 and cefotaxime were the most active compounds tested. Both drugs showed extremely high in vitro activities (minimal inhibitory concentration, -0.125,g/ml) against all Haemophilus and gonococcal strains, including the 5 and 11 /8-lactamase-producing strains of each group, respectively. All of the H. influenzae and N. gonorrhoeae strains were susceptible to the second-generation cephalosporins cefuroxime, cefamandole, and cefoxitin, and none of the strains required minimal inhibitory concentrations of >4 ,ug/ml. In contrast, a great proportion of H. influenzae strains were resistant to the firstgeneration cephalosp...

Comparative study of ceftriaxone and aqueous procaine penicillin G in the treatment of uncomplicated gonorrhea in women

“…The APPG regimen does, however, have important shortcomings, including inconsistent manufacturer supplies, low patient acceptability (owing to discomfort from the two large 5-ml injections, frightening toxic procaine reactions, which in our clinic occur with rates of 1 to 3% and allergic reactions), vulnerability to N. gonorrhoeae-produced j-lactamase, and rising cost. In vitro, ceftriaxone is many times more active than penicillin G (5, 8,9,12). Because of this high activity, together with its high serum levels and very long half-life, it is not surprising that, in a dose-ranging study in men (5) and in our study in women, 250 mg was completely effective at all sites.…”

“…Neither we nor Handsfield et al (5) treated infections caused by ,-lactamase-producing N. gonorrhoeae, but in vitro studies indicate that these strains are as susceptible to ceftriaxone as are ,-lactamase-negative strains (9,12). Although the third-generation cephalosporins marketed to date are very expensive by gram weight, on a cost-per-treatment basis ceftriaxone has the potential to compete with the recommended spectinomycin regimen and perhaps with the APPG regimen as well.…”

“…All gonococcal strains tested, whether ,-lactamase positive (9, 12) or negative (2,5,8,9,12,14), were sensitive to 0.03 ,ug/ml or less. The pharmacokinetics of ceftriaxone make it favorable for treating gonorrhea (10, 11); a single intramuscular 0.5-g dose in 1% lidocaine (10) produces peak serum levels of 42 jig/ml, with an elimination half-life of 7.0 h, uniquely long among P-lactam antibiotics.…”

“…All 122 pretreatment isolates were inhibited by 0.0125 ,ug or less of ceftriaxone per ml. The minimal concentration needed to inhibit 90% of isolates was 0.006 ,ug/ml for ceftriaxone and 0.2 ,ug/ml for penicillin G. Ceftriaxone was very well tolerated and caused no toxicity.Ceftriaxone (Ro 13-9904) is a new third-generation cephalosporin with enhanced in vitro activity against most gram-negative aerobic bacteria (2-4, 12, 14), including Neisseria gonorrhoeae (2,5,8,9,12,14). All gonococcal strains tested, whether ,-lactamase positive (9, 12) or negative (2,5,8,9,12,14), were sensitive to 0.03 ,ug/ml or less.…”

Ceftriaxone: in vitro studies and clinical evaluation

“…Cefoperazone (16), ceftazidime (20), and cefsulodin (25) may prove to be more effective antipseudomonal cephalosporins. Ceftriaxone, moxalactam, and cefotaxime have all proved to be extremely active against Salmonella species (6,8), Shigella species (1, 18), Neisseria meningititis (18), Neisseria gonorrheae (including penicillin-resistant strains) (24,32), and Haemophilus influenzae (including ampicillin-resistant strains) (19,24).…”