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PubMed2004

Inability of L22 ribosomal protein alteration to increase macrolide MICs in the absence of efflux mechanism in Haemophilus influenzae HMC-S.

BACKGROUND: Haemophilus influenzae HMC-C with high-level macrolide resistance after multi-step selection by clarithromycin reverted spontaneously and became hypersusceptible to macrolides. OBJECTIVE: Determination of macrolide resistance mechanism(s) in hypersusceptible and hyperresistant strains. METHODS: The presence of macrolide efflux in the strains was studied by radioactive erythromycin accumulation. Ribosomal mutations were investigated by sequencing. The possible role of acrAB clusters in macrolide resistance was studied by sequencing and expression analysis. RESULTS: The parent strain had no ribosomal alteration, but both high-level resistant and hypersusceptible strains had R88P mutations in ribosomal protein L22. Radioactive macrolide accumulation studies pointed to the presence of macrolide efflux in the high-level resistant and parent strains, but not in the hypersusceptible derivative. Transformation of hypersusceptible strains using total DNA from the parent strain restored the macrolide efflux system in the hypersusceptible strain, which was confirmed by MIC levels and radioactive erythromycin accumulation similar to that of the mutant resistant strain. Analysis of sequence and transcription of acrAB gene clusters showed no significant differences between resistant and hypersusceptible derivatives. CONCLUSION: Mutation in ribosomal protein L22 alone does not confer high-level macrolide resistance unless efflux is present.

Anti-Bacterial Agents↗
PubMed2006

Clinical evaluation of macrolide-resistant Mycoplasma pneumoniae.

Macrolide-resistant Mycoplasma pneumoniae (MR M. pneumoniae) has been isolated from clinical specimens in Japan since 2000. A comparative study was carried out to determine whether or not macrolides are effective in treating patients infected with MR M. pneumoniae. The clinical courses of 11 patients with MR M. pneumoniae infection (MR patients) treated with macrolides were compared with those of 26 patients with macrolide-susceptible M. pneumoniae infection (MS patients). The total febrile days and the number of febrile days during macrolide administration were longer in the MR patients than in the MS patients (median of 8 days versus median of 5 days [P = 0.019] and 3 days versus 1 day [P = 0.002], respectively). In addition, the MR patients were more likely than the MS patients to have had a change of the initially prescribed macrolide to another antimicrobial agent (63.6% versus 3.8%; odds ratio, 43.8; P < 0.001), which might reflect the pediatrician's judgment that the initially prescribed macrolide was not sufficiently effective in these patients. Despite the fact that the febrile period was prolonged in MR patients given macrolides, the fever resolved even when the initial prescription was not changed. These results show that macrolides are certainly less effective in MR patients.

Adolescent↗
PubMed1992

Pharmacokinetic drug interactions of macrolides.

The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) and triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids and cholestatic jaundice in those taking oral contraceptives. Erythromycin and its different prodrugs appear to be less potent inhibitors of drug metabolism. Case reports and controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide and bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these compounds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined administration should be carried out only with careful patient monitoring.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-Bacterial Agents↗
PubMed2003

Structural consideration of macrolide antibiotics in relation to the ribosomal interaction and drug design.

Macrolide antibiotics exert antimicrobial effects by binding to the peptidyl transferase center of the 50S subunit of bacterial ribosomes and inhibiting protein synthesis. Hence, the structure of macrolides and their interaction with bacterial ribosomes have been investigated in order to understand the structural mechanisms of macrolide-ribosome interaction. Most macrolides have been found tom adopt a common conformation both in crystal form and in solution, which is believed to play an important role for binding to bacterial ribosomes as well as representing bi-facial property essential for excellent biological functions of macrolides. Chemical footprinting and mutant analysis have offered topological information on macrolide-ribosome interaction at the nucleotide level. Recently, crystal structures of the 50S ribosomal subunit and the 50S subunit with macrolide antibiotics have been published. These crystal structures provide much structural information on macrolide-ribosome interaction at the atomic level and will enable structure-based drug design of novel macrolide antibiotics with potent activity against resistant strains.

Anti-Bacterial Agents↗
PubMed2000

[Allergy to macrolide antibiotics. Review of the literature].

MACROLIDE CLASSES: Macrolides are characterized by their basic structure made up of a lactonic cycle with 2 osidic chains. They are classified according to the number of carbon atoms in the cycle: 14-membered macrolides (erythromycin, troleandomycin, roxithromycin, dirithromycin, clarithromycin), 15-membered macrolides (azithromycin) and 16-membered macrolides (spiramycin, josamycin, midecamycin). MACROLIDE ALLERGY: Allergy to macrolides is extremely rare (0.4% to 3% of treatments). The little information available in the literature is insufficient to establish the usefulness of diagnostic tests. An immediate IgE-dependent hypersensitivity has been shown with erythromycin in some cases but the mechanism remains unknown and skin tests are quite often negative. Clinical manifestations are the same as those encountered with beta-lactams. It would appear that macrolide allergies are unlikely to be class allergies. This is important as eviction advice could be limited to the single causal macrolide.

Anti-Bacterial Agents↗
PubMed1997

Macrolides are ideal for empiric therapy of community-acquired pneumonia in the immunocompetent host.

We propose that macrolides, especially the newer macrolides (azithromycin, clarithromycin, roxithromycin), are ideal agents for community-acquired pneumonia in the immunocompetent host who is not a resident of a nursing home or long-term care facility. Macrolides have proven effective in clinical trials against typical and atypical pathogens; thus, unlike beta-lactam agents, they can be given as monotherapy. Streptococcus pneumoniae isolates exhibiting high-level resistance to penicillin and cephalosporins pose a problem not only for the macrolides, but also for quinolones, tetracyclines, and most other beta-lactam agents. The tetracycines, quinolones, and beta-lactam agents have broader spectrum activity against aerobic gram-negative bacilli, which are uncommon pathogens of community-acquired pneumonia in the immunocompetent host. This broader spectrum is not only superfluous, but the potential of emergence of resistant bacteria is enhanced unnecessarily. Serious adverse reactions to the macrolides are rare. The newer macrolides have improved bioavailability and improved pharmacokinetics such that once- or twice-daily dosing regimens can be used. Finally, a comparison of the costs of macrolides to quinolones and beta-lactam agents (especially cephalosporins) show that the oral macrolides are among the least expensive antibiotics that can be prescribed for pneumonia. Thus, macrolides seem to be the ideal empiric antibiotic for community-acquired pneumonia based on spectrum of activity, safety, and cost.

Anti-Bacterial Agents↗
PubMed2004

What Is the Clinical Impact of Macrolide Resistance?

Respiratory tract infections are treated empirically. Treatment is based on the likely pathogens and their antibiotic susceptibility. The most common respiratory tract pathogen is Streptococcus pneumoniae. In the United States, approximately 25% to 30% of S. pneumoniae are resistant to erythromycin and other macrolides. There are two mechanisms of resistance: ribosomal methylation that causes high-level resistance, and an efflux pump that causes low-level resistance. Macrolides are ineffective in animal models that use pneumococcal isolates with the methylase- or efflux-mediated resistance mechanisms. There are many case reports that describe clinical failure and isolation of a macrolide-resistant pneumococcus while a patient receives macrolide treatment. Two recent studies that included macrolide-susceptible and macrolide-resistant pneumococci showed that breakthrough bacteremia in patients receiving macrolide treatment occurred only with macrolide-resistant isolates. Study of bacteremic disease ensures the pathogenic role of the pneumococcus; however, it underestimates the true clinical impact of macrolide resistance.

Journal Article↗
PubMed1988

Mechanism of action of spiramycin and other macrolides.

Macrolide antibiotics constitute a group of 12 to 16-membered lactone rings substituted with one or more sugar residues, some of which may be amino sugars. They inhibit bacterial protein synthesis both in vivo and in vitro with varying potencies. Macrolides are generally bacteriostatic, although some of these drugs may be bactericidal at very high concentrations. The mechanism of action of macrolides has been a matter of controversy for some time. Spiramycin, a 16-membered macrolide, inhibits translocation by binding to bacterial 50S ribosomal subunits with an apparent 1:1 stoichiometry. This antibiotic is a potent inhibitor of the binding to the ribosome of both donor and acceptor substrates. Spiramycin induces rapid breakdown of polyribosomes, an effect which has formerly been interpreted as occurring by normal ribosomal run-off followed by an antibiotic-induced block at or shortly after initiation of a new peptide. However, there is now convincing evidence that spiramycin, and probably all macrolides, act primarily by stimulating the dissociation of peptidyl-tRNA from ribosomes during translocation. Although the ribosomes of both Gram-positive and Gram-negative organisms are susceptible to macrolides, these antibiotics are mainly used against Gram-positive bacteria since they are unable to enter the porins of Gram-negative bacteria. Resistance to macrolides in clinical isolates is most frequently due to post-transcriptional methylation of an adenine residue of 23S ribosomal RNA, which leads to co-resistance to macrolides, lincosamides and streptogramins type B (the so-called MLSB phenotype). Other mechanisms of resistance involving cell impermeability or drug inactivation have been detected in Staphylococcus spp. and Escherichia coli. These strains are resistant to 14-membered macrolides (erythromycin and oleandomycin) but remain susceptible to spiramycin.

Anti-Bacterial Agents↗
PubMed2000

Streptococcus pyogenes resistance to erythromycin in relation to macrolide consumption in Spain (1986-1997).

The relationship between Streptococcus pyogenes resistance to erythromycin and macrolide consumption in Spain was studied. Erythromycin resistance was highly correlated with the consumption of total macrolides (r = 0.88, P<0.01). When macrolides were grouped into posological subgroups according to their pharmacokinetic and pharmacodynamic properties and analysed separately, erythromycin resistance appeared to be related mainly to those macrolides taken twice daily (bd) (r = 0.86, P<0.01) and those taken once daily (od) (r = 0.87, P<0.01), but not to those taken four (qds) or three times a day (tds) (r = -0.04, P: = 0.90). A progressive increase in the erythromycin resistance curve was seen after the consecutive introduction of both bd and od macrolides, which contributed to the increase in the total macrolide consumption, replacing tds macrolide prescription. Although this ecological analysis cannot establish an unequivocal causal relationship between antibiotic consumption and S. pyogenes resistance, the data are consistent with the hypothesis that widespread use of macrolides, mainly of bd and od macrolides, resulted in an increased prevalence of S. pyogenes resistant to erythromycin in Spain.

Anti-Bacterial Agents↗
PubMed2003

Pharmacodynamic activity of azithromycin against macrolide-susceptible and -resistant Streptococcus pneumoniae simulating clinically achievable free serum, epithelial lining fluid and middle ear fluid concentrations.

BACKGROUND: The association between macrolide resistance mechanisms and bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro pharmacodynamic model, assessed azithromycin activity against macrolide-susceptible and -resistant S. pneumoniae simulating clinically achievable free serum (S), epithelial lining fluid (ELF) and middle ear fluid (MEF) concentrations. MATERIALS AND METHODS: Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Azithromycin was modelled simulating a dosage of 500 mg/250 mg by mouth, once a day [free S: maximum concentration (Cmax) 0.2 mg/L, t1/2 68 h; free ELF Cmax 1.0 mg/L, t1/2 68 h] and 10 mg/kg by mouth, once a day (free MEF: Cmax 1.0 mg/L, t1/2 68 h) using a one compartment model. Starting inocula were 1 x 10(6) cfu/mL in Mueller-Hinton broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24 and 48 h assessed the extent of bacterial killing (decrease in log10 cfu/mL versus initial inoculum). RESULTS: Free azithromycin concentrations in serum, ELF and MEF simulating time above the MIC (T > MIC) of 100% [area under the curve to MIC (AUC0-24/MIC] > or = 36.7] were bactericidal (> or = 3 log10 killing) at 24 and 48 h versus macrolide-susceptible S. pneumoniae. Against macrolide-resistant S. pneumoniae, free serum concentrations providing T > MIC of 0% or AUC0-24/MIC < or = 1.1 demonstrated no bacterial inhibition followed by regrowth at 24 and 48 h, whereas free ELF and MEF providing T > MIC of 0% or AUC0-24/MIC of 4.6 produced a bacteriostatic (0.2-0.5 log10 killing at 24 h) effect with a mef(A) strain with an azithromycin MIC of 2 mg/L. Against mef(A)-positive S. pneumoniae strains with azithromycin MICs > or = 4 mg/L, no bacterial killing occurred at any time point and rapid regrowth was observed simulating ELF or MEF T > MIC of 0% or AUC0-24/MIC < or = 2.3. CONCLUSION: Azithromycin serum, ELF and MEF concentrations rapidly eradicated macrolide-susceptible S. pneumoniae but did not eradicate macrolide-resistant S. pneumoniae regardless of resistance phenotype.

Anti-Bacterial Agents↗
PubMed2003

Macrolide resistance: an increasing concern for treatment failure in children.

BACKGROUND: Antimicrobial treatment of pediatric respiratory tract infections has evolved during the past 30 years as a result of antimicrobial resistance. The focus of antimicrobial therapy in these conditions has shifted from penicillins to other agents because of the dramatic increase in antimicrobial resistance among common respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. It is important for clinicians to understand how resistance develops so that they can help prevent this phenomenon from occurring with other antimicrobials. METHODS: This article reviews the published literature on resistance to macrolide antimicrobials among common pediatric respiratory tract pathogens and clinical and bacteriologic outcomes of infections with these pathogens. RESULTS: Resistance among common pediatric respiratory tract pathogens to macrolides occurs through two main mechanisms, alteration of the target site and active efflux. Although resistance patterns vary by geographic region, the widespread use of macrolides has contributed to the emergence of both types of macrolide-resistant organisms. Conditions that favor the selection and proliferation of resistant strains include children with repeated, close contact who frequently receive antimicrobial treatment or prophylaxis, such as children who attend day care. Recent US surveillance data show that 20 to 30% of S. pneumoniae are resistant to macrolides, with approximately two-thirds of macrolide-resistant strains associated with an efflux mechanism and the remainder associated with a ribosomal methylase. Additionally, although less well-known, virtually all strains of H. influenzae have an intrinsic macrolide efflux pump. As resistance to macrolides has increased, clinical failures have resulted, and these agents are no longer considered appropriate for empiric first line antimicrobial therapy of acute otitis media and sinusitis unless patients are truly penicillin-allergic. Therefore, other antimicrobials are recommended for the empiric treatment of children with respiratory tract infections, including higher doses of amoxicillin and amoxicillin/clavulanate (90 mg/kg/day amoxicillin), cefuroxime axetil and intramuscular ceftriaxone. CONCLUSIONS: As resistance to macrolides increases and clinical failures in children become more common with this class of antimicrobials, judicious use of antimicrobials is needed. This includes limiting antimicrobial use for viral infections and using the most effective agents when antimicrobials are clinically indicated, such as higher doses of amoxicillin and amoxicillin/clavulanate. Application of these principles may prevent proliferation and further development of resistance.

Child↗
PubMed2003

Effects of an efflux mechanism and ribosomal mutations on macrolide susceptibility of Haemophilus influenzae clinical isolates.

This study investigated macrolide resistance mechanisms in clinical Haemophilus influenzae strains with different levels of susceptibility to macrolides. A total of 6,382 isolates were collected during the Alexander Project from 1997 to 2000. For 96.9% of these isolates, the azithromycin MICs were 0.25 to 4 micro g/ml, and these were defined as baseline strains. For 1.8% of the isolates, the azithromycin MICs were lower (<0.25 micro g/ml), and for 1.3% of the isolates, the MICs were higher (>4 micro g/ml). These isolates were defined as hypersusceptible and high-level macrolide-resistant strains, respectively. To identify the mechanisms associated with these three susceptibility patterns, representative strains were studied for the presence of macrolide efflux pumps and for ribosomal alterations. Macrolide efflux was studied by measuring the accumulation of radioactive azithromycin and clarithromycin in the presence or absence of carbonyl cyanide m-chlorophenylhydrazone (CCCP), a protonophore. Treatment with CCCP increased the accumulation of macrolides in baseline as well as high-level resistant strains, demonstrating the presence of an efflux mechanism, but not in the 20 hypersusceptible strains tested. Among the 31 strains studied that showed high-level resistance to both azithromycin and clarithromycin, 28 had ribosomal alterations, 7 had mutations in ribosomal protein L4, 11 had mutations in L22, 2 had mutations in 23S rRNA, 8 had multiple mutations, and 3 had no mutations. From these results, we conclude that the vast majority (>98%) of H. influenzae strains have a macrolide efflux mechanism, with a few of these being hyperresistant (1.3%) due to one or several ribosomal mutations. Occasional hypersusceptible strains (1.8%) were found and had no macrolide resistance mechanisms and appeared to be the only truly macrolide-susceptible variants of H. influenzae.

Anti-Bacterial Agents↗
PubMed2004

Mutation at the position 2058 of the 23S rRNA as a cause of macrolide resistance in Streptococcus pyogenes.

BACKGROUND: In streptococci, three macrolide resistance determinants (erm(B), erm(TR) and mef(A)) have been found. In addition, certain mutations at the ribosomal 23S RNA can cause resistance to macrolides. Mutation at the position 2058 of the 23S rRNA of the Streptococcus pyogenes as a cause of macrolide resistance has not been described before. METHODS: Antibiotic resistance determinations for the clinical S. pyogenes strain ni4277 were done using the agar dilution technique. Macrolide resistance mechanisms were studied by PCR and sequencing. All six rRNA operons were amplified using operon-specific PCR. The PCR products were partially sequenced in order to resolve the sequences of different 23S rRNA genes. RESULTS: One clinical isolate of S. pyogenes carrying an adenine to guanine mutation at the position 2058 of the 23S rRNA in five of the six possible rRNA genes but having no other known macrolide resistance determinants is described. The strain was highly resistant to macrolides and azalides, having erythromycin and azithromycin MICs > 256 microgram/ml. It was resistant to lincosamides (clindamycin MIC 16 microgram/ml) and also MIC values for ketolides were clearly elevated. The MIC for telithromycin was 16 microgram/ml. CONCLUSION: In this clinical S. pyogenes strain, a mutation at the position 2058 was detected. No other macrolide resistance-causing determinants were detected. This mutation is known to cause macrolide resistance in other bacteria. We can conclude that this mutation was the most probable cause of macrolide, lincosamide and ketolide resistance in this strain.

Journal Article↗
PubMed2000

Potential role of macrolides in the treatment of asthma.

A body of evidence highlights the fact that macrolides may not only enhance the host defence system through increased cytokine synthesis by host cells but also exhibit anti-inflammatory activity by including anti-inflammatory cytokines. Several authors have stressed the possibility that macrolides are useful in the treatment of asthma because of their antimicrobial activity rather than any anti-inflammatory action. However, the mechanism of action of macrolides in improving asthma and reducing airway responsiveness is speculated not to be due to their antibiotic properties, especially when these agents are active in noninfectious asthma. The steroid-sparing effect of macrolide antibiotics has been postulated to contribute to their beneficial actions in the treatment of asthma. Nevertheless, a number of studies have shown that macrolides antibiotics have an anti-inflammatory effect which is independent of their antibiotic action or any influence on corticosteroid metabolism. Macrolides may be useful in the treatment of patients with steroid-dependent asthma, probably because they inhibit eosinophilic inflammation. It has also been suggested that the effect of macrolides on bronchial hyperresponsiveness is mediated by their inhibitory action on superoxide production and chemotaxis of polymorphonuclear neutrophils and the mixed lymphocyte reaction. In any case, it is clear that the mechanism of action of macrolides in asthmatic syndrome is not unequivocal. Only well-designed and -conducted clinical studies are capable of assessing the efficacy and safety of immunosuppressive macrolides in the treatment of asthma.

Anti-Asthmatic Agents↗
PubMed1991

The in vitro activity of some 14-, 15- and 16- membered macrolides against Staphylococcus spp., Legionella spp., Mycoplasma spp. and Ureaplasma urealyticum.

Erythromycin is a macrolide antimicrobial chemically comprised of a 14-membered lactone ring substituted with a neutral (cladinose) and an amino (desosamine) sugar. Recently, a number of new macrolide molecules have been identified containing either 14-, 15- or 16-membered substituted lactone rings. In this study the authors have determined the in vitro activity of roxithromycin and clarithromycin (both 14-membered macrolides), azithromycin (a 15-membered macrolide or azalide) and midecamycin acetate (a 16-membered macrolide) against clinical isolates of Staphylococcus spp., (including methicillin-susceptible and -resistant isolates), Legionella spp., Mycoplasma spp. and Ureaplasma urealyticum. Minimum inhibitory concentrations of the macrolides for the clinical isolates of Staphylococcus spp. examined were widely distributed. However, midecamycin acetate retained activity against those isolates of Staphylococcus spp. exhibiting inducible resistance to erythromycin and the other macrolides tested. Isolates characterised by constitutive resistance to erythromycin were also resistant to midecamycin acetate. All of the macrolides were very active against Legionella spp., with clarithromycin demonstrating the greatest potency (MIC range: less than or equal to 0.03-0.06 mg/l). Isolates of Mycoplasma pneumoniae and Ureaplasma urealyticum were susceptible to all of the macrolides tested. However, erythromycin, roxithromycin, clarithromycin and azithromycin were poorly active against isolates of Mycoplasma hominis. By contrast, the same isolates were susceptible (MIC range: 0.008-0.12 mg/l) to midecamycin acetate.

Anti-Bacterial Agents↗
PubMed2006

The use of macrolides in treatment of upper respiratory tract infections.

Antimicrobial resistance is a growing problem among upper respiratory tract pathogens. Resistance to beta-lactam drugs among Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes is increasing. As safe and well-tolerated antibiotics, macrolides play a key role in the treatment of community-acquired upper respiratory tract infections (RTIs). Their broad spectrum of activity against gram-positive cocci, such as S. pneumoniae and S. pyogenes, atypical pathogens, H. influenzae (azithromycin and clarithromycin), and Moraxella catarrhalis, has led to the widespread use of macrolides for empiric treatment of upper RTIs and as alternatives for patients allergic to beta-lactams. Macrolide resistance is increasing among pneumococci and recently among S. pyogenes, and is associated with increasing use of the newer macrolides, such as azithromycin. Ribosomal target modification mediated by erm(A) and erm(B) genes and active efflux due to mef(A) and mef(E) are the principal mechanisms of resistance in both S. pneumoniae and S. pyogenes. Recently, ribosomal protein and RNA mutations have been found to be responsible for acquired resistance to macrolides in S. pneumoniae, S. pyogenes, and H. influenzae. Although macrolides are only weakly active against macrolide-resistant streptococci species, producing an efflux pump (mef), and are inactive against pathogens with ribosomal target modification (erm), treatment failures are uncommon. Therefore, macrolide therapy, for now, remains a good alternative for treatment of upper RTIs; however, continuous monitoring of the local resistance patterns is essential.

Anti-Bacterial Agents↗
PubMed2004

Clinical implications of the immunomodulatory effects of macrolides.

Macrolide antibiotics are known for their efficacy in treating acute airway infections, but just as importantly, they are also effective anti-inflammatory agents. Their anti-inflammatory properties have been studied most thoroughly in chronic inflammatory airway diseases, particularly diffuse panbronchiolitis (DPB). Erythromycin, azithromycin, clarithromycin, and roxithromycin inhibit chemotaxis and infiltration of neutrophils into the airway and, subsequently, decrease mucus secretion. Mucus formation, a significant cause of morbidity and mortality in patients with chronic airway inflammation, is directly inhibited by macrolides and suppressed by decreased inflammation in the airway. The mechanisms of action for the anti-inflammatory properties of the macrolides are still being investigated, but they are clearly multifactorial. Macrolides inhibit the production of many proinflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor-alpha, perhaps by suppressing the transcription factor nuclear factor-kappaB or activator protein-1. Inhibition of cytokine production has been seen in vitro and also in bronchoalveolar lavage fluid, which contains less IL-8 and fewer neutrophils after treatment with macrolides. Macrolides also inhibit formation of leukotriene B4, which attracts neutrophils, and inhibit the release of superoxide anion by neutrophils that may be present in the airway. An important aspect of inflammation is extravasation of neutrophils into the tissues. Macrolides block formation of adhesion molecules necessary for neutrophil migration. Together, these anti-inflammatory effects result in improved pulmonary functions and fewer airway infections. In patients with DPB, the anti-inflammatory effects lead to a significant increase in survival. Further work is needed to characterize the clinical benefits of macrolides in patients with other chronic inflammatory airway diseases.

Anti-Bacterial Agents↗
PubMed2005

Establishment of a Fast Chemical Identification System for screening of counterfeit drugs of macrolide antibiotics.

A Fast Chemical Identification System (FCIS) consisting of two colour reactions based on functional groups in molecules of macrolide antibiotics and two TLC methods was developed for screening of fake macrolide drugs. The active ingredients could be extracted from their oral preparations by absolute alcohol. Sulfuric acid reaction as a common reaction of macrolides was first used to distinguish the macrolides from other types of drugs and then 16-membered macrolides and 14-membered ones were distinguished by potassium permanganate reactions depending on the time of loss of colour in the test solution; after which a TLC method carried out on a GF(254) plate (5 cm x 10 cm) was chosen to further identification of the macrolides. The mobile phase A consisting of ethyl acetate, hexane and ammonia (100:15:15, v/v) was used for the identification of 14-membered macrolides, and the mobile phase B consisting of trichloromethane, methanol and ammonia (100:5:1, v/v) was used for the identification of 16-membered ones. A suspected counterfeit macrolide preparation can be identified within 40 min. The system can be used under different conditions and has the virtues of robustness, simplicity and speed.

Ammonia↗