Comparative in-vitro activity of azithromycin and erymromycin against Gram-positive cocci, Haemophilus influenzae and anaerobes

The MIC at which 50% of strains are inhibited (MIC 50 ) and the MIC 90 of GW 773546, a novel macrolide, were 1.0 and 2.0 g/ml, respectively, for 223 ␤-lactamase-positive, ␤-lactamase-negative, and ␤-lactamasenegative ampicillin-resistant Haemophilus influenzae strains. The MIC 50 s and MIC 90 s of GW 708408, a second novel macrolide, and telithromycin, an established ketolide, were 2.0 and 4.0 g/ml, respectively, while the MIC 50 and MIC 90 of azithromycin were 1.0 and 2.0 g/ml, respectively. The MIC 50 and MIC 90 of erythromycin were 4.0 and 8.0 g/ml, respectively; and those of clarithromycin were 4.0 and 16.0 g/ml, respectively. All compounds except telithromycin were bactericidal (99.9% killing) against nine strains at two times the MIC after 24 h. Telithromycin was bactericidal against eight of the nine strains. In addition, both novel macrolides and telithromycin at two times the MIC showed 99% killing of all nine strains after 12 h and 90% killing of all strains after 6 h. After 24 h, all drugs were bactericidal against four to seven strains when they were tested at the MIC. Ten of 11 strains tested by multistep selection analysis yielded resistant clones after 14 to 43 passages with erythromycin. Azithromycin gave resistant clones of all strains after 20 to 50 passages, and clarithromycin gave resistant clones of 9 of 11 strains after 14 to 41 passages. By comparison, GW 708408 gave resistant clones of 9 of 11 strains after 14 to 44 passages, and GW 773546 gave resistant clones of 10 of 11 strains after 14 to 45 passages. Telithromycin gave resistant clones of 7 of 11 strains after 18 to 45 passages. Mutations mostly in the L22 and L4 ribosomal proteins and 23S rRNA were detected in resistant strains selected with all compounds, with alterations in the L22 protein predominating. Single-step resistance selection studies at the MIC yielded spontaneous resistant mutants at frequencies of 1.5 ؋ 10 ؊9 to 2.2 ؋ 10 ؊6 with GW 773546, 1.5 ؋ 10 ؊9 to 6.0 ؋ 10 ؊4 with GW 708408, and 7.1 ؋ 10 ؊9 to 3.8 ؋ 10 ؊4 with telithromycin, whereas the frequencies were 1.3 ؋ 10 ؊9 to 6.0 ؋ 10 ؊4 with erythromycin and azithromycin and 2.0 ؋ 10 ؊9 to 2.0 ؋ 10 ؊3with clarithromycin. Alterations in the L22 protein (which were predominant) and the L4 protein were present in mutants selected by the single-step selection process. The postantibiotic effects of GW 773546, GW 708408, and telithromycin for seven H. influenzae strains were 6.6 h (range, 5.2 to 8.8 h), 4.7 h (range, 2.6 to 6.9 h), and 6.4 h (range, 3.8 to 9.7 h), respectively. The results of in vitro studies obtained with both novel macrolides were similar to those obtained with telithromycin and better than those obtained with older macrolides.

Section: Discussionsupporting

confidence: 89%

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confidence: 99%

Activities of Two Novel Macrolides, GW 773546 and GW 708408, Compared with Those of Telithromycin, Erythromycin, Azithromycin, and Clarithromycin against Haemophilus influenzae

Kosowska

Credito

Pankuch

et al. 2004

“…These organisms (followed by Streptococcus pneumoniae and Moraxella catarrhalis) are now considered to be the leading cause of acute exacerbations of chronic bronchitis and an important cause, together with S. pneumoniae and M. catarrhalis, of acute otitis media, sinusitis, and community-acquired respiratory tract infections (1,8,10,12,14,23).…”

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confidence: 99%

Susceptibilities of Haemophilus influenzae and Moraxella catarrhalis to ABT-773 Compared to Their Susceptibilities to 11 Other Agents

Credito

Lin

Pankuch

et al. 2001

The activity of the ketolide ABT-773 against Haemophilus and Moraxella was compared to those of 11 other agents. Against 210 Haemophilus influenzae strains (39.0% ␤-lactamase positive), microbroth dilution tests showed that azithromycin and ABT-773 had the lowest MICs (0.5 to 4.0 and 1.0 to 8.0 g/ml, respectively), followed by clarithromycin and roxithromycin (4.0 to >32.0 g/ml). Of the ␤-lactams, ceftriaxone had the lowest MICs (<0.004 to 0.016 g/ml), followed by cefixime and cefpodoxime (0.008 to 0.125 and <0.125 to 0.25 g/ml, respectively), amoxicillin-clavulanate (0.125 to 4.0 g/ml), and cefuroxime (0.25 to 8.0 g/ml). Amoxicillin was only active against ␤-lactamase-negative strains, and cefprozil had the highest MICs of all oral cephalosporins tested (0.5 to >32.0 g/ml). Against 50 Moraxella catarrhalis strains, all of the compounds except amoxicillin and cefprozil were active. Time-kill studies against 10 H. influenzae strains showed that ABT-773, at two times the MIC, was bactericidal against 9 of 10 strains, with 99% killing of all strains at the MIC after 24 h; at 12 h, ABT-773 gave 90% killing of all strains at two times the MIC. At 3 and 6 h, killing by ABT-773 was slower, with 99.9% killing of four strains at two times the MIC after 6 h. Similar results were found for azithromycin, with slightly slower killing by erythromycin, clarithromycin, and roxithromycin, especially at earlier times. ␤-Lactams were bactericidal against 8 to 10 strains at two times the MIC after 24 h, with slower killing at earlier time periods. Most compounds gave good killing of five M. catarrhalis strains, with ␤-lactams killing more rapidly than other drugs. ABT-773 and azithromycin gave the longest postantibiotic effects (PAEs) of the ketolide-macrolide-azalide group tested (4.4 to >8.0 h), followed by clarithromycin, erythromycin, and roxithromycin. ␤-Lactam PAEs were similar and shorter than those of the ketolidemacrolide-azalide group for all strains tested.Although development of an effective vaccine against Haemophilus influenzae type b has led to the disappearance of the organism in many parts of the world, its place has been taken by untypeable H. influenzae strains. These organisms (followed by Streptococcus pneumoniae and Moraxella catarrhalis) are now considered to be the leading cause of acute exacerbations of chronic bronchitis and an important cause, together with S. pneumoniae and M. catarrhalis, of acute otitis media, sinusitis, and community-acquired respiratory tract infections (1,8,10,12,14,23).Current recommendations by the National Committee for Clinical Laboratory Standards (NCCLS) for use of Haemophilus test medium (HTM) for Haemophilus susceptibility testing (13) have been complicated by difficulty in commercial manufacture of this medium and its short half-life when made in house. Reliable Haemophilus susceptibility testing with HTM requires the use of freshly made medium within 3 weeks of manufacture (11,22 , abstr. 2136, 1999). This study further examined activity of ABT-773 against Haemophilus an...

“…AZM has a broad spectrum of antimicrobial activity, which includes most gram-positive bacteria (22) and certain other organisms, including Mycoplasma spp. (30) and Legionella spp.…”

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confidence: 99%

Comparative in vitro exoenzyme-suppressing activities of azithromycin and other macrolide antibiotics against Pseudomonas aeruginosa

Mizukane

Hirakata

Kaku

et al. 1994

The inhibitory effects of azithromycin (AZM), a new 15-membered macrolide antibiotic, on the production of exotoxin A, total protease, elastase, and phospholipase C by Pseudomonas aeruginosa were determined, and the virulence-suppressing effects of AZM were compared with those of erythromycin (EM), roxithromycin (RXM), and rokitamycin (RKM). The elfect of exposure ofP. aeruginosa PA103 or B16 in cultures to sub-MICs of these macrolide antibiotics on the production of exoenzymes was determined. AZM suppressed the in vitro production of extracellular and intracellular exotoxin A by P. aeruginosa PA103 more than did EM, even at a concentration of only 2 ,ug/ml. At concentrations of between 4 and 32 ,ug/ml, AZM also inhibited total protease, elastase, and phospholipase C production by P. aeruginosa B16 more than did EM, RXM, and RKM. AZM was effective in suppressing exotoxin A and total protease production through 24 h of incubation in the presence of drug at sub-MICs, but it had no significant effect on either the growth of P. aeruginosa or its total protein production. Moreover, at a concentration of 4 ,ug/ml, AZM suppressed exoenzyme production by other strains of P. aeruginosa more than did EM. These findings indicate that AZM, EM, RXM, and RKM each has an inhibitory effect on exoenzyme production separate from the antimicrobial effect and that, of these macrolides, AZM has the strongest virulence-suppressing effect.Pseudomonas aeruginosa is an opportunistic pathogen which frequently causes severe septicemia in immunocompromised hosts (4, 5). It is also the principal pulmonary pathogen in patients with cystic fibrosis (24, 33) and diffuse panbronchiolitis (16). P. aeruginosa exoenzymes, including exotoxin A, alkaline protease, elastase, and phospholipase C, are known to be virulence factors of importance in the various types of P. aeruginosa infections (26). The findings of our previous studies have suggested that P. aeruginosa isolates from blood cultures produce large quantities of exotoxin A and total protease (10) and that the production of exotoxin A plays an important role in the pathogenesis of endogenous P. aeruginosa septicemia in mice (13).It has recently been reported that treatment with erythromycin (EM) improves the clinical symptoms and prognosis of patients with chronic pulmonary infections (18). Kita et al. (18) have shown that erythromycin stearate (EMS) suppresses the production of protease and leukocidin by P. aeruginosa without affecting cell growth and speculated that EMS may affect the virulence factors of this organism (18) and host defense mechanisms (7, 9, 17). More recently, we have shown that erythromycin lactobionate (EML) suppresses the in vitro pro-