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PubMed2002

Mutations in 23S rRNA account for intrinsic resistance to macrolides in Mycoplasma hominis and Mycoplasma fermentans and for acquired resistance to macrolides in M. hominis.

The mechanisms of intrinsic resistance of Mycoplasma hominis to 14- and 15-membered macrolides were investigated in comparison with those of M. pneumoniae, which is naturally susceptible to macrolides. Radiolabeled erythromycin was not accumulated by M. hominis PG21, but addition of an ABC transporter inhibitor increased the level of erythromycin uptake more than two times, suggesting the existence of an active efflux process. The affinity of [(14)C]erythromycin to ribosomes isolated from M. hominis was dramatically reduced relative to that to ribosomes isolated from M. pneumoniae. The nucleotide sequences of 23S rRNA of both ribosomal operons rrnA and rrnB and ribosomal proteins L4 and L22 of M. hominis were obtained. Compared to the sequence of M. pneumoniae, M. hominis harbored a G2057A transition in its 23S rRNA sequence, as did M. fermentans, another mycoplasma that is erythromycin resistant. An additional C2610U change was also found in the sequence of M. hominis. Moreover, two M. hominis clinical isolates with acquired resistance to 16-membered macrolides were examined for mutations in domain II and domain V of 23S rRNA and in ribosomal proteins L4 and L22. Compared to the sequence of reference strain PG21, one isolate harbored a A2059G transition and a C2611U transition in one of the two rrn operons, while the other one was mutated only at position 2059, also on the same operon. No mutation was found in the two ribosomal protein sequences. Overall, the present study is an exhaustive characterization of the intrinsic resistance of M. hominis to 14- and 15-membered macrolides and the first description of mycoplasma clinical isolates resistant to macrolide, lincosamide, and streptogramin antibiotics harboring a mutation at position 2611 in the 23S rRNA.

Anti-Bacterial Agents↗
PubMed2005

In vitro activity of telithromycin against macrolide-susceptible and macrolide-resistant pharyngeal isolates of group A streptococci in the United States.

In vitro susceptibility testing of 2,797 group A streptococcus (GAS) isolates demonstrated that telithromycin was fully active against all macrolide-susceptible strains and among 80 of 115 macrolide-resistant GAS expressing the M phenotype. Telithromycin resistance was identified in 2 of 45 strains expressing the inducible macrolide-lincosamide-streptogramin B phenotype and four of nine isolates expressing the constitutive macrolide-lincosamide-streptogramin B resistance phenotype.

Anti-Bacterial Agents↗
PubMed2005

Infection site concentrations: their therapeutic importance and the macrolide and macrolide-like class of antibiotics.

Much confusion exists over the pharmacodynamics of macrolides, azalides, and ketolides, as the concentration-time profile for these agents is low relative to the minimum inhibitory concentration (MIC) of the pathogens for which they are used. Studies of respiratory tract infection have highlighted the importance of drug concentrations at the site of infection and have demonstrated a role for white blood cells in the delivery of drug to the infection site. Population mathematical modeling and Monte Carlo simulation have shown that the ability of macrolides, azalides, and ketolides to concentrate at the infection site has a considerable effect on microbial activity. Studies of the pharmacodynamics of these agents in animal models have centered on the mouse thigh model; however, the suitability of this model for investigation of respiratory tract infections for macrolides and macrolide-like drugs is questionable. Comparison of the mouse thigh model with the mouse lung model shows immediate discrepancies, such as a need for higher area under the concentration-time curve (AUC):MIC ratios in the mouse thigh. There are obvious failings in the use of a thigh model, as it does not take into account the accumulation of white blood cells in the epithelial lining fluid and therefore ignores the impact of white blood cell delivery to the site of infection and release of significant amounts of drug during phagocytosis. Ultimately, whereas the mouse pneumonia model is useful in identifying pharmacodynamically linked variables and the magnitude of variable required for a successful microbiologic outcome, extrapolation to human dosing must involve the use of human epithelial lining fluid penetration data.

Animals↗
PubMed1999

Appearance in Japan of highly macrolide-resistant Escherichia coli producing macrolide 2'-phosphotransferase II.

Escherichia coli CU1, a clinical isolate recovered in Japan in 1997, was found to be highly-resistant to both 14-membered and 16-membered ring macrolide antibiotics. A crude extract prepared from strain CU1 inactivated 14-, 15- and 16-membered ring macrolides in the presence of ATP and the Rf value of inactivated oleandomycin was identical to that of oleandomycin 2'-phosphate. This suggested that strain CU1 produced the enzyme macrolide 2'-phosphotransferase [MPH(2')]. Substrate specificity of the crude enzyme from strain CU1 against 14-, 15- and 16-membered ring macrolides was basically similar to that of MPH(2')II from strain BM2506, differing in that the former more effectively inactivated roxithromycin and tylosin. Subsequent attempts were made to clone the novel mph gene encoding for MPH(2') in strain CU1. The mph gene carried by strain CU1 was located on nontransmissible plasmid DNA, designated pCU001. Its molecular weight, estimated by agarose electrophoresis, was approximately 57 kD. The DNA sequence of the cloned mph gene from the Japanese isolate CU1 was identical to that of mphB, which until now had only been recovered in France. The variance in the substrate specificity of MPH(2')II from each strain led us to speculate that other factors in the reaction affect the enzymatic inactivation activity.

Anti-Bacterial Agents↗
PubMed1993

[Reaction mechanism of macrolide 2'-phosphotransferase from Escherichia coli to the 2'-modified macrolide antibiotics].

Reaction mechanism of macrolide 2'-phosphotransferase [MPH(2')] from Escherichia coli to the 2'-modified macrolide antibiotics was analyzed by using microbioassay, nuclear magnetic resonance (NMR) spectrometric assay and mass spectrometry. It was found by microbioassay that the 2'-modified macrolide antibiotics as triacetyloleandomycin (TAO), erythromycin ethyl succinate (EME) and erythromycin estolate were inactivated with adenosine triphosphate (ATP) by MPH(2'). The NMR spectrometric assay for the analysis of the reaction with the 2'-modified macrolide antibiotics and MPH(2') was established using guanosine triphosphate, which was higher reaction rate than ATP, as a cofactor. It was clearly shown by NMR spectrometric assay and mass spectrometry that the C2'-side chain of TAO and EME was naturally released in phosphate buffer solution, and then, the C2' position was phosphorylated with GTP by MPH(2').

Anti-Bacterial Agents↗
PubMed2001

Macrolide therapy of group A streptococcal pharyngitis: 10 days of macrolide therapy (clarithromycin) is more effective in streptococcal eradication than 5 days (azithromycin).

We compared recommended doses of 2 oral macrolide antibiotics (10 days of clarithromycin, 5 days of azithromycin) for eradicating group A streptococci from the throats of individuals aged > or = 12 years with symptomatic pharyngitis and a positive throat culture. Patients received either clarithromycin (250 mg b.i.d. for 10 days [n=260]) or azythromycin (500 mg on day 1, followed by 250 mg q.d. for 4 days [n=265]). Follow-up throat cultures were obtained both at 13--19 days and at 28--38 days. We evaluated 392 patients (median age, 26 years; clarithromycin, 194 patients; azyithromycin, 198 patients). Ten days of clarithromycin therapy was more effective than 5 days of azithromycin therapy in eradicating the organism (91% [176/194] vs. 82% [162/198]; P=.012). More than 97% of all streptococcal isolates were macrolide-sensitive. Whether these bacteriologic eradication rates were the result of the 2 macrolides compared or were due to differences in duration of therapy could not be determined, but the statistically significant difference in eradication of group A streptococci does raise additional questions about shortened courses of macrolide therapy for this common infection.

Administration, Oral↗
PubMed2007

Clarithromycin alone and in combination with ceftriaxone inhibits the production of pneumolysin by both macrolide-susceptible and macrolide-resistant strains of Streptococcus pneumoniae.

OBJECTIVES: To investigate the effects of clarithromycin (0.01-0.5 mg/L) alone or in combination with ceftriaxone (0.1 and 0.25 mg/L) on pneumolysin production by both macrolide-susceptible and -resistant [2 erm(B) positive and 2 mef(A) positive] strains of Streptococcus pneumoniae. METHODS: The bacteria were cultured for 6 h at 37 degrees C/5% CO(2) in tryptone soy broth, washed, enumerated and resuspended to 0.5-3 x 10(8) cfu/mL in tissue culture medium, RPMI 1640. After 16 h of incubation at 37 degrees C / 5% CO(2), pneumolysin was assayed in the bacteria-free supernatants, as well as in lysates, using a functional assay based on the influx of calcium into human neutrophils. RESULTS: Exposure of not only macrolide-susceptible strains, but also the macrolide-resistant strains, of S. pneumoniae to sub-MICs of clarithromycin resulted in dose-related inhibition of the pneumolysin production, whereas production of the toxin was unaffected by ceftriaxone. CONCLUSIONS: These observations demonstrate that even in the setting of macrolide resistance the production of pneumolysin, a key virulence factor of the pneumococcus, is attenuated by exposure of this microbial pathogen to clarithromycin.

Anti-Bacterial Agents↗
PubMedDate not supplied

Occurrence of macrolide-lincosamide-streptogramin resistances among staphylococcal clinical isolates at a university medical center. Is false susceptibility to new macrolides and clindamycin a contemporary clinical and in vitro testing problem?

A total of 2189 staphylococcal strains at the University of Iowa Hospitals and Clinics (Iowa City, IA) were initially screened to determine the incidence of constitutive (29.8%) and potential inducible macrolide-lincosamide-streptogramin (MLS) resistance (11.3%). Staphylococcus haemolyticus and S. epidermidis (62.5% and 55.3%) showed the highest incidence of constitutive resistance. Staphylococcus hominis had the highest incidence of inducible resistance (40.6%), while S. aureus had the lowest rate for both resistance types. The overall ratio of constitutive-inducible MLS resistance was 4:1. Among strains initially speciated using the Vitek System GPI card, there was only a 69% species identification reproducibility, and 78% accuracy versus a reference identification method. A random sample of 105 Staphylococcus spp. isolates with discordant macrolide (erythromycin resistant) and lincosamide (clindamycin susceptible) susceptibility patterns were tested against 16 antimicrobial agents by using a reference broth microdilution method. All erythromycin-resistant Staphylococcus spp. were also resistant to other 14-member macrolides and azithromycin, while all organisms remained susceptible to clindamycin, rifampin, vancomycin, and the streptogramin compounds (RP59500 and virginiamycin). Resistance to teicoplanin was identified among some oxacillin-resistant S. haemolyticus strains. Of 105 isolates, 65 (62%) showed inducible MLS resistance, 28 (27%) were noninducible, and 12 (11%) were either fully susceptible or resistant to the MLS drugs (Vitek System interpretation errors). MLS disk induction tests revealed two inducible resistance phenotypes: ML and MLS. Staphylococcus aureus showed the highest inducible resistance rate at 95% with an MLS-predominant pattern. In contrast, endemic S. haemolyticus isolates did not demonstrate inducible resistance that is, efflux-mediated erythromycin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Bacterial Agents↗
PubMed2001

Macrolide resistance in Peptostreptococcus spp. mediated by ermTR: possible source of macrolide-lincosamide-streptogramin B resistance in Streptococcus pyogenes.

Eighty percent (21 of 26) of macrolide-resistant Peptostreptococcus strains studied harbored the ermTR gene. This methyltransferase gene is also the most frequently found gene among macrolide-lincosamide-streptogramin B-resistant Streptococcus pyogenes strains. Transfer of the ermTR gene from Peptostreptococcus magnus to macrolide-susceptible S. pyogenes strains indicates that this resistance determinant may circulate among gram-positive aerobic and anaerobic species of the oropharyngeal bacterial flora.

Anti-Bacterial Agents↗
PubMed1999

Incidence of severe streptococcal-related diseases in Italian children in an era of high group A streptococcal resistance to macrolides. Italian Group A Streptococcal Resistance to Macrolides Study Group.

Macrolides are still widely prescribed for adult and pediatric respiratory infections in Italy despite the fact that it is known that the resistance of group A streptococci has dramatically increased since 1994. The aim of this study was to evaluate the incidence of severe streptococcal-related diseases from 1990 to 1996 on the basis of data derived from computer-generated lists of children hospitalized in 35 Pediatric Departments. The clinical record of each case was reviewed in order to gather data concerning clinical diagnoses, laboratory investigations and antibiotic therapies in the preceding four weeks. Six hundred and twenty of the total of 321,612 hospitalized children had severe streptococcal diseases; the overall annual rate remained stable at 2.13/1000 admissions in 1990 to 1.7/1000 admissions in 1996. Severe diseases were preceded by a microbiologically confirmed acute streptococcal infection treated with antibiotics in only 392 of the 620 children (63.2%). Between 1993 and 1996 (with the exception of 1995), macrolides were more frequently prescribed than beta-lactam antibiotics for acute streptococcal infections that subsequently developed into severe disease. There was no difference in the rate of severe streptococcal complications between the patients adequately treated with antibiotics and those who were inadequately or not treated. Possible explanations for the relatively stable rate of severe streptococcal complications in Italian children could be (1) a relative absence of invasive, rheumatogenic or nephritogenic strains and/or (2) a difference between in vitro and in vivo resistance of group A streptococci to macrolides. Further studies are needed to investigate the biological characteristics of resistant group A streptococcal strains and their relationships to short- and long-term clinical outcomes.

Adolescent↗
PubMed1978

Polyene macrolide antibiotic cytotoxicity and membrane permeability alterations. I. Comparative effects of four classes of polyene macrolides on mammalian cells.

The relationship between polyene macrolide-induced early membrane damage and cytotoxicity in B1 (hamster), B82 (mouse), and RAG (mouse) cells has been investigated. Filipin (FIL) induced the greatest immediate damage, as monitored by 51Cr release, followed by mediocidin (MED), amphotericin B-deoxycholate (Fungizone) (FZ) and pimaricin (PIM). For long term effect, PIM was the least toxic followed by MED, FZ, and FIL as indicated by 24-hour survival, 72-hour viability, and growth rate of cells. In evaluating polyene macrolide-induced permeability alterations and cytotoxicity two types of interactions with mammalian cells were found: (1) cell toxicity at polyene macrolide levels not eliciting immediate membrane permeability changes; and (2) immediate membrane damage without long range toxicity.

Antibiotics, Antineoplastic↗
PubMed2005

Macrolide resistance of Streptococcus pneumoniae isolated during long-term macrolide therapy: difference between erythromycin and clarithromycin.

Longterm macrolide therapy (LTMT) has been employed as an effective therapy both for diffuse panbronchiolitis in Japan and for cystic fibrosis in European countries. However, effects on antibiotic susceptibility profiles of microorganisms, associated with such long-term administration of antibiotics, are of concern. We retrospectively identified 57 pneumococcal isolates, recovered from the same number of patients receiving either LTMT with 400 mg of clarithromycin daily (CAM group; n = 31) or 600 mg of erythromycin daily (EM group; n = 26) by reviewing the patients' records at Nara Medical University. On analysis, we found that all isolates recovered from the CAM group and 25 of the 26 recovered from the EM group were resistant to EM, showing either an MLSB: or an M phenotype. Interestingly, isolates exhibiting the M phenotype were much less frequent in the CAM group (2 of 31; 6.5%) than in the EM group (15 of 26; 57.7%). No increase in the rate of penicillin resistance was observed in either group. The macrolide resistance profiles of microorganisms may be influenced differently according to differences in the kind of macrolide antibiotics used.

Anti-Bacterial Agents↗
PubMed2000

Glycosylation of macrolide antibiotics. Purification and kinetic studies of a macrolide glycosyltransferase from Streptomyces antibioticus.

The oleD gene has been identified in the oleandomycin producer Streptomyces antibioticus and it codes a macrolide glycosyltransferase that is able to transfer a glucose moiety from UDP-glucose (UDP-Glc) to many macrolides. The glycosyltransferase coded by the oleD gene has been purified 371-fold from a Streptomyces lividans clone expressing this protein. The reaction product was isolated, and its structure determined by NMR spectroscopy. The kinetic mechanism of the reaction was analyzed using the macrolide antibiotic lankamycin (LK) as substrate. The reaction operates via a compulsory order mechanism. This has been shown by steady-state kinetic studies and by isotopic exchange reactions at equilibrium. LK binds first to the enzyme, followed by UDP-glucose. A ternary complex is thus formed prior to transfer of glucose. UDP is then released, followed by the glycosylated lankamycin (GS-LK). A pH study of the reaction was performed to determine values for the molecular pK values, suggesting possible amino acid residues involved in the catalytic process.

Amino Acid Sequence↗
PubMed1975

Sequence of biosynthesis of the components of the polyene macrolides candidin and candihexin: macrolide aglycones as intracellular components.

A sequential formation of the single components of the polyene macrolide candidin complex (heptaene) has been found. In addition to the three components occurring in the candidin complex at the end of the fermentation, two other "early" all-trans heptaene components have been characterized. They exist only during the phase of active biosynthesis of candidin. Two of the components of the polyene macrolide candihexin complex (hexaene) that have been described as lacking amino sugar were the only intracellular (mycelium-associated) components observed under conditions in which no extracellular polyene remained attached to the producing cell. The results indicate that glycosylation of the macrolide ring takes place during the secretion process.

Antifungal Agents↗
PubMed1994

Cloning of the macrolide antibiotic biosynthesis gene acyA, which encodes 3-O-acyltransferase, from Streptomyces thermotolerans and its use for direct fermentative production of a hybrid macrolide antibiotic.

A gene encoding the macrolide modification enzyme 3-O-acyltransferase (acyA) was cloned by chromosome walking onto the carbomycin biosynthetic region in Streptomyces thermotolerans TH475, with the 3' region of the gene encoding the macrolide modification enzyme 4"-O-acyltransferase (acyB1) as a probe. A shortened fragment (1.8 kb) containing acyA was subcloned with pIJ350. A high-level tylosin producer, Streptomyces fradiae MBBF, transformed with the plasmid could produce a hybrid macrolide, 3-O-acetyltylosin, most efficiently.

Acyltransferases↗
PubMed1996

Microbial glycosylation of macrolide antibiotics by Streptomyces hygroscopicus ATCC 31080 and distribution of a macrolide glycosyl transferase in several Streptomyces strains.

In the course of our microbial transformation study on erythromycin derivatives, Streptomyces hygroscopicus ATCC 31080, which produces a polyether antibiotic carriomycin, was found to transform erythromycin derivatives to their inactivated derivatives. The structures of inactivated derivatives prepared by enzyme reaction using the cell extract, UDP-glucose (or UDP-galactose) and Mg2+ (or Mn2+) were elucidated on the basis of analysis of thei spectral data to be the compounds glycosylated at C-2' of a desosamine moiety, indicating that the enzyme is a macrolide glycosyl transferase (MGT). The MGT activity of cell extract from S. antibioticus ATCC 11891, a producing organism of oleandomycin, could be distinguished from that of ATCC 31080, based on the ability to glycosylate tylosin. We examined 32 actinomycete strains producing such polyketides as macrolide and polyether antibiotics, and found that 15 strains of Streptomyces have macrolide glycosyl transferase activity. It suggests that the MGTs have been distributed among at least polyketide producing Streptomyces strains.

Anti-Bacterial Agents↗
PubMed1989

[Comparison of the in vitro post-antibiotic effect of C14 macrolides (erythromycin and roxithromycin) and C16 macrolides (josamycin and spiramycin) against Staphylococcus aureus].

In vitro post-antibiotic effect (PAE) induced by erythromycin, roxithromycin, josamycin and spiramycin has been compared on Staphylococcus aureus. Three MLSB sensitive and three MLSB inducible resistant S. aureus strains have been used. delta t was the time required for culture to increase by 1 log10 after drug removal in comparison with controls. For erythromycin and roxithromycin delta t ranged from 6 minutes at 1 x MIC to 48 minutes at 4 x MIC (average of the six strains at 4 x MIC: 33 minutes). For josamycin and spiramycin, delta t ranged from 36 at 1/2 x MIC to 138 minutes at 4 x MIC (average at 4 x MIC: 101 minutes). No difference was observed between MLSB sensitive and MLSB inducible resistant S. aureus strains. In our experimental conditions, PAEs observed with josamycin and spiramycin (16-membered-ring macrolides) were 2.5 to 3 times longer than those observed with erythromycin and roxithromycin (14-membered-ring macrolides). These results added to biological differences previously observed between 14-membered-ring and 16-membered-ring macrolides.

Erythromycin↗
PubMed1993

[Inducible resistance to macrolide-lincosamide-streptogramin type B antibiotics in Bacillus licheniformis: common structures of macrolide antibiotics capable of inducing the resistance].

Whether or not resistance to macrolide-lincosamide-streptogramin type B antibiotics (MLS) can be induced by many macrolide antibiotics (Mac), was inquired in Bacillus licheniformis EMR. Resistance to MLS in the strain was induced by erythromycin, oleandomycin, clarithromycin, roxithromycin, narbomycin, picromycin, kujimycin A or B, mycinamicin I, or rosamicin. On the contrary, josamycin, spiramycin, tylosin, rokitamycin, midecamycin, and miokamycin as well as lincosamide and streptogramin type B antibiotics could not induce MLS-resistance. The results suggest that two common chemical residues of the inducer Mac, that is, 1) a single monosaccharide at C5 in the 14- and 16-membered lactone rings, and 2) one polar group such as dimethylamino or methoxyl at C3' in the sugar, are likely to be responsible for showing the activity of MLS-resistance inducer in Bacillus licheniformis EMR.

Anti-Bacterial Agents↗