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PubMed1999

Patterns of macrolide resistance determinants among community-acquired Streptococcus pneumoniae isolates over a 5-year period of decreased macrolide susceptibility rates.

Erythromycin resistance rates were found to be increased, from 7.1 in 1993 to 32.8% in 1997, among community-acquired Streptococcus pneumoniae isolates from the Siena area of central Italy. Most of the erythromycin-resistant isolates carried ermAM determinants and were also resistant to josamycin and clindamycin, whereas a minority (5.8%) carried mefA determinants and remained susceptible to the latter drugs.

Anti-Bacterial Agents↗
PubMed1982

[Drug interactions with macrolids compared action of two macrolids on liver microsomal activity ].

Pharmacokinetic parameters for elimination of antipyrine, regarded as a marker of the oxidative activity of liver microsomes, were studied in six health volunteers after oral administration of 1 g of the drug. Elimination half life and metabolic clearance were determined prior to (controls) and on day 2 of a treatment with troleandomycin (1500 mg/day), on days 7 and 14 of a treatment with midecamycin (1200 mg/day) and on days 7 and 14 of a treatment with phenobarbital (100 mg/day) as reference. A marked difference was evident between troleandomycin (whose inhibitor effects on the liver metabolism of certain drugs (ergot derivatives, theophylline, etc) are known, and midecamycin. This one had no inhibitor action and this finding is consistent with previous results bearing on the pharmacokinetics of theophylline during antibiotic therapy: only on the 14th day was a slight inductor effect seen, but it remained much lower than that of phenobarbital whose effects were significant on both the 7th and the 14th days.

Adult↗
PubMed2001

Review of macrolides and ketolides: focus on respiratory tract infections.

The first macrolide, erythromycin A, demonstrated broad-spectrum antimicrobial activity and was used primarily for respiratory and skin and soft tissue infections. Newer 14-, 15- and 16-membered ring macrolides such as clarithromycin and the azalide, azithromycin, have been developed to address the limitations of erythromycin. The main structural component of the macrolides is a large lactone ring that varies in size from 12 to 16 atoms. A new group of 14-membered macrolides known as the ketolides have recently been developed which have a 3-keto in place of the L-cladinose moiety. Macrolides reversibly bind to the 23S rRNA and thus, inhibit protein synthesis by blocking elongation. The ketolides have also been reported to bind to 23S rRNA and their mechanism of action is similar to that of macrolides. Macrolide resistance mechanisms include target site alteration, alteration in antibiotic transport and modification of the antibiotic. The macrolides and ketolides exhibit good activity against gram-positive aerobes and some gram-negative aerobes. Ketolides have excellent activity versus macrolide-resistant Streptococcus spp. Including mefA and ermB producing Streptococcus pneumoniae. The newer macrolides, such as azithromycin and clarithromycin, and the ketolides exhibit greater activity against Haemophilus influenzae than erythromycin. The bioavailability of macrolides ranges from 25 to 85%, with corresponding serum concentrations ranging from 0.4 to 12 mg/L and area under the concentration-time curves from 3 to 115 mg/L x h. Half-lives range from short for erythromycin to medium for clarithromycin, roxithromycin and ketolides, to very long for dirithromycin and azithromycin. All of these agents display large volumes of distribution with excellent uptake into respiratory tissues and fluids relative to serum. The majority of the agents are hepatically metabolised and excretion in the urine is limited, with the exception of clarithromycin. Clinical trials involving the macrolides are available for various respiratory infections. In general, macrolides are the preferred treatment for community-acquired pneumonia and alternative treatment for other respiratory infections. These agents are frequently used in patients with penicillin allergies. The macrolides are well-tolerated agents. Macrolides are divided into 3 groups for likely occurrence of drug-drug interactions: group 1 (e.g. erythromycin) are frequently involved, group 2 (e.g. clarithromycin, roxithromycin) are less commonly involved, whereas drug interactions have not been described for group 3 (e.g. azithromycin, dirithromycin). Few pharmacoeconomic studies involving macrolides are presently available. The ketolides are being developed in an attempt to address the increasingly prevalent problems of macrolide-resistant and multiresistant organisms.

Adolescent↗
PubMed1999

Mechanisms of bacterial resistance to macrolide antibiotics.

Macrolides have been used in the treatment of infectious diseases since the late 1950s. Since that time, a finding of antagonistic action between erythromycin and spiramycin in clinical isolates1 led to evidence of the biochemical mechanism and to the current understanding of inducible or constitutive resistance to macrolides mediated by erm genes containing, respectively, the functional regulation mechanism or constitutively mutated regulatory region. These resistant mechanisms to macrolides are recognized in clinically isolated bacteria. (1) A methylase encoded by the erm gene can transform an adenine residue at 2058 (Escherichia coli equivalent) position of 23S rRNA into an 6N, 6N-dimethyladenine. Position 2058 is known to reside either in peptidyltransferase or in the vicinity of the enzyme region of domain V. Dimethylation renders the ribosome resistant to macrolides (MLS). Moreover, another finding adduced as evidence is that a mutation in the domain plays an important role in MLS resistance: one of several mutations (transition and transversion) such as A2058G, A2058C or U, and A2059G, is usually associated with MLS resistance in a few genera of bacteria. (2) M (macrolide antibiotics)- and MS (macrolide and streptogramin type B antibiotics)- or PMS (partial macrolide and streptogramin type B antibiotics)-phenotype resistant bacteria cause decreased accumulation of macrolides, occasionally including streptogramin type B antibiotics. The decreased accumulation, probably via enhanced efflux, is usually inferred from two findings: (i) the extent of the accumulated drug in a resistant cell increases as much as that in a susceptible cell in the presence of an uncoupling agent such as carbonylcyanide-m-chlorophenylhydrazone (CCCP), 2,4-dinitrophenol (DNP), and arsenate; (ii) transporter proteins, in M-type resistants, have mutual similarity to the 12-transmembrane domain present in efflux protein driven by proton-motive force, and in MS- or PMS-type resistants, transporter proteins have mutual homology to one or two ATP-binding segments in efflux protein driven by ATP. (3) Two major macrolide mechanisms based on antibiotic inactivation are dealt with here: degradation due to hydrolysis of the macrolide lactone ring by an esterase encoded by the ere gene; and modification due to macrolide phosphorylation and lincosamide nucleotidylation mediated by the mph and lin genes, respectively. But enzymatic mechanisms that hydrolyze or modify macrolide and lincosamide antibiotics appear to be relatively rare in clinically isolated bacteria at present. (4) Important developments in macrolide antibiotics are briefly featured. On the basis of information obtained from extensive references and studies of resistance mechanisms to macrolide antibiotics, the mode of action of the drugs, as effectors, and a hypothetical explanation of the regulation of the mechanism with regard to induction of macrolide resistance are discussed.

Journal Article↗
PubMed2000

Macrolide esterase-producing Escherichia coli clinically isolated in Japan.

Current Japanese clinical practice involves the usage of large amounts of new macrolides such as clarithromycin and roxithromycin for the treatment of diffuse panbronchiolitis, Helicobacter pylori and Mycobacterium avium complex infections. In this study, the phenotypes, genotypes, and macrolide resistance mechanisms of macrolide-inactivating Escherichia coli recovered in Japan from 1996 to 1997, were investigated. The isolation rate of erythromycin A highly-resistant E. coli (MIC > or = 1,600 microg/ml) in Japan slightly increased from 0.5% in 1986 to 1.2% in 1997. In six macrolide-resistant strains, recovered from the strains collected for this study during 1996 to 1997, the inactivation of macrolide could be detected with or without added ATP in the assay system. The appearance of erythromycin A-inactivating enzyme independent of ATP was novel from Japanese isolates, and the 1H NMR spectra of oleandomycin hydrolyzed by the three ATP-independent isolates were examined. It was clearly shown that the lactone ring at the position of C-13 was cleaved as 13-H signal in aglycon of oleandomycin upper shifted. These results suggested the first detection of macrolide-lactone ring-hydrolase from clinical isolates in Japan. These results suggested the first detection of an ATP-independent macrolide-hydrolyzing enzyme from Japanese clinical isolates. Substrate specificity of the macrolide-hydrolyzing enzyme was determined with twelve macrolides including the newer members of this group and it was found that not only erythromycin A but also the new macrolides, such as clarithromycin, roxithromycin, and azithromycin were inactivated. The NMR data, broad spectrum of activity, and independence of co-enzyme supported our naming of the enzyme as a macrolide esterase. PCR methodology was employed to detect an ereB-like gene from the 3 isolates producing macrolide esterase, and one of these was subsequently shown to contain both ereB-like and ermB-like genes. It was also clearly shown that the other three isolates, which inactivated macrolide in the presence of ATP, had an mphA-like gene.

Anti-Bacterial Agents↗
PubMed1991

Macrolides: present and future. An appraisal of in-vitro activity and pharmacokinetic behavior.

Macrolides belong to a large family of drugs called macrocyclic antibiotics, that can be divided into four groups: macrolactamas or ansamycins, polyene macrolides, macrolide-like compounds and macrolide antibiotics. Macrolide antibiotics comprise a large group of drugs, which are very much alike, characterized by large lactonic cycle with 12, 14, 15 or 16 atoms, to which are bound sugar and/or aminosugar. Although there are very large structural differences, macrolides represent a homogeneous group of drugs for which both a spectrum and a mode of action are similar. Macrolide antibiotics bind to the large subunit of prokaryotic ribosomes and perturb protein synthesis. The antimicrobial activity of macrolides is broad spectrum, being exhibited against gram-positive and gram-negative bacteria, including actinomyces and mycobacteria, as well as against treponemes, mycoplasmas, chlamydiae, rickettsias and also against some protozoa. Depending on the drug concentrations, bacterial species and phase of growth, macrolides may be bacteriostatic or bactericidal. Macrolides show high tissue/serum rations and greater concentrations of antibiotics are though to be achieved at the presumed site of infection. Such findings are in agreement with the apparent volumes of distribution for all the macrolide drugs, which are generally large. The worldwide resurgence of interest in macrolide antibiotics has yielded several semisynthetic derivatives of 14- and 16-membered macrolides which have progressed to clinical trials.

Anti-Bacterial Agents↗
PubMed2006

Macrolide resistance in bacteremic pneumococcal disease: implications for patient management.

BACKGROUND: Despite pneumococcal antibiotic resistance rates in excess of 25%, macrolides remain first-line agents for the treatment of community-acquired pneumonia. METHODS: Prospective, population-based surveillance was conducted to identify cases of pneumococcal bacteremia in Toronto and Peel, Canada, between 2000 and 2004. "Macrolide failures" were defined as cases of bacteremia occurring during outpatient treatment with macrolide antibiotics or within 2 days after treatment. Macrolide susceptibility was determined according to Clinical Laboratory Standards Institute guidelines; common macrolide resistance mechanisms were determined by genotyping. RESULTS: During the 5 years of surveillance, there were 1696 episodes of pneumococcal bacteremia (8.5 cases/100,000 population/year), of which 60 (3.5%) were failures of outpatient macrolide therapy. Resistant isolates were more common among cases of bacteremia after failure of macrolide therapy (37 [64%] of 58 cases) than among cases of bacteremia after failure of nonmacrolide antibiotics (16 [22%] of 74 cases; P<.001) or cases of bacteremia that occurred without prior antibiotic therapy (193 [12%] of 1569 cases; P<.001). Macrolide failures were significantly more common among cases of pneumococcal bacteremia with isolates exhibiting an erythromycin MIC of 1 microg/mL than among isolates exhibiting MICs < or = 0.25 microg/mL (3 [38%] of 8 cases vs. 21 [1.5%] of 1394 cases of bacteremia; P<.001). Increases in the MIC to 1 microg/mL were not associated with further increases in the likelihood of macrolide failure. Low-level resistance conferred by mefA and high-level resistance conferred by ermB were equally overrepresented among macrolide failures. CONCLUSIONS: Macrolide resistance contributes to an increased risk of macrolide failure, irrespective of the underlying resistance mechanism or of the degree of elevation in erythromycin MIC.

Bacteremia↗
PubMed2003

Macrolide resistance among middle ear isolates of Streptococcus pneumoniae observed at eight United States pediatric centers: prevalence of M and MLSB phenotypes.

BACKGROUND: Increasing macrolide resistance among middle ear isolates complicates treatment of otitis media in children. When macrolide resistance is mediated via an efflux pump (M phenotype), the MICs of erythromycin, clarithromycin and azithromycin are usually below 32 microg/ml, and the pneumococcus remains susceptible to clindamycin. The association of prior specific macrolide therapy with the isolation of a macrolide resistant strain has not been reported. OBJECTIVES: To determine the mechanism of macrolide resistance in Streptococcus pneumoniae recovered from the middle ears of children with otitis media and their association, if any, with ethnicity, age, serogroup/serotype and prior antibiotic therapy. METHODS: Middle ear isolates collected by members of the United States Pediatric Multicenter Pneumococcal Surveillance Group during a 6-year period from September 1994 through August 2000 were studied. Antibiotic susceptibility to penicillin and ceftriaxone was determined by microbroth dilution. Disc diffusion susceptibility to erythromycin and clindamycin was performed to categorize macrolide resistance mechanisms. The medical record was reviewed to determine demographics and history of previous antibiotic therapy. Isolates were serogrouped or serotyped by the capsular swelling method. RESULTS: Of the 1088 isolates available for testing, 51% were nonsusceptible to penicillin and 37% were nonsusceptible to erythromycin. Erythromycin resistance increased form 15% in 1994 through 1995 to 56% in 1999 through 2000. Seventy-five percent of macrolide-resistant strains were M phenotype. Macrolide resistance was less likely in isolates recovered from African-Americans and more likely in isolates obtained from children <3 years of age and from isolates obtained at time of tympanostomy tube placement. Neither erythromycin, nor clarithromycin nor azithromycin prescribed in the 30 days before infection was more likely than another to be associated with increased macrolide resistance. However, any macrolide alone or in combination with another antimicrobial taken before infection was associated with increased macrolide resistance among the S. pneumoniae organisms isolated from the middle ear. CONCLUSIONS: Macrolide resistance among middle ear isolates of S. pneumoniae increased during the 6-year study. The proportion of M phenotype remained constant at 75%, meaning that these isolates remain susceptible to clindamycin. Continued surveillance to document potential changes is essential.

Anti-Bacterial Agents↗
PubMed2001

Binding site of macrolide antibiotics on the ribosome: new resistance mutation identifies a specific interaction of ketolides with rRNA.

Macrolides represent a clinically important class of antibiotics that block protein synthesis by interacting with the large ribosomal subunit. The macrolide binding site is composed primarily of rRNA. However, the mode of interaction of macrolides with rRNA and the exact location of the drug binding site have yet to be described. A new class of macrolide antibiotics, known as ketolides, show improved activity against organisms that have developed resistance to previously used macrolides. The biochemical reasons for increased potency of ketolides remain unknown. Here we describe the first mutation that confers resistance to ketolide antibiotics while leaving cells sensitive to other types of macrolides. A transition of U to C at position 2609 of 23S rRNA rendered E. coli cells resistant to two different types of ketolides, telithromycin and ABT-773, but increased slightly the sensitivity to erythromycin, azithromycin, and a cladinose-containing derivative of telithromycin. Ribosomes isolated from the mutant cells had reduced affinity for ketolides, while their affinity for erythromycin was not diminished. Possible direct interaction of ketolides with position 2609 in 23S rRNA was further confirmed by RNA footprinting. The newly isolated ketolide-resistance mutation, as well as 23S rRNA positions shown previously to be involved in interaction with macrolide antibiotics, have been modeled in the crystallographic structure of the large ribosomal subunit. The location of the macrolide binding site in the nascent peptide exit tunnel at some distance from the peptidyl transferase center agrees with the proposed model of macrolide inhibitory action and explains the dominant nature of macrolide resistance mutations. Spatial separation of the rRNA residues involved in universal contacts with macrolides from those believed to participate in structure-specific interactions with ketolides provides the structural basis for the improved activity of the broader spectrum group of macrolide antibiotics.

Anti-Bacterial Agents↗
PubMed2004

The structural basis of macrolide-ribosome binding assessed using mutagenesis of 23S rRNA positions 2058 and 2059.

Macrolides are a diverse group of antibiotics that inhibit bacterial growth by binding within the peptide tunnel of the 50S ribosomal subunit. There is good agreement about the architecture of the macrolide site from different crystallography studies of bacterial and archaeal 50S subunits. These structures show plainly that 23S rRNA nucleotides A2058 and A2059 are located accessibly on the surface of the tunnel wall where they act as key contact sites for macrolide binding. However, the molecular details of how macrolides fit into this site remain a matter of contention. Here, we have generated an isogenic set of single and dual substitutions at A2058 and A2059 in Mycobacterium smegmatis to investigate the effects of the rRNA mutations on macrolide binding. Resistances conferred to a comprehensive array of 11 macrolide compounds are used to assess models of macrolide binding predicted from the crystal structures. The data indicate that all macrolides and their derivatives bind at the same site in the tunnel with their C5 amino sugar in a similar orientation. Our data are compatible with the lactone rings of 14-membered and 16-membered macrolides adopting different conformations, enabling the latter compounds to avoid a steric clash with 2058G. This difference, together with interactions conveyed via substituents that are specific to certain ketolide and macrolide sub-classes, influences the binding to the large ribosomal subunit. Our genetic data show no support for a derivatized-macrolide binding site that has been proposed to be located further down the tunnel.

Anti-Bacterial Agents↗