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PubMed2002

Pharmacoepidemiological analysis of provincial differences between consumption of macrolides and rates of erythromycin resistance among Streptococcus pyogenes isolates in Spain.

The M phenotype is by far the most common mechanism of erythromycin resistance among Streptococcus pyogenes isolates in Spain. A geographic analysis of the relationship between within-country differences in the prevalence of M-type resistance to erythromycin in S. pyogenes and the level of consumption of 14- and 15-membered macrolides within different provinces was carried out. From 1998 to 1999, a nationwide multicenter surveillance study yielded 2,039 consecutive pharyngeal isolates of S. pyogenes. Data on antibiotic consumption for the same period were gathered from IMS Health, and the corresponding daily defined doses per 1,000 inhabitants per day were calculated according to the Anatomic Therapeutic Classification index. Macrolide use was subdivided into dosages given three times a day (TID), twice a day (BID), or once a day (OD). Spearman nonparametric correlation coefficients (R) were calculated, and variables proving to be significantly associated (P < 0.1) were introduced into a linear regression model. The total consumption of macrolides presented a significant correlation with the prevalence of resistance (R = 0.527; P = 0.032). Neither TID nor BID macrolide consumption showed significant correlations. Only OD consumption had a significance below 0.1. These data are consistent with the hypothesis that only the total consumption of macrolides influences the local rates of M-type erythromycin resistance in S. pyogenes, and subgroups of macrolides seem to have an additive rather than a selective effect by contributing to increasing the final amount of macrolides used. Local variations in total consumption were associated only with BID consumption (R = 0.849; P = 0.004). The simple linear regression with total macrolide consumption showed a considerable determination coefficient (R(2) = 0.678; P = 0.006). The model explains up to 68% of the measured variation and is clearly better as a predictor of the prevalence of resistance than the mere mean is. By solving the regression equation, the resultant value of 2.2 defined doses per 1,000 inhabitants per day fits with the existence of a critical threshold of selective pressure.

Anti-Bacterial Agents↗
PubMed1998

[Inhibitory effect of macrolide antibiotics on biofilm formation by Pseudomonas aeruginosa].

In recent years, various medical indwelling devices have been developed and used. Bacteria adhering to these devices often cause refractory infection. In the field of otolaryngology, refractory infection accompanying these medical indwelling devices such as middle ear ventilation tubes and artificial auditory ossicles has been reported. The concept of bacterial biofilm infection has been suggested as an explanation for the refractory infection. Furthermore it has been reported that a bacterial biofilm is involved in refractory infection unrelated to medical indwelling devices. Topical biofilm formation was detected in patients with chronic sinusitis, chronic purulent otitis media or habitual tonsillitis. In this study, we morphologically and quantitatively examined the biofilm-forming capacity of a clinically isolated strain of mucoid type Psecudomonas aeruginosa on Teflon to investigate the effects of macrolide antibiotics on bacterial biofilm formation. In the morphological examination, P.aeruginosa was cultured together with a Teflon sheet in minimal medium containing various concentrations of the macrolide antibiotics clarithromycin (CAM), erythromycin (EM) and midecamycin (MDM), at 37 degrees C for 7 days. The surfaces of the Teflon sheets were examined by electron microscopy. The adherent bacteria and biofilm formation on Teflon sheets soaked in minimal medium containing CAM or EM were found to be decreased in a dose-dependent manner. However, in the Teflon sheets soaked in minimal medium containing MDM, there was no decrease in biofilm formation regardless of the MDM concentration. In the quantitative examination, P. aeruginosa was cultured in minimal medium containing various concentrations of the macrolide antibiotics at 37 degrees C for 7 days together with Teflon beads. The levels of hexose, protein and alginate adhering to the Telfon beads were quantified as an estimation of biofilm formation. On Teflon beads treated with CAM or EM, there were dose-dependent decreases in hexose, protein and alginate levels. In particular, marked decreases were noted when CAM and EM concentrations were 10 micrograms/ml or more. Furthermore, there was no significant difference between CAM and EM. However, in the presence of MDM, there was no decrease in hexose, protein or alginate levels regardless of the MDM concentration. The minimal inhibitory concentration (MIC100) of each macrolide against P. aeruginosa used in this experiment was 100 micrograms/ml or more. There may be no bactericidal effect on this strain at the macrolide concentrations used in this experiment. However, this experiment used 7-day treatment. The long-term bactericidal activity of macrolides was examined. In the presence of CAM or MDM, bacterial levels after culture were similar to preculture levels or slightly lower than the preculture levels. In the presence of EM, bacterial levels were similar to the preculture levels. These results demonstrated that CAM and EM, which are 14-membered macrolides inhibited biofilm formation, while MDM which is 16-membered macrolide, did not. These inhibitory effects of CAM and EM may be related to actions other than bactericidal activity. In our experiment, CAM and EM inhibited biofilm formation at 10 micrograms/ml or more. This concentration corresponded to 1/20 x MIC. This concentration can be achieved in tissues, nasal discharge and sputum with actual clinical doses. Therefore, these agents may be effective against biofilm disease caused by P. aeruginosa in the field of otolaryngology.

Anti-Bacterial Agents↗
PubMed2004

Macrolide antibiotics for cystic fibrosis.

BACKGROUND: Chronic severe infection with Pseudomonas aeruginosa, affects many people with cystic fibrosis (CF). There is evidence from the laboratory and from other disease processes that macrolide antibiotics, whilst not directly active against Pseudomonas aeruginosa, may have indirect actions against this organism. OBJECTIVES: We aimed to test the hypotheses that, in people with CF, macrolide antibiotics:(1) improve clinical status compared to placebo or another antibiotic;(2) do not have unacceptable adverse effects. If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of macrolide therapy. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group trials register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We contacted principal investigators known to work in the field, previous authors and pharmaceutical companies who manufacture macrolide antibiotics for unpublished or follow-up data (December 2003). Most recent search of the Group's register: January 2004 SELECTION CRITERIA: Published or unpublished randomised controlled trials of macrolide antibiotics compared to placebo, another class of antibiotic or another macrolide antibiotic. Studies comparing regimens of the same macrolide antibiotic at different doses will also be included. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed study quality. Three groups were contacted for missing data and we hope to include these in future reviews. MAIN RESULTS: Searches identified 14 studies, four were included in this review (296 participants). Two studies enrolled adults, one children (a significant number of whom were not colonised with Pseudomonas aeruginosa) and one both adults and children. All the clinical studies reported small but significant improvements in respiratory function with azithromycin versus placebo. Meta-analysis at the one-month and six-month time points demonstrates a significant benefit with respect to relative change in FEV1 (at six months, for n = 104, azithromycin and n = 114, placebo; WMD 5.82% (95% CI 2.45 to 9.20)). The largest study reported a significant increase in mild adverse events (nausea, diarrhoea and wheezing). REVIEWERS' CONCLUSIONS: There is clear evidence from these studies of a small but significant improvement in respiratory function following treatment with azithromycin. The largest study employed a three times a week dose and, in this study, treatment with azithromycin was associated with a significant increase in mild adverse events. Further studies are needed to clarify the precise role of azithromycin in the treatment of CF lung disease.

Anti-Bacterial Agents↗
PubMed2005

Macrolides for chronic asthma.

BACKGROUND: Asthma is a chronic disease of the airways in which inflammation of the respiratory mucosa plays a crucial role. The mechanisms responsible for the maintaining of this inflammatory response are only partially known and there is evidence that a role could be paid by chronic infection by intracellular pathogens (such as Chlamydia pneumoniae). Macrolides are antibiotics with both antimicrobic and antiinflammatory activities and thus their use in asthmatic patients could lead to reduction of the airways inflammation and therefore improvement of symptoms and pulmonary function. OBJECTIVES: To determine whether macrolides are effective in the management of patients with chronic asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of trials up to May 2004. This was also supplemented by manually searching bibliographies of previously published reviews, conference proceedings, and contacting study authors. All languages were included in the initial search. SELECTION CRITERIA: Randomised, controlled clinical trials involving both children and adult patients with chronic asthma treated with macrolides for more than 4 weeks, versus placebo. DATA COLLECTION AND ANALYSIS: Two reviewers independently examined all identified articles. The full text of any potentially relevant article was reviewed independently by two reviewers. MAIN RESULTS: Seven studies recruiting a total of 416 participants met the inclusion criteria. The quality of reporting of study methodology was generally low. We assembled findings from studies comparing macrolide treatment for at least 4 weeks in adult and pediatric patients treated for chronic asthma. Four studies showed a positive effect on symptoms of macrolides in different types of asthmatic patients. There were limited data available for meta-analysis. There was no significant difference in FEV1 for either parallel or crossover trials. However, there were significant differences in eosinophilic inflammation and symptoms. One large parallel group trial reported significant differences in peak flow but these differences abated within six months of treatment. AUTHORS' CONCLUSIONS: Considering the small number of patients studied, there is insufficient evidence to support or to refute the use of macrolides in patients with chronic asthma. Further studies are needed in particular to clarify the potential role of macrolides in some subgroups of asthmatics such as those with evidence of chronic bacterial infection.

Anti-Bacterial Agents↗
PubMed2005

Macrolides for chronic asthma.

BACKGROUND: Asthma is a chronic disease of the airways in which inflammation of the respiratory mucosa plays a crucial role. The mechanisms responsible for the maintaining of this inflammatory response are only partially known and there is evidence that a role could be paid by chronic infection by intracellular pathogens (such as Chlamydia pneumoniae). Macrolides are antibiotics with both antimicrobic and antiinflammatory activities and thus their use in asthmatic patients could lead to reduction of the airways inflammation and therefore improvement of symptoms and pulmonary function. OBJECTIVES: To determine whether macrolides are effective in the management of patients with chronic asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of trials up to May 2005. This was also supplemented by manually searching bibliographies of previously published reviews, conference proceedings, and contacting study authors. All languages were included in the initial search. SELECTION CRITERIA: Randomised, controlled clinical trials involving both children and adult patients with chronic asthma treated with macrolides for more than 4 weeks, versus placebo. DATA COLLECTION AND ANALYSIS: Two reviewers independently examined all identified articles. The full text of any potentially relevant article was reviewed independently by two reviewers. MAIN RESULTS: Seven studies recruiting a total of 416 participants met the inclusion criteria. The quality of reporting of study methodology was generally low. We assembled findings from studies comparing macrolide treatment for at least 4 weeks in adult and pediatric patients treated for chronic asthma. Four studies showed a positive effect on symptoms of macrolides in different types of asthmatic patients. There were limited data available for meta-analysis. There was no significant difference in FEV1 for either parallel or crossover trials. However, there were significant differences in eosinophilic inflammation and symptoms. One large parallel group trial reported significant differences in peak flow but these differences abated within six months of treatment. AUTHORS' CONCLUSIONS: Considering the small number of patients studied, there is insufficient evidence to support or to refute the use of macrolides in patients with chronic asthma. Further studies are needed in particular to clarify the potential role of macrolides in some subgroups of asthmatics such as those with evidence of chronic bacterial infection.

Anti-Bacterial Agents↗
PubMed2003

Novel macrolide-adjustable bidirectional expression modules for coordinated expression of two different transgenes in mice.

BACKGROUND: Precise control of transgene expression is essential for a variety of applications ranging from gene-function analysis, biopharmaceutical manufacturing to next-generation molecular interventions in gene therapy and tissue engineering. The regulation of gene expression is currently a key issue for clinical implementation of gene-therapy-based treatments since desired transgene expression may need to be maintained within a narrow therapeutic window for successful treatment of a particular human disease. METHODS: We have designed a novel bidirectional expression module that enables adjustable coregulation of two different transgenes in response to clinical doses of macrolide antibiotics. A bidirectional macrolide-responsive promoter consisting of a central operator module (ETR) specific for the macrolide-dependent transactivator (ET1) is flanked by two minimal promoters (P(hCMVmin); P(hsp70min)) which drive expression of two divergently oriented transgenes. Macrolide antibiotics modulate the binding affinity of ET1 to ETR and adjust expression of both transgenes to desired levels. RESULTS: Bidirectional expression configurations enabled excellent macrolide-adjustable coregulation profiles of two secreted reporter genes or one-vector-based autoregulated fine-tuning of a single transgene in various transgenic rodent and human cell lines. Following implantation of microencapsulated CHO-K1 cell derivatives transgenic for macrolide-controlled bidirectional expression of erythropoietin (EPO) and the human secreted alkaline phosphatase (SEAP) intraperitoneally into mice, serum EPO and SEAP levels could be coadjusted to desired levels by administration of different erythromycin doses. CONCLUSIONS: Based on their in vivo compatibility, the versatile bidirectional and macrolide-responsive expression modules represent an important advancement on the way to implementing targeted and conditional molecular interventions into a clinical reality.

Alkaline Phosphatase↗
PubMed2006

Macrolide and ketolide resistance with Streptococcus pneumoniae.

Antimicrobial agents in the macrolide family have long been considered drugs of potential utility in the management of infections caused by Streptococcus pneumoniae. However, with the emergence of macrolide resistance, the clinical value of macrolides in pneumococcal infections is threatened. In part, as a consequence of the development of macrolide resistance, recently the first agent in the ketolide antimicrobial class, telithromycin, was developed and introduced into clinical practice. The ketolides are macrolide antimicrobials whose chemistry has been modified so as avoid the effects of the most common mechanisms of macrolide resistance with S pneumoniae. This discussion reviews the current state of resistance to macrolides and ketolides with S pneumoniae in North America.

Anti-Bacterial Agents↗
PubMed1998

[New macrolides].

INTRODUCTION: Following their use for a few years, the place of new macrolides can be assessed. CURRENT KNOWLEDGE AND KEY POINTS: "New macrolides", ie, roxithromycin, clarithromycin, azithromycin and dirithromycin, are derivated from erythromycin and defined by different pharmacokinetic parameters: longer half time with better oral administration and shorter duration of treatment, better tissue concentrations with reduction of dosages and better tolerance, high cellular concentration with good activity. However, new macrolides and erythromycin do not show major differences in their antibacterial spectrum against usual pyogenic strains. Clinical use of new macrolides extends to opportunistic infections, such as atypical mycobacterial infections or toxoplasmosis, occurring in the course of HIV infection. New macrolides are also recommended for the treatment of Helicobacter pylori-related gastroduodenal ulcer. FUTURE PROSPECTS AND PROJECTS: New macrolides have opened new avenues in the development of anti-infectious strategies. Due to their good efficacy against Chlamydia pneumoniae which is suspected of inducing vascular diseases, the upcoming use of ketolids and the development of their non-antibiotic effects, the future of macrolides is favorable.

AIDS-Related Opportunistic Infections↗
PubMed2003

Macrolide resistance in Streptococcus pneumoniae isolated from patients with community-acquired lower respiratory tract infections in Portugal: results of a 3-year (1999-2001) multicenter surveillance study.

A nationwide multicenter study (including 31 laboratories) of the antimicrobial susceptibility of 1210 Streptococcus pneumoniae isolates from patients with community-acquired lower respiratory tract infections (LRTI) was carried out over 3 years (1999-2001) in Portugal. Testing of all isolates was undertaken in a central laboratory. Overall macrolide resistance was 13.1%. Decreased susceptibility to penicillin was 24.5% (15.5% low-level and 9.0% high-level resistance). Taken into consideration, the resistance rates reported in a previous surveillance study of 1989-1993, a six-fold increase of erythromycin resistance in the last decade was documented. Resistance to erythromycin, clarithromycin, and azithromycin was higher in pediatric patients than in adults. The overwhelming majority (82.3%) of macrolide-resistant isolates were multidrug resistant, although 44.9% were fully susceptible to penicillin. Most macrolide-resistant isolates (80.4%) showed the MLSB phenotype (76.6% MLSB-constitutive resistance, and 3.8% MLSB-inducible resistance) and were also resistant to clindamycin, tetracycline, and co-trimoxazole. The M phenotype was seen in 19.6% isolates and these had MIC90 values of 8 mg/L for erythromycin and clarithromycin, and of 12 mg/L for azithromycin. The clinical significance of macrolide resistance in the management of LRTI is discussed. Because of the specific situation concerning macrolide resistance described in S. pneumoniae, careful use of macrolide antibiotics in therapy and cautious monitoring of macrolide resistance should be continued in Portugal.

Adult↗
PubMed1993

Comparison of macrolide antibiotics.

Macrolides have been in use since the early 1950s. In recent years new macrolides have been developed to try to overcome the problems associated with erythromycin. In general they have fairly similar in-vitro activity, although azithromycin has superior activity against Haemophilus influenzae and some Gram-negative organisms. Clarithromycin shows superior in-vitro activity against Legionella spp. and against the type strain of Chlamydia pneumoniae. The pharmacology of macrolides produces many interpretive problems, and macrolides show marked variation in their pharmacokinetic parameters, tissue affinity and intracellular penetration. Newer macrolides such as clarithromycin, roxithromycin, dirithromycin and azithromycin only need to be taken once or twice a day, which is likely to improve patient compliance. Few objective side-effect studies have been performed with the newer macrolides. Clinical efficacy studies are essential to elucidate the significance of the complex pharmacology of macrolides.

Absorption↗
PubMed2004

Anti-inflammatory effects of macrolides--an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions?

BACKGROUND: It has been recognized for more than 20 years that the macrolides have immunomodulatory effects that are beneficial for those suffering from chronic pulmonary inflammatory syndromes, such as diffuse panbronchiolitis, cystic fibrosis, asthma and bronchiectasis. The macrolides have consistently been associated with decreased length of stay and mortality when used alone or in combination with beta-lactam antibiotics. This effect can be demonstrated against combinations consisting of beta-lactams and other antibiotics active against 'atypical chest pathogens' when treating community-acquired pneumonia (CAP) in hospitalized patients. As such, it appears that the macrolides' effects in CAP patients are more than just antibacterial in nature. AIMS OF THIS REVIEW: This review aims: to give the reader information on the background areas described, as well as related areas; to review the CAP benefits with macrolides and how they may be related to the immunomodulatory properties they demonstrate, albeit in a shorter period of time than previously demonstrated with chronic pulmonary disorders; to use ex vivo data to support these extrapolations. LITERATURE SEARCH: A literature search using Medline was conducted from 1966 onwards, searching for articles with relevant key words such as macrolide, diffuse panbronchiolitis, community-acquired pneumonia, biofilm, immunomodulation, cystic fibrosis, erythromycin, clarithromycin, roxithromycin and azithromycin, bronchiectasis and asthma. When appropriate, additional references were found from the bibliographies of identified papers of interest. Any relevant scientific conference proceedings or medical texts were checked when necessary. CONCLUSIONS: (1) Research into macrolide immunomodulation for chronic pulmonary disorders demonstrates consistent positive effects, although of types other than seen with diffuse panbronchiolitis. These effects, together with their inhibitory activity on biofilms, have the potential to make them a useful option. (2) The benefits for CAP are consistent, and higher when a macrolide is given with another atypical agent than if the other atypical agent is given alone, suggesting a non-antibacterial benefit. (3) Recent research of the immunomodulatory properties of azithromycin imply that azithromycin may have a previously unknown short-term biphasic effect on inflammation modulation: enhancement of host defence mechanisms shortly after initial administration followed by curtailment of local infection/inflammation in the following period. (4) Additional in vivo research is needed prior to developing any firm conclusions.

Anti-Bacterial Agents↗
PubMed2006

European Surveillance of Antimicrobial Consumption (ESAC): outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe.

BACKGROUND: Data on outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe were collected from 25 countries within the ESAC project, funded by DG SANCO of the European Commission, using the WHO ATC/DDD methodology. METHODS: For the period 1997-2003, data on outpatient use of systemic MLS aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2004) per 1000 inhabitants per day (DID). Macrolide use was analysed in detail, using a classification based on their mean plasma elimination half-life. RESULTS: Total outpatient MLS use in 2003 varied by a factor of 11 between the country with the highest (9.36 DID in Greece) and lowest (0.85 DID in Sweden) use. MLS use showed high seasonal variation. Short-, intermediate- and long-acting macrolides were used most in 6, 18 and 1 countries, respectively (mainly erythromycin, clarithromyin and azithromycin, respectively). Lincosamide use was observed in all countries (mainly clindamycin) and substantial streptogramin use only in France (pristinamycin). From 1997 to 2003, MLS use increased in 14 countries and was most pronounced in Greece (increase of >5 DID). Except for Sweden, a relative increase of intermediate- (mainly clarithromycin) and/or long-acting (mainly azithromycin) macrolide use was observed, at the expense of short-acting macrolide (mainly erythromycin) use. CONCLUSION: The observed differences between European countries in the levels of MLS use and the extreme seasonal variations in their use suggest that this class of antibiotics is prescribed inappropriately in many countries. The MLS classification developed here facilitates a more comprehensive description of macrolide use in Europe. These data (collected as part of ESAC) could promote investigations that lead to a deeper understanding of the link between macrolide use and resistance.

Anti-Bacterial Agents↗
PubMed2004

Therapeutic implications of macrolide resistance in pneumococcal community-acquired lower respiratory tract infections.

Macrolide anti-bacterials are widely used for the empirical treatment of lower respiratory tract infections (RTIs) due to their activity against Streptococcus pneumoniae and other common respiratory pathogens and good safety/tolerability profile. However, the prevalence of macrolide resistance, particularly pneumococcal macrolide resistance, is increasing all around the world. The mechanisms underlying macrolide resistance include efflux pump, methylase activity and, less commonly, ribosomal mutation, which produce differing levels of resistance. Growth in macrolide resistance has been linked to the increased use of these agents, and several risk factors for the development of resistance have been identified. There are emerging data to suggest that in vitro macrolide resistance may increase the likelihood of treatment failure in patients with lower RTIs. However, at present, treatment failure is rare and randomised; intervention-based trials investigating the impact of anti-bacterial resistance on clinical outcomes are lacking. Strategies to promote appropriate use of macrolides and other anti-bacterials are needed, both to maximise therapeutic impact and to minimise the development of resistance. Furthermore, there is a need for alternative anti-bacterial agents which have high efficacy against respiratory pathogens (including resistant strains) and a low potential to induce resistance.

Community-Acquired Infections↗
PubMed1991

Comparative activity of macrolides against Toxoplasma gondii demonstrating utility of an in vitro microassay.

The utility of spiramycin for preventing transplacental transmission of toxoplasmosis and the efficacy of conventional macrolides against Toxoplasma gondii are subjects of active debate. An in vitro microassay was developed to determine the relative inhibitory activity against T. gondii of 24 conventional macrolides derived from erythromycin and tylosin (14- and 16-membered macrolides, respectively). Macrolides and T. gondii RH tachyzoites were added to monolayers of BT cells grown in 96-well plates. Plates were incubated for 20 h at 37 degrees C, and the growth of T. gondii was then measured by the selective incorporation of [3H]uracil in trichloroacetic acid-precipitable material during an additional incubation of 20 h. Dose-response curves and 50 and 90% inhibitory concentrations (IC50 and IC90, respectively) were determined for each drug. Microscopic examination was performed on stained replicates of the infected monolayers, and the relative toxicities of the drugs for host cells were determined. Spiramycin and tylosin showed only limited activity against T. gondii (IC50 of 20.16 and 20.00 micrograms/ml, respectively). Erythromycin and azithromycin had a better anti-Toxoplasma activity with IC50 of 14.38 and 8.61 micrograms/ml, respectively, whereas drugs like desmycosin, dirithromycin, and roxithromycin had no detectable activity. Although many macrolides inhibited intracellular proliferation of T. gondii, azithromycin was the only macrolide demonstrating prolonged inhibitory activity on the replication of intracellular tachyzoites. We conclude that conventional 14- and 16-membered macrolides often interfere with the growth of, but may not kill, T. gondii RH tachyzoites in vitro.

Animals↗
PubMed1997

Induction of ermSV by 16-membered-ring macrolide antibiotics.

The erm family of 23S rRNA adenine-N6-methyltransferases confers resistance to all macrolide-lincosamide-streptograminB (MLS) antibiotics, but not all MLS antibiotics induce synthesis of Erm methyltransferase with equal efficiency in a given organism. The induction efficiency of a test panel of MLS antibiotics was studied by using two translational attenuator-lac reporter gene fusion constructs, one based on ermSV from Streptomyces viridochromogenes NRRL 2860 and the other based on ermC from Staphylococcus aureus RN2442. Four types of responses which were correlated with the macrolide ring size were seen, as follows: group 1, both ermSV and ermC were induced by the 14-membered-ring macrolides erythromycin, lankamycin, and matromycin, as well as by the lincosamide celesticetin; group 2, neither ermSV nor ermC was induced by the 12-membered-ring macrolide methymycin or by the lincosamide lincomycin or the streptogramin type B antibiotic ostreogrycin B; group 3, ermSV was selectively induced over ermC by the 16-membered-ring macrolides carbomycin, chalcomycin, cirramycin, kitasamycin, maridomycin, and tylosin; and group 4, ermC was selectively induced over ermSV by the 14-membered-ring macrolide megalomicin. These data suggest that the leader peptide determines the specificity of induction by different classes of MLS antibiotics and that for a given attenuator, a major factor which determines whether a given macrolide induces resistance is its size.

Anti-Bacterial Agents↗
PubMed2003

Intrinsic macrolide resistance in Mycobacterium smegmatis is conferred by a novel erm gene, erm(38).

High-level, acquired macrolide resistance in mycobacteria is conferred by mutation within the 23S rRNA gene. However, several mycobacteria are naturally resistant to macrolides, including the Mycobacterium smegmatis group and Mycobacterium tuberculosis complex. Thus, the aim of this study was to characterize this resistance. Intrinsic macrolide resistance in M. smegmatis was inducible and showed cross-resistance to lincosamides but not to streptogramin B (i.e., ML resistance). A similar phenotype was found with Mycobacterium microti and macrolide-resistant Mycobacterium fortuitum. A search of the DNA sequence data for M. smegmatis strain mc(2)155 identified a novel erm gene, erm(38), and expression analysis showed that erm(38) RNA levels increased >10-fold after a 2-h incubation with macrolide. Inducible ML resistance was not expressed by an erm(38) knockout mutant, and complementation of this mutant with intact erm(38) in trans resulted in high-level ML resistance (e.g., clarithromycin MIC of >512 micro g/ml). Thus, the results indicate that erm(38) confers the intrinsic ML resistance of M. smegmatis. Southern blot analysis with an erm(38)-specific probe indicated that a similar gene may be present in macrolide-resistant M. fortuitum. This finding, with the presence of the erm(37) gene (Rv1988) in the M. tuberculosis complex, suggests that such genes are widespread in mycobacteria with intrinsic macrolide resistance.

Amino Acid Sequence↗
PubMed2004

Antipneumococcal activities of two novel macrolides, GW 773546 and GW 708408, compared with those of erythromycin, azithromycin, clarithromycin, clindamycin, and telithromycin.

The MICs of GW 773546, GW 708408, and telithromycin for 164 macrolide-susceptible and 161 macrolide-resistant pneumococci were low. The MICs of GW 773546, GW 708408, and telithromycin for macrolide-resistant strains were similar, irrespective of the resistance genotypes of the strains. Clindamycin was active against all macrolide-resistant strains except those with erm(B) and one strain with a 23S rRNA mutation. GW 773546, GW 708408, and telithromycin at two times their MICs were bactericidal after 24 h for 7 to 8 of 12 strains. Serial passages of 12 strains in the presence of sub-MICs yielded 54 mutants, 29 of which had changes in the L4 or L22 protein or the 23S rRNA sequence. Among the macrolide-susceptible strains, resistant mutants developed most rapidly after passage in the presence of clindamycin, GW 773546, erythromycin, azithromycin, and clarithromycin and slowest after passage in the presence of GW 708408 and telithromycin. Selection of strains for which MICs were >/=0.5 microg/ml from susceptible parents occurred only with erythromycin, azithromycin, clarithromycin, and clindamycin; 36 resistant clones from susceptible parent strains had changes in the sequences of the L4 or L22 protein or 23S rRNA. No mef(E) strains yielded resistant clones after passage in the presence of erythromycin and azithromycin. Selection with GW 773546, GW 708408, telithromycin, and clindamycin in two mef(E) strains did not raise the erythromycin, azithromycin, and clarithromycin MICs more than twofold. There were no change in the ribosomal protein (L4 or L22) or 23S rRNA sequences for 15 of 18 mutants selected for macrolide resistance; 3 mutants had changes in the L22-protein sequence. GW 773546, GW 708408, and telithromycin selected clones for which MICs were 0.03 to >2.0 microg/ml. Single-step studies showed mutation frequencies <5.0 x 10(-10) to 3.5 x 10(-7) for GW 773546, GW 708408, and telithromycin for macrolide-susceptible strains and 1.1 x 10(-7) to >4.3 x 10(-3) for resistant strains. The postantibiotic effects of GW 773546, GW 708408, and telithromycin were 2.4 to 9.8 h.

Anti-Bacterial Agents↗
PubMed2005

In vitro and in vivo activities of macrolide derivatives against Mycobacterium tuberculosis.

Existing macrolides have never shown definitive clinical efficacy in tuberculosis. Recent reports suggest that ribosome methylation is involved in macrolide resistance in Mycobacterium tuberculosis, a mechanism that newer macrolides have been designed to overcome in gram-positive bacteria. Therefore, selected macrolides and ketolides (descladinose) with substitutions at positions 9, 11,12, and 6 were assessed for activity against M. tuberculosis, and those with MICs of < or = 4 microM were evaluated for cytotoxicity to Vero cells and J774A.1 macrophages. Several compounds with 9-oxime substitutions or aryl substitutions at position 6 or on 11,12 carbamates or carbazates demonstrated submicromolar MICs. For the three macrolide-ketolide pairs, macrolides demonstrated superior activity. Four compounds with low MICs and low cytotoxicity also effected significant reductions in CFU in infected macrophages. Active compounds were assessed for tolerance and the ability to reduce CFU in the lungs of BALB/c mice in an aerosol infection model. A substituted 11,12 carbazate macrolide demonstrated significant dose-dependent inhibition of M. tuberculosis growth in mice, with a 10- to 20-fold reduction of CFU in lung tissue. Structure-activity relationships, some of which are unique to M. tuberculosis, suggest several synthetic directions for further improvement of antituberculosis activity. This class appears promising for yielding a clinically useful agent for tuberculosis.

Amino Acid Substitution↗