Do Macorlides Work Agains Gram Pos or Neg
Resistance to macrolides and lincosamides is increasingly reported in clinical isolates of gram-positive leaner. The multiplicity of mechanisms of resistance, which include ribosomal modification, efflux of the antibiotic, and drug inactivation, results in a variety of phenotypes of resistance. There is controversy concerning the clinical relevance of in vitro macrolide resistance. Recent data, yet, have shown that eradication of bacteria correlates with clinical upshot of acute otitis media in children and that macrolide therapy results in delayed eradication of macrolide-resistant pneumococci. These results support the need for in vitro detection of macrolide resistance and correct interpretation of susceptibility tests to guide therapy.
Macrolides accept been known for >5 decades, and, since the introduction of erythromycin into therapy, a number of these molecules have been developed for clinical use. For years, these antibiotics have represented a major culling to the use of penicillins and cephalosporins for the treatment of infections due to gram-positive microorganisms (mostly β-hemolytic streptococci and pneumococci); notwithstanding, the worldwide evolution of macrolide resistance with wide variations, according to both the country and the bacterial species, has sometimes constrained to limit the use of these antibiotics to certain indications. Although the development of the macrolide class has been marked, in the 1990s, by the evolution of semisynthetic macrolides with improved pharmacokinetics and tolerability, these new derivatives have proved unable to overcome erythromycin resistance. By contrast, our increasing noesis of the molecular mechanisms of resistance to macrolides has led to the pharmaceutical industry'due south blueprint of derivatives, such as the ketolides, that have action against certain types of erythromycin-resistant organisms [one]. The information on these antimicrobials that are in development will not be discussed in this review, which is devoted to commercially available drugs. In addition, although certain mechanisms of resistance to macrolides affect streptogramins, these antimicrobials also will not be discussed. Other aspects of macrolide resistance are the multiplicity of resistance mechanisms and the diversity in phenotypic expression of several of these mechanisms. These aspects render information technology hard to correctly interpret the in vitro susceptibility tests and, ultimately, the right therapeutic use of this class of antibiotics. The present review aims to describe the genetic determinants and the practical implications of the resistance mechanisms of clinically important pathogens.
Macrolides, Lincosamides, and Their Spectrum of Activity
Macrolide and lincosamide antibiotics are chemically distinct but share a similar fashion of action. They have a spectrum of activity limited to gram-positive cocci (mainly staphylococci and streptococci) and bacilli, to gram-negative cocci, and intracellular bacteria (Chlamydia and Rickettsia species). Gram-negative bacilli are generally resistant, with some of import exceptions (i.e., Bordetella pertussis, Campylobacter, Chlamydia, Helicobacter, and Legionella species).
Macrolides are composed of ⩾2 amino or neutral sugars attached to a lactone ring of variable size. Commercially available macrolides accept a 14-membered (clarithromycin, dirithromycin, erythromycin, and roxithromycin) or xv-membered (azithromycin) lactone band. Xvi-membered band macrolides (josamycin, midecamycin, miocamycin, rokitamyin, and spiramycin) are available in certain countries or in veterinarian exercise (tylosin). Lincosamides (clindamycin and lincomycin) are devoid of a lactone ring.
Mechanisms of Acquisition of Resistance to Macrolides and Lincosamides
Bacteria resist macrolide and lincosamide antibiotics in three means: (i) through target-site modification past methylation or mutation that prevents the bounden of the antibiotic to its ribosomal target, (two) through efflux of the antibiotic, and (3) past drug inactivation. These mechanisms have been found in the macrolide and lincosamide producers, which ofttimes combine several approaches to protect themselves against the antimicrobial that they produce. In pathogenic microorganisms, the impact of the 3 mechanisms is unequal in terms of incidence and of clinical implications. Modification of the ribosomal target confers broad-spectrum resistance to macrolides and lincosamides, whereas efflux and inactivation impact merely some of these molecules.
Ribosomal Methylation
In 1956, soon after the introduction of erythromycin into therapy, resistance emerged in staphylococci [2]. Biochemical studies indicated that resistance was caused by methylation of the ribosomal target of the antibiotics, which leads to cantankerous-resistance to macrolides, lincosamides, and streptogramins B, the so-called MLSB phenotype [two]. Subsequently, the MLSB phenotype encoded by a diversity of erm (erythromycin ribosome 1000ethylase) genes was reported in a big number of microorganisms [3]. The starting time erythromycin-resistant strains of streptococci were reported in the United Kingdom in 1959 and in N America in 1967 [four, 5]. So far, ribosomal methylation remains the most widespread machinery of resistance to macrolides and lincosamides.
In pathogenic bacteria, Erm proteins dimethylate a single adenine in nascent 23S rRNA, which is part of the large (50S) ribosomal subunit [2]. The A2058 rest is located within a conserved region of domain V of 23S ribosomal RNA, which plays a key role in the binding of MLSB antibiotics. Equally a result of methylation, bounden of erythromycin to its target is impaired. The overlapping binding sites of macrolides, lincosamides, and streptogramins B in 23S rRNA account for cross-resistance to the 3 classes of drugs. A broad range of microorganisms that are targets for macrolides and lincosamides, including gram-positive species, spirochetes, and anaerobes, express Erm methylases.
Nearly 40 erm genes accept been reported so far [3]. In pathogenic bacteria, these determinants are mostly borne by plasmids and transposons that are self-transferable. A classification system has been devised to avoid increasing complexity in designation. erm genes with deduced amino acid sequence identity of <80% accept different letter designations. This new nomenclature distinguishes 21 classes of erm genes and as many respective Erm proteins. Four major classes are detected in pathogenic microorganisms: erm(A), erm(B), erm(C), and erm(F) [2, three]. erm(A) and erm(C) typically are staphylococcal factor classes. erm(B) class genes are mostly spread in streptococci and enterococci, and the erm(F) class genes in Bacteroides species and other anaerobic leaner [3]. In addition to the erm(B) genes, the ermTR genes, which are at present considered a subset of the erm(A) class on the basis of sequence homology, can be detected in β-hemolytic streptococci [three]. That each course is relatively specific—only not strictly bars—to a bacterial genus, reflects like shooting fish in a barrel gene substitution.
Variety in MLSB Resistance Expression
Expression of MLSB resistance can be constitutive or inducible. In inducible resistance, the bacteria produce inactive mRNA that is unable to encode methylase. The mRNA becomes active only in the presence of a macrolide inducer. Past dissimilarity, in constitutive expression, active methylase mRNA is produced in the absence of an inducer. Induction is related to the presence of an attenuator upstream from the structural erm gene for the methylase. Induction occurs posttranscriptionally, according to the model of translation attenuation in the case of the erm(C) (a staphylococcal determinant) and likewise probably in the case of the erm(A) and erm(B) determinants [6]. The presence of an inducer leads to rearrangements of mRNA, which permit ribosomes to translate the methylase coding sequence. The strains harboring an inducible erm gene are resistant to the inducers but remain susceptible to noninducer macrolides and lincosamides. The pattern of macrolide inducers depends on the erm factor or, more precisely, on the structure of the attenuator controlling the gene expression. Because the construction of the attenuator differs in each class or subclass of erm gene, dissimilar patterns of MLSB-inducible resistance are observed. The genetic background or bacterial host as well plays a office in the specificity of consecration, perchance in relation to differences in ribosomal construction or methylase expression. In exercise, however, the preferential distribution of erm genes in certain bacterial species leads us to consider only a few major phenotypes of inducible MLSB resistance characterized in staphylococci and streptococci/enterococci.
Therefore, the variety of inducible macrolide resistance may pb to complex phenotypes. By contrast, constitutive production of a methylase more often than not confers a feature phenotype with high-level cantankerous-resistance to the MLSB drugs.
Expression of MLS B resistance in staphylococci . The erm(A) and erm(C) determinants are predominant in staphylococci [7]. The erm(A) genes are mostly spread in methicillin-resistant strains and are borne by transposons related to Tn554, whereas erm(C) genes are mostly responsible for erythromycin resistance in methicillin-susceptible strains and are borne by plasmids. The resistance phenotypes conferred by inducible expression of both determinants are similar and are characterized by dissociated resistance to MLSB antibiotics considering of differences in the inducing capacity of the antibiotics. The strains are resistant to 14- and 15-membered ring macrolides, which are inducers. Past contrast, sixteen-membered band macrolides, commercially available lincosamides, and streptogramins B that are not inducers remain active (table i). In disk-diffusion tests, a D-shaped zone caused by induction of methylase product by erythromycin can exist observed when a deejay of erythromycin is placed near a disk of clindamycin or any noninducer 16-membered band macrolide.
The employ of clindamycin (or of a noninducer macrolide) for the treatment of an infection due to an inducibly resistant strain of Staphylococcus aureus is not devoid of risk. Constitutive mutants tin be selected in vitro at frequencies of ∼10-seven cfu in the presence of these antibiotics. Bacterial inocula exceeding 10vii cfu can be found in mediastinitis and in certain lower respiratory tract infections. The risk to patients is illustrated by reports of selection of constitutive mutants during the class of clindamycin therapy administered to patients with severe infections due to inducibly erythromycin-resistant Southward. aureus [8, 9]. If the staphylococcal inoculum at the site of infection is college, the adventure for option of a constitutive mutant should exist college. In fact, clinical isolates that are constitutively resistant to MLSB antibiotics are widespread, especially in methicillin-resistant strains.
Expression of MLS B resistance in streptococci and enterococci . The spread of erm genes belonging to the erm(B) class and, rarely, to the erm(TR) subset of the erm(A) course accounts for the vast majority of resistance acquired by ribosomal methylation in streptococci and enterococci. Inducible expression of these genes gives rise to a large multifariousness of phenotypes differing from that of staphylococci; these phenotypes include high- or low-level resistance to erythromycin with susceptibility or resistance to clindamycin. The phenotypes and their correlation with the genotypes are yet far from being understood. Inducibly expressed erm(B) genes are present in a variety of streptococcal species, including β-hemolytic streptococci, oral streptococci, Streptococcus pneumoniae, and enterococci. Near members of the MLSB grouping, including clindamycin and sixteen-membered macrolides, are inducers at various degrees of ErmB methylase production [x]. In inducibly resistant S. pneumoniae, this feature, combined with the production of various basal levels of enzyme—probably in relation to a relaxed command of methylase synthesis by the erm(B) attenuator, might explicate, at least in office, the complexity of phenotypes (table 1) [11, 12]. It has been shown, past consecration studies including fusions of attenuators with a reporter gene, that the MLSB phenotype characterized by loftier-level cross-resistance to macrolides and lincosamides, which is ordinarily detected in pneumococci, is oftentimes inducible [11, 12, 13]. Similar to the case of the constitutive phenotype, no macrolide or lincosamide can be used. Other strains of Due south. pneumoniae that contain erm(B) are apparently susceptible to clindamycin while being resistant to the fourteen-, 15-, and 16-membered macrolides. The occurrence of an antagonism betwixt erythromycin and clindamycin, as made obvious by the double-disk improvidence exam, indicates inducible production of methylase. Again, the apply of clindamycin should be discouraged. In Streptococcus pyogenes, the phenotypes conferred by erm(B) are similar. Some erythromycin-resistant strains that obviously are susceptible to clindamycin express, by disk diffusion, a zonal resistance characterized by regrowth near the deejay of clindamycin later on extended incubation. The erm(TR) gene is spread in β-hemolytic streptococci and has been found in a single strain of S. pneumoniae [14, 15]. Presence of the factor mostly results in inducible erythromycin resistance expressed at depression (MIC, 1–eight µg/mL) or high (MIC, >128 µg/mL) levels, whereas 16-membered macrolides and clindamycin remain patently active. Antagonism between erythromycin and clindamycin is also observed. Once more, constitutive MLSB resistance, irrespective of the erm factor grade, leads to cross-resistance between macrolides and lincosamides.
An Emerging Machinery: Target Mutation
In vitro selection of Escherichia coli mutants that are highly resistant to erythromycin has been of considerable value for characterization of the bounden site of this antibiotic to the ribosome. The clinical importance of this mechanism was simply recently recognized with identification of mutations at either A2058 or A2059 in domain V of rRNA; A2058 and A2059 confer MLSB and ML resistance, respectively [16]. Depending on the species, leaner possess from 1 to several rrn operons encoding 23S rRNA. In general, the mutations are observed in pathogens with one or 2 rrn copies, oftentimes with each copy conveying the mutation. This mechanism is responsible for clarithromycin resistance in the vast majority of, if not all, strains of Mycobacterium avium and Helicobacter pylori [xvi]. Similar mutations have besides been reported in Treponema pallidum and Propionibacterium species. Clinical strains and laboratory mutants accept recently been identified in South. pneumoniae, which harbors 4 rrn copies [17].
Mutations in ribosomal proteins L4 and L22 that confer erythromycin resistance have been documented in laboratory and clinical isolates of Southward. pneumoniae [17]. The changes are clustered in a highly conserved sequence of L4 and confer resistance to macrolides but not to clindamycin. Although these types of resistance are considered, past definition, to be nontransferable, the ability displayed by pneumococci to larn extrinsic genes easily by transformation followed by homologous recombination might then lead to spread.
The prevalence and clinical importance of the pneumococcal mutants are not known. In particular, the in vivo conditions that lead to selection of mutant strains have not been studied. Because attention has been brought on these new types of resistance only recently, nevertheless, we believe that, so far, their importance has been underestimated.
Antibiotic Efflux
In gram-negative leaner, chromosomally encoded pumps contribute to intrinsic resistance to hydrophobic compounds, such every bit macrolides. The pumps oftentimes belong to the resistance/nodulation/division family composed of proteins with 12 membrane-spanning regions. In gram-positive organisms, acquisition of macrolide resistance by active efflux is acquired by two classes of pumps, members of the ATP-bounden-cassette (ABC) transporter superfamily and of the major facilitator superfamily (MFS).
To date, the just efflux proteins conferring acquired macrolide resistance characterized in Staphylococccus species are ABC transporters encoded by plasmidborne msr(A) genes [eighteen]. The msr(A) resistance determinant was originally detected in Staphylococcus epidermidis, and, since so, it has been plant in a variety of staphylococcal species, including Due south. aureus. ABC transporters require ATP to function and are normally formed by a channel composed of 2 membrane-spanning domains and 2 ATP-binding domains located at the cytosolic surface of the membrane.
The msr(A) gene encodes a poly peptide with 2 ATP-binding domains characteristic of ABC transporters. The nature of the transmembrane component of the MsrA pump remains unknown. The efflux system appears to be multicomponent in nature, involving msr(A) and chromosomal genes to found a fully operational efflux pump that has specificity for 14- and 15-membered macrolides and type B streptogramins (the MSB phenotype) [xviii]. The resistance is inducibly expressed. Erythromycin and other xiv- and the fifteen-membered macrolides are inducers, whereas streptogramins B are not. Therefore, the strains are resistant to streptogramins B just after induction with erythromycin. Clindamycin is neither an inducer nor a substrate for the pump, and thus the strains are fully susceptible to this antimicrobial (table 1).
As expected, constitutive mutants are resistant to both erythromycin and streptogramins B but remain fully susceptible to clindamycin. This phenotype can be easily distinguished from the MLSB-inducible phenotype by use of the double-disk diffusion test, which shows a lack of interaction betwixt erythromycin and clindamycin. This determinant is common in coagulase-negative staphylococci and increasingly is plant in methicillin-susceptible strains of S. aureus, with a reported incidence of 13% in a recent European study [19]. Another factor, msrB from Staphylococcus xylosus, which is near identical to the 3′ end of msr(A), has been reclassified as msr(A) [three]. It contains a single ATP-binding domain but also confers an MSB phenotype.
The msr(A) gene has not been institute in streptococci. In the genus Streptococcus, mef(A) genes encode an efflux pump, which tin exist constitute in clinical isolates of Southward. pneumoniae and S. pyogenes, in other species of streptococci (oral streptococci, grouping C and G streptococci, and Streptococcus agalactiae), and in enterococci. The original mef(A) gene was reported in South. pyogenes [20]. A similar gene, once called mef(E), merely now reclassified as mef(A), was reported later in S. pneumoniae [21]. The Mef(A) protein belongs to the MFS family and spans the membrane 12 times. The efflux is driven past the proton motive force and affects only 14- and 15-membered ring macrolides (Thou phenotype). There is no resistance to 16-membered band macrolides, clindamycin, or streptogramin B, even after consecration with erythromycin (tabular array i). Resistance is inducible by 14- and 15-membered macrolides just not by the other macrolides and clindamycin. S. pneumoniae, Southward. pyogenes, or S. agalactiae strains that harbor mef(A) are resistant to low or moderate levels of macrolides, with MICs of clarithromycin, azithromycin, and erythromycin generally comprising betwixt 4 and 32 µg/mL, but sometimes less (0.12–2 µg/mL).
The mef(A) genes can be transferred by conjugation in S. pyogenes and Southward. pneumoniae and are borne by large transposons in S. pneumoniae [22]. Combinations of erm(B) and mef(A) genes can be found in Southward. pneumoniae, S. pyogenes, or Southward. agalactiae strains [23, 24]. These strains have an MLSB phenotype.
Drug Modification
Inherent to this mechanism of resistance, and unlike target modification, inactivation of antibiotics confers resistance to structurally related antibiotics only. Esterases and phosphotransferases reported in enterobacteria confer resistance to erythromycin and other 14- and 15-membered macrolides but not to lincosamides. So far, these resistances have not been considered of major clinical importance, considering enterobacteria are non targets for macrolides, apart from the particular utilize of oral erythromycin for selective decontamination of the digestive tract. More than worrisome is the finding of clinical isolates of S. aureus producing phosphotransferases encoded by mph(C) genes, although only a few strains accept been reported to date [25]. Lincosamide nucleotidyltransferases encoded past lnu(A) (formerly linA) and lnu(B) (formerly linB) genes in staphylococci (S. aureus and coagulase-negative staphylococci) and Enterococcus faecium, respectively, inactivate lincosamides only [iii]. Both genes confer frank resistance to lincomycin, but clindamycin remains agile, with MICs that are increased by only i or 2 dilutions [26, 27]. However, the bactericidal activeness of clindamycin, which is already weak against susceptible strains, is totally abolished [26]. Considering of dissociated resistance among lincosamides, detection of this phenotype is possible only if lincomycin, instead of clindamycin, is tested. The impact of the in vitro alteration of clindamycin activity on the therapeutic efficacy of the drug is unknown. In addition, this resistance is rare in S. aureus (having been found in <i% of the strains) merely is more frequent in coagulase-negative staphylococci (estimated frequency i%–7% of strains), depending on the staphylococcal species [26]. The lnu(B) cistron was detected in ten% of E. faecium strains in 1 study, just its expression was masked by the coexistence of erm in all strains [27].
On the whole, although a console of genes is able to inactivate macrolides and lincosamides, their presence in gram-positive cocci has not turned out to exist a success story for bacteria. This could be the result of (1) a weak clinical impact caused by the low-level of resistance conferred to erythromycin, by mph(C) when present alone and to clindamycin, by the lnu genes, or (2) of a failure of detection.
Touch of Macrolide Resistance on Patient Outcome
There is controversy apropos the clinical relevance of in vitro macrolide resistance, because few patients with clinical failure and resistant strains have been reported [28, 29]. Sure authors have attributed this paradox to the ability of newer macrolides—in particular, azithromycin—to attain high concentrations in the infected tissues [28]. It should be stressed, even so, that newer macrolides are, in fact, full-bodied in the phagocytic cells rather than in the extracellular fluids [30]. Because Due south. pneumoniae and Southward. pyogenes are idea to be primarily extracellular pathogens, extracellular drug concentrations should be considered equally being predictive of therapeutic success. Internalization of a few S. pyogenes organisms, however, might contribute to the building of a reservoir of persisting bacteria that escape penicillins that do not enter eukaryotic cells or macrolides when the strains are resistant to these antimicrobials [31]. A contempo study has shown that Italian erythromycin-resistant S. pyogenes has a greater ability to be internalized in human cells than does the erythromycin-susceptible strains, possibly leading to difficulties in eradication [28].
In fact, the frequent employ of macrolides for nonsevere infections that frequently have a spontaneous favorable development makes it difficult to constitute the correlation betwixt the in vitro resistance of microorganisms to macrolides and the clinical outcome of patients treated with these antibiotics. Therefore, to reach house conclusions, studies based on clinical evaluation should include a big number of patients infected with macrolide-resistant microorganisms and treated with these antibiotics. For these reasons, bacterial eradication is often used equally an evaluation benchmark. The question of the accurateness and clinical relevance of this criterion has been addressed in few studies and is not completely solved [29]. Articulate correlation between eradication of leaner on days 4–5 and clinical event was, however, shown in children with acute otitis media due to S. pneumoniae [29, 32]. The affect of macrolide resistance on bacterial eradication has been evaluated in children with acute otitis media or tonsillitis and in adults with pneumonia. In a written report comparing the efficacies of azithromycin and cefaclor in young children with acute otitis media, Dagan et al. [33] constitute that pneumococcal eradication by azithromycin was accomplished at day four or 5 in a grouping of 12 patients infected with strains for which the MIC of the antibiotic was <0.06 µg/mL. Past contrast, pneumococcal strains with an MIC of azithromycin ⩾32 µg/mL persisted in all v patients initially infected with resistant strains, whereas 1 patient acquired a resistant strain during treatment. Although the genetic content of the strains had not been studied, the high level of resistance to macrolides suggested that resistance was due to erm genes. In another study, the review of the records of 41 patients with pneumococcal bacteremia revealed that 7 had previously received antibody therapy [34]. Iii of the patients did non appear to take true antibody therapy failure, whereas the 4 remaining patients had previously been treated with azithromycin or clarithromycin for 3–five days. The 4 claret isolates had an M phenotype and a moderate level of resistance to macrolides, with MICs of erythromycin equal to 8 µg/mL or 16 µg/mL.
The data from the studies of astute pharyngitis are fifty-fifty more than difficult to analyze, because recolonization or spontaneous clearance of S. pyogenes in the throat appears to occur frequently. Varaldo et al. [35] failed to find a correlation between in vitro resistance to macrolides and noneradication in children with pharyngotonsilitis due to S. pyogenes who were receiving macrolide therapy. In another written report, the rate of eradication of S. pyogenes in patients who had pharyngitis and who were treated with clarithromycin did not differ significantly from that in patients with erythromycin-resistant strains or those in patients with erythromycin-susceptible strains, despite a tendency toward a higher rate of eradication in the latter grouping [36]. Of annotation, none of the 6 patients with strains highly resistant to erythromycin were cured. Failure of erythromycin could be demonstrated by Seppälä et al. [37], who found that this antibiotic significantly failed to cure ix (47%) of 19 patients infected with erythromycin-resistant group A streptococci (including moderately resistant strains), as compared with 1 (4%) of 26 patients with erythromycin-susceptible isolates. Taken together, these studies tend to suggest a correlation between macrolide resistance, at least when expressed at a high level, and clinical failure. Because of differences in pharmacokinetics, all macrolides probably are not equivalent in their ability to eradicate strains with low-level macrolide resistance. Finally, more studies that include homogeneous groups of patients are needed to confirm the in vivo affect of in vitro resistance—in particular, that caused by drug efflux—and to propose breakpoints that are predictive of clinical failure or success.
Incidence of Macrolide Resistance
Tabular array ii provides data on the incidence of macrolide resistance in Southward. pneumoniae published for <2 years. Huge geographic differences, from iii% to 74%, are observed in the resistance frequencies reported for individual countries. In addition, considerable variations tin exist seen inside a country, depending on the source of the strains (teaching/nonteaching hospital, or customs), patient age, sample origin, seasonal factors, and pneumococcal serotype [39, 58]. Like to the case of penicillin resistance, college prevalence of macrolide resistance is generally seen amidst children and for pneumococci from centre ear fluids. These differences have obvious bear upon on the therapeutic efficacy of agents of the MLS class. Although useful for analysis global trends toward resistance, nationwide surveys practice not e'er accept into business relationship these parameters, and there is a need for physicians to exist aware of local resistance patterns according to patient age and type of infection. In general, the college the rate of penicillin resistance, the higher the rate of macrolide resistance. In a big report that involved hospitals from 21 countries around the world, macrolide resistance was detected in 12.viii% of penicillin-susceptible pneumococci versus 55.7% of penicillin-resistant strains [59]. In another contempo study [42], similar variations between penicillin-susceptible and -resistant strains (4% and 61% in the U.s., four% and 27% in Latin America, x% and 52% in Europe, and 22% and 76% in Asia, respectively), were found. This relationship is especially marked in the U.s.a. (table 2) and is also shown for trimethoprim-sulfamethoxazole resistance. At that place are, however, some exceptions. For instance, in Italian republic, the low rate of penicillin resistance contrasts with the loftier rate of erythromycin resistance (table 2).
No substantial departure tin be observed between percentages of resistance to azithromycin, clarithromycin, and erythromycin, which confirms cantankerous-resistance betwixt the 3 antimicrobials [42, 44, 52]. By contrast, in several countries, the incidence of clindamycin resistance may be much lower than that of erythromycin resistance. The spread of erythromycin-resistant strains that harbor the mef(A) factor accounts for this difference. This holds true especially in the United States, in dissimilarity to most European countries, where erm(B)-containing strains are widespread. The reasons for these differences are unexplained. Longitudinal studies showed that the incidence of macrolide resistance, which was 10%–sixteen% in 1994, doubled in 1999 in several areas of the United States [41, 58]. This marked increment was, for the about role, related to the emergence of mef(A)-containing strains [41].
Several European countries (i.due east., Finland, Italy, and Spain) faced an increment in erythromycin resistance in S. pyogenes at the beginning of the 1990s [37, 60, 61] (table iii). Contempo information testify that very high frequencies of macrolide resistance are reported in Asia, whereas, to engagement, resistance does not seem to be a problem in the United States (table iii); however, particular loftier frequencies tin can exist seen, as exemplified past a 32% rate of erythromycin resistance in Due south. pyogenes nerveless from invasive disease-related specimens in San Francisco County [63]. In the vast bulk of S. pyogenes strains, erythromycin resistance is acquired by the presence of the efflux factor mef(A) or the methylase genes erm(TR) [erm(A)] and erm(B). The mef(A) and erm(TR) genes are frequently predominant [24, 64].
In several studies, investigators take tried to establish connections between consumption of macrolides and widespread resistance. Frequent coresistance to several antibiotics in pneumococci makes evaluation of the touch of a specific class of antibiotic on resistance problematic. This is not the case for S. pyogenes, which remains susceptible to penicillins. The most convincing data, from Republic of finland, were high rates of macrolide resistance in Due south. pyogenes, along with an increase in macrolide consumption and a subsequent decrease afterward significant reduction in the utilise of macrolides in outpatients [67]. Similarly, an increase in macrolide resistance in Spain since 1995 was related to the increase in consumption of macrolides, particularly those that are taken in one case or twice daily [61]. This relationship was not found in a Canadian study [64], yet, and temporal relations do not prove causality. To explicate differences between countries with regard to sudden emergences of resistance, Granizo et al. [61] have hypothesized that spread of resistance occurs when macrolide consumption exceeds a disquisitional threshold of selective pressure level. It is remarkable that, in intracellular pathogens, such equally Legionella, Chlamydia, and Mycoplasma species, findings of resistance remain anecdotal.
Conclusions
The multiplicity of mechanisms that confer resistance to macrolides is reflected by the complexity of the resistance phenotypes; nevertheless, the virtually clinically important and widespread determinants in gram-positive organisms are the methylase and efflux genes. Identification of the resistance mechanisms is important with regard to the use of clindamycin and 16-membered band macrolides. The double-deejay diffusion technique with erythromycin and lincomycin (or clindamycin) is useful to guide interpretation of the susceptibility exam [72] (Fig. 1 and Fig. two). The incidence of resistance is highly variable with regard to the country and, most importantly, the patterns of infections observed amidst patients. For this reason, local statistics are of crucial value for empiric therapy. Surveillance of both the incidence of macrolide resistance and the corresponding prevalence of the various resistance mechanisms is justified by the rapid variations in macrolide resistance observed in several countries.
Acknowledgements
I wish to thank Patrice Courvalin for reading the manuscript.
References
1
Denis
A
, Agouridas C Auger JM
Synthesis and antibacterial action of HMR 3647, a new ketolide highly potent against erythromycin-resistant and susceptible pathogens
Bioorg Med Chem Lett
1999
9
3075
eighty
.
2
Weisblum
B
.
Erythromycin resistance past ribosome modification
Antimicrob Agents Chemother
1995
39
577
85
.
3
Roberts
MC
, Sutcliffe J Courvalin P Jensen LB Rood J Seppala H
Nomenclature for macrolide and macrolide-lincosamide-streptogramin B resistance determinants
Antimicrob Agents Chemother
1999
43
2823
30
.
4
Lowbury
EJL
, Hurst 50
The sensitivity of staphylococcal and other wound bacteria to erythromycin
J Clin Pathol
1959
12
163
nine
.
v
Dixon
JMS
.
Grouping A streptococcus resistant to erythromycin and lincomycin
Can Med Assoc J
1968
99
1093
iv
.
6
Weisblum
B
.
Insights into erythromycin activity from studies of its activity every bit inducer of resistance
Antimicrob Agents Chemother
1995
39
797
805
.
7
Lina
1000
, Quaglia A Reverdy ME Leclercq R Vandenesch F Etienne J
Distribution of genes encoding resistance to macrolides, lincosamides, and streptogramins among staphylococci
Antimicrob Agents Chemother
1999
43
1062
six
.
8
Watanakunakorn
C
.
Clindamycin therapy of Staphylococcus aureus endocarditis: clinical relapse and development of resistance to clindamycin, lincomycin and erythromycin
Am J Med
1976
60
419
25
.
9
Drinkovic
D
, Fuller ER Shore KP Kingdom of the netherlands DJ Ellis-Pegler R
Clindamycin treatment of Staphylococcus aureus expressing inducible clindamycin resistance
J Antimicrob Chemother
2001
48
315
6
.
x
Horinouchi
S
, Byeon WH Weisblum B
A complex attenuator regulates inducible resistance to macrolides, lincosamides, and streptogramin type B antibiotics in Streptococcus sanguis
J Bacteriol
1983
154
1252
62
.
11
Rosato
A
, Vicarini H Bonnefoy A Chantot JF Leclercq R
A new ketolide, HMR 3004, agile against streptococci inducibly resistant to erythromycin
Antimicrob Agents Chemother
1998
42
1392
6
.
12
Zhong
P
, Cao Z Hammond R
Consecration of ribosome methylation in MLS-resistant Streptococcus pneumoniae past macrolides and ketolides
Microb Drug Resist
1999
five
183
viii
.
13
Rosato
A
, Vicarini H Leclercq R
Inducible or constitutive expression of resistance in clinical isolates of streptococci and enterococci cross-resistant to erythromycin and lincomycin
J Antimicrob Chemother
1999
43
559
62
.
fourteen
Kataja
J
, Huovinen P Skurnik M Seppälä H
Erythromycin resistance genes in grouping A streptococci in Republic of finland: The Finnish Study Group for Antimicrobial Resistance
Antimicrob Agents Chemother
1999
43
48
52
.
xv
Syrogiannopoulos
GA
, Grivea IN Tait-Kamradt A
Identification of an erm(A) erythromycin resistance methylase factor in Streptococcus pneumoniae isolated in Hellenic republic
Antimicrob Agents Chemother
2001
45
342
4
.
16
Vester
B
, Douthwaite S
Macrolide resistance conferred by base substitutions in 23S rRNA
Antimicrob Agents Chemother
2001
45
i
12
.
17
Tait-Kamradt
A
, Davies T Appelbaum PC
2 new mechanisms of macrolide resistance in clinical strains of Streptococcus pneumoniae from Eastern Europe and Due north America
Antimicrob Agents Chemother
2000
44
3395
401
.
18
Ross
JI
, Eady EA Cove JH Cunliffe WJ Baumberg S Wootton JC
Inducible erythromycin resistance in staphylococci is encoded by a fellow member of the ATP-binding transport super-factor family
Mol Microbiol
1990
4
1207
14
.
19
Schmitz
FJ
, Sadurski R Kray A
Prevalence of macrolide-resistance genes in Staphylococcus aureus and Enterococcus faecium isolates from 24 European university hospitals
J Antimicrob Chemother
2000
45
891
4
.
20
Clancy
J
, Petitpas J Dib-Hajj F
Molecular cloning and functional analysis of a novel macrolide-resistance determinant, mefA, from Streptococcus pyogenes
Mol Microbiol
1996
22
867
79
.
21
Tait-Kamradt
A
, Clancy J Cronan K
mefE is necessary for the erythromycin-resistant K phenotype in Streptococcus pneumoniae
Antimicrob Agents Chemother
1997
41
2251
5
.
22
Santagati
M
, Iannelli F Oggioni MR Stefani S Pozzi G
Characterization of a genetic element carrying the macrolide efflux gene mef(A) in Streptococcus pneumoniae
Antimicrob Agents Chemother
2000
44
2585
seven
.
23
McGee
L
, Klugman KP Wasas A Capper T Brink A
Serotype 19f multiresistant pneumococcal clone harboring two erythromycin resistance determinants (erm[B] and mef[A]) in South Africa
Antimicrob Agents Chemother
2001
45
1595
viii
.
24
Kataja
J
, Huovinen P Seppala H
Erythromycin resistance genes in grouping A streptococci of dissimilar geographical origins: the Macrolide Resistance Study Group
J Antimicrob Chemother
2000
46
789
92
.
25
Matsuoka
M
, Endou K Kobayashi H Inoue Thousand Nakajima Y
A plasmid that encodes three genes for resistance to macrolide antibiotics in Staphylococcus aureus
FEMS Microbiol Lett
1998
167
221
7
.
26
Leclercq
R
, Brisson-Noel A Duval J Courvalin P
Phenotypic expression and genetic heterogeneity of lincosamide inactivation in Staphylococcus spp
Antimicrob Agents Chemother
1987
31
1887
91
.
27
Bozdogan
B
, Berrezouga 50 Kuo MS
A new resistance gene, linB, conferring resistance to lincosamides by nucleotidylation in Enterococcus faecium HM1025
Antimicrob Agents Chemother
1999
43
925
9
.
28
Amsden
GW
.
Pneumococcal macrolide resistance: myth or reality?
J Antimicrob Chemother
1999
44
one
6
.
29
Dagan
R
, Klugman KP Craig WA Baquero F
Evidence to support the rationale that bacterial eradication in respiratory tract infection is an of import aim of antimicrobial therapy
J Antimicrob Chemother
2001
47
129
40
.
30
Mtairag
EM
, Abdelghaffar H Douhet C Labro MT
Intraphagocytic location of macrolides
Antimicrob Agents Chemother
1995
39
1676
82
.
31
Facinelli
B
, Spinaci C Magi 1000 Giovanetti Eastward E Varaldo P
Clan between erythromycin resistance and power to enter human respiratory cells in group A streptococci
Lancet
2001
358
30
iii
.
32
Dagan
R
, Leibovitz E Greenberg D Yagupsky P Fliss DM Leiberman A
Early eradication of pathogens from middle ear fluid during antibiotic treatment of acute otitis media is associated with improved clinical consequence
Pediatr Infect Dis J
1998
17
776
82
.
33
Dagan
R
, Leibovitz Eastward Fliss DM
Bacteriologic efficacies of oral azithromycin and oral cefaclor in handling of acute otitis media in infants and young children
Antimicrob Agents Chemother
2000
44
43
50
.
34
Kelley
MA
, Weber DJ Gilligan P Cohen MS
Breakthrough pneumococcal bacteremia in patients being treated with azithromycin and clarithromycin
Clin Infect Dis
2000
31
1008
11
.
35
Varaldo
PE
, Debbia EA Nicoletti G
Nationwide survey in Italy of treatment of Streptococcus pyogenes pharyngitis in children: influence of macrolide resistance on clinical and microbiological outcomes. Artemis-Italia Study Group
Clin Infect Dis
1999
29
869
73
.
36
Bassetti
M
, Manno 1000 Collida A
Erythromycin resistance in Streptococcus pyogenes in Italian republic
Emerg Infect Dis
2000
half dozen
180
iii
.
37
Seppala
H
, Nissinen A Jarvinen H
Resistance to erythromycin in group A streptococci
N Engl J Med
1992
326
292
7
.
38
Sahm
DF
, Karlowsky JA Kelly LJ
Need for annual surveillance of antimicrobial resistance in Streptococcus pneumoniae in the United states of america: 2-year longitudinal analysis
Antimicrob Agents Chemother
2001
45
1037
42
.
39
Whitney
CG
, Farley MM Hadler J
Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United states
N Engl J Med
2000
343
1917
24
.
40
Mason
EO
Jr Lamberth LB Kershaw NL Prosser BL Zoe A Ambrose PG
Streptococcus pneumoniae in the USA: in vitro susceptibility and pharmacodynamic analysis
J Antimicrob Chemother
2000
45
623
31
.
41
Gay
K
, Baughman Westward Miller Y
The emergence of Streptococcus pneumoniae resistant to macrolide antimicrobial agents: a 6-year population-based assessment
J Infect Dis
2000
182
1417
24
.
42
Hoban
DJ
, Doern GV Fluit AC Roussel-Delvallez M Jones RN
Worldwide prevalence of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the SENTRY Antimicrobial Surveillance Programme, 1997–1999
Clin Infect Dis
2001
32
Suppl 2
S81
93
.
43
Zhanel
GG
, Karlowsky JA Palatnick 50 Vercaigne Fifty Depression DE Hoban DJ
Prevalence of antimicrobial resistance in respiratory tract isolates of Streptococcus pneumoniae: results of a Canadian national surveillance study. The Canadian Respiratory Infection Study Group
Antimicrob Agents Chemother
1999
43
2504
9
.
44
Critchley
IA
, Thornsberry C Piazza G
Antimicrobial susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis collected from five centers in Brazil, 1997–98
Clin Microbiol Infect
2000
6
178
84
.
45
Schmitz
FJ
, Verhoef J Fluit AC
Prevalence of resistance to MLS antibiotics in twenty European academy hospitals participating in the European SENTRY surveillance programme. Watch Participants Grouping
J Antimicrob Chemother
1999
43
783
92
.
46
Schito
GC
, Debbia EA Marchese A
The evolving threat of antibiotic resistance in Europe: new data from the Alexander Project
J Antimicrob Chemother
2000
46
Suppl T1
iii
9
.
47
Verhaegen
J
, Van De Ven J Verbiest North Van Eldere J Verbist L
Evolution of Streptococcus pneumoniae serotypes and antibiotic resistance in Belgium-update (1994–98)
Clin Microbiol Infect
2000
6
308
15
.
48
Sahm
DF
, Jones ME Hickey ML Diakun DR Mani SV Thornsberry C
Resistance surveillance of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis isolated in Asia and Europe, 1997–1998
J Antimicrob Chemother
2000
45
457
66
.
49
Vergnaud
M
, Laaberki MF
Pneumococcal antibiotic resistance: results from 21 regional registries for 1999 [French]
Presse Med
2001
one
7
ten
.
fifty
Tarasi
A
, Venditti Yard D'Ambrosio F Pantosti A
Antimicrobial susceptibility of invasive Streptococcus pneumoniae in Italy by agar dilution method and Due east test
Microb Drug Resist
1999
five
215
viii
.
51
Melo-Cristino
J
, Fernandes ML Serrano N
A multicenter study of the antimicrobial susceptibility of Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis isolated from patients with customs-caused lower respiratory tract infections in 1999 in Portugal
Microb Drug Resist
2001
7
33
eight
.
52
Baquero
F
, Garcia-Rodriguez JA Garcia de Lomas J Aguilar L
Antimicrobial resistance of i,113 Streptococcus pneumoniae isolates from patients with respiratory tract infections in Kingdom of spain: results of a ane-yr (1996–1997) multicenter surveillance written report. The Spanish Surveillance Group for Respiratory Pathogens
Antimicrob Agents Chemother
1999
43
357
9
.
53
Henwood
CJ
, Livermore DM Johnson AP James D Warner Grand Gardiner A
Susceptibility of gram-positive cocci from 25 UK hospitals to antimicrobial agents including linezolid. The Linezolid Written report Grouping. J
Antimicrob Chemother
2000
46
931
xl
.
54
Chang
SC
, Hsieh WC Liu CY
High prevalence of antibiotic resistance of common pathogenic bacteria in Taiwan. The Antibiotic Resistance Study Grouping of the Infectious disease Order of the Republic of China
Diagn Microbiol Infect Dis
2000
36
107
12
.
55
Wang
Thou
, Zhang Y Zhu D Wang F
Prevalence and phenotypes of erythromycin-resistant Streptococcus pneumoniae in Shanghai, Prc
Diagn Microbiol Infect Dis
2001
39
187
nine
.
56
Benbachir
M
, Benredjeb Southward Boye CS
Two-twelvemonth surveillance of antibody resistance in Streptococcus pneumoniae in four African cities
Antimicrob Agents Chemother
2001
45
627
9
.
57
Widdowson
CA
, Klugman KP
Emergence of the Yard phenotype of erythromycin-resistant pneumococci in Due south Africa
Emerg Infect Dis
1998
4
277
81
.
58
Felmingham
D
, Gruneberg RN
The Alexander Project, 1996–1997: latest susceptibility information from this international study of bacterial pathogens from customs-acquired lower respiratory tract infections
J Antimicrob Chemother
2000
45
191
203
.
59
Doern
GV
, Heilmann KP Huynh HK Rhomberg PR Coffman SL Brueggemann AB
Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the United states during 1999–2000, including a comparison of resistance rates since 1994–1995
Antimicrob Agents Chemother
2001
45
1721
9
.
lx
Cornaglia
M
, Ligozzi K Mazzariol A Valentini M Orefici G Fontana R
Rapid increase of resistance to erythromycin and clindamycin in Streptococcus pyogenes in Italy, 1993–1995. The Italian Surveillance Group for Antimicrobial Resistance
Emerg Infect Dis
1996
2
339
42
.
61
Granizo
JJ
, Aguilar L Casal J Dal-Re R Baquero F
Streptococcus pyogenes resistance to erythromycin in relation to macrolide consumption in Espana (1986–1997)
J Antimicrob Chemother
2000
46
959
64
.
62
Kaplan
EL
, Johnson DR Del Rosario MC Horn DL
Susceptibility of group A beta-hemolytic streptococci to xiii antibiotics: examination of 301 strains isolated in the United States betwixt 1994 and 1997
Pediatr Infect Dis J
1999
18
1069
72
.
63
York
MK
, Gibbs L Perdreau-Remington F Brooks GF
Characterization of antimicrobial resistance in Streptococcus pyogenes isolates from the San Francisco Bay area of northern California
J Clin Microbiol
1999
37
1727
31
.
64
Weiss
Thousand
, De Azavedo J Restieri C
Phenotypic and genotypic label of macrolide-resistant grouping A streptococcus strains in the province of Quebec, Canada
J Antimicrob Chemother
2001
47
345
viii
.
65
Palavecino
EL
, Riedel I Berrios X
Prevalence and mechanisms of macrolide resistance in Streptococcus pyogenes in Santiago, Republic of chile
Antimicrob Agents Chemother
2001
45
339
41
.
66
Descheemaeker
P
, Chapelle S Lammens C
Macrolide resistance and erythromycin resistance determinants among Belgian Streptococcus pyogenes and Streptococcus pneumoniae isolates
J Antimicrob Chemother
2000
45
167
73
.
67
Seppala
H
, Klaukka T Vuopio-Varkila J
The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance
Northward Engl J Med
1997
337
441
6
.
68
Bingen
Eastward
, Fitoussi F Doit C
Resistance to macrolides in Streptococcus pyogenes in France in pediatric patients
Antimicrob Agents Chemother
2000
44
1453
seven
.
69
Alos
JI
, Aracil B Oteo J Torres C Gomez-Garces JL
Loftier prevalence of erythromycin-resistant, clindamycin/miocamycin-susceptible (M phenotype) Streptococcus pyogenes: results of a Spanish multicentre study in 1998. Castilian Grouping for the Study of Infection in the Primary Wellness Care Setting
J Antimicrob Chemother
2000
45
605
ix
.
70
Cha
S
, Lee H Lee G Hwang Yard Bae S Lee Y
The emergence of erythromycin-resistant Streptococcus pyogenes in Seoul, Korea
J Infect Chemother
2001
7
81
6
.
71
Yan
JJ
, Wu HM Huang AH Fu HM Lee CT Wu JJ
Prevalence of polyclonal mefA-containing isolates among erythromycin-resistant grouping A streptococci in Southern Taiwan
J Clin Microbiol
2000
38
2475
9
.
72
Waites
K
, Johnson C Grey B Edwards One thousand Crain K Benjamin W
Utilise of clindamycin disks to find macrolide resistance mediated by ermB and mefE in Streptococcus pneumoniae isolates from adults and children
J Clin Microbiol
2000
38
1731
4
.
Figures and Tables
Figure 1
Detection of resistance to macrolides and lincosamides in staphylococci. Resistance phenotypes were identified on the footing of erythromycin- and clindamycin- or lincomycin-susceptibility tests and on the ground of clinical implications. Fifty, lincosamides; MSB, macrolides and streptogramins B; Doctor, membered; R, resistant; S, susceptible.
Figure 1
Detection of resistance to macrolides and lincosamides in staphylococci. Resistance phenotypes were identified on the footing of erythromycin- and clindamycin- or lincomycin-susceptibility tests and on the basis of clinical implications. L, lincosamides; MSB, macrolides and streptogramins B; Dr., membered; R, resistant; S, susceptible.
Effigy 2
Detection of resistance to macrolides and lincosamides in streptococci. Resistance phenotypes were identified on the basis of erythromycin- and clindamycin-susceptibility tests and on the footing of clinical implications. I/R, intermediate/resistant; MSB, macrolides and streptogramins B; Md, membered; Southward, susceptible.
Effigy ii
Detection of resistance to macrolides and lincosamides in streptococci. Resistance phenotypes were identified on the basis of erythromycin- and clindamycin-susceptibility tests and on the basis of clinical implications. I/R, intermediate/resistant; MSB, macrolides and streptogramins B; Medico, membered; S, susceptible.
Tabular array 1
Phenotypes and genotypes of macrolide resistance resulting from due to ribosomal methylation, drug efflux, or drug inactivation in gram-positive cocci.
Table 1
Phenotypes and genotypes of macrolide resistance resulting from due to ribosomal methylation, drug efflux, or drug inactivation in gram-positive cocci.
Table two
Macrolide resistance amidst Streptococcus pneumoniae isolates, by region or country.
Table 2
Macrolide resistance among Streptococcus pneumoniae isolates, by region or land.
Tabular array iii
Macrolide resistance among Streptococcus pyogenes isolates past region or state.
Table 3
Macrolide resistance among Streptococcus pyogenes isolates by region or country.
© 2002 by the Infectious Diseases Social club of America
Submit a comment
You have entered an invalid code
Thank you for submitting a comment on this article. Your comment will be reviewed and published at the journal's discretion. Please bank check for further notifications past e-mail.
Source: https://academic.oup.com/cid/article/34/4/482/412492
0 Response to "Do Macorlides Work Agains Gram Pos or Neg"
Post a Comment