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PubMed2000

Macrolide antibiotics for cystic fibrosis.

BACKGROUND: Cystic Fibrosis is characterised by chest infection, the antibiotic treatment of which has significantly improved the outlook for people with this condition. The unusual nature of organisms that infect the chest of individuals with cystic fibrosis has restricted antibiotic choice. In particular the bacteria, Pseudomonas aeruginosa, is resistant to nearly all antibiotics that can be taken by mouth. There is laboratory evidence and evidence from other disease processes that macrolide antibiotics, whilst not directly active against Pseudomonas aeruginosa, may have indirect actions against this bacteria. OBJECTIVES: This review aimed to test the hypotheses that macrolide antibiotics; 1) Improve clinical status compared to placebo or another antibiotic 2) do not have unacceptable adverse effects If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of macrolide therapy. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. In addition, Principal Investigators, known to work in the field and previous authors were contacted for unpublished or follow up data. Pharmaceutical companies, that manufacture macrolide antibiotics, were approached. SELECTION CRITERIA: Randomised controlled trials, published or unpublished, of macrolide compared to placebo, another class of antibiotic or another macrolide. Studies which compare regimes of the same macrolide at different doses will also be included. DATA COLLECTION AND ANALYSIS: No completed randomised controlled trials were identified. MAIN RESULTS: Three open studies excluded. Four ongoing randomised controlled trials were identified. No completed randomised controlled trials were identified. REVIEWER'S CONCLUSIONS: At present, there are no randomised controlled trials to evaluate the use of macrolide antibiotics for the treatment of chest infection in people with cystic fibrosis. Such trials, with clear outcome measures, are needed to properly evaluate this potentially useful treatment for cystic fibrosis.

Anti-Bacterial Agents↗

PubMed2004

Macrolide activities beyond their antimicrobial effects: macrolides in diffuse panbronchiolitis and cystic fibrosis.

Diffuse panbronchiolitis (DPB) is a pulmonary disease characterized by chronic inflammation of the bronchioles and chronic infiltration of inflammatory cells in the lungs. DPB has several features in common with cystic fibrosis (CF). Clinical trials in patients with DPB or CF suggest a potential role for maintenance (long-term and low-dose) macrolide therapy in the treatment of these chronic pulmonary conditions. Indeed, these studies demonstrate improved clinical and physiological states with macrolide therapy. The beneficial effects of long-term low-dose macrolides are not related to their antimicrobial properties, since levels of macrolides with low-dose treatment are too low to have sufficient antimicrobial effects. Data indicate that macrolides may have immunomodulatory activities: (1) in vitro and ex vivo studies clearly show that macrolides can influence cytokine production by several cell types; (2) furthermore, macrolides can alter polymorphonuclear cell functions in vitro and ex vivo. Although immunomodulation may serve as one explanation for the beneficial effects of macrolides in patients with chronic pulmonary inflammation, the effect of low-dose macrolide therapy on biofilm-formation may form a second explanation for the positive effects of long-term low-dose macrolide therapy. In the present paper, the clinical trials on maintenance macrolide therapy in patients with DPB or CF are reviewed. This is followed by a discussion on the immunomodulating effects of macrolides, and the effects of macrolides on biofilm formation.

Adjuvants, Immunologic↗

PubMed2004

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

BACKGROUND: The association between macrolide resistance mechanisms and ketolide bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity against macrolide-susceptible and macrolide-resistant S. pneumoniae simulating clinically achievable free serum and epithelial lining fluid (ELF) 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. Telithromycin was modelled simulating a dosage of 800 mg by mouth once daily [free serum: maximum concentration (C(max)) 0.7 mg/L, t(1/2) 10 h; and free ELF: C(max) 6.0 mg/L, t(1/2) 10 h]. 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 log(10) cfu/mL versus initial inoculum). RESULTS: Telithromycin free serum concentrations achieved in the model were: C(max) 0.9+/-0.08 mg/L, AUC(0-24) 6.4+/-1.5 mg.h/L and t(1/2) of 10.6+/-1.6 h. Telithromycin free ELF concentrations achieved in the model were: C(max) 6.6+/-0.8 mg/L, AUC(0-24) 45.5+/-5.5 mg.h/L and t(1/2) of 10.5+/-1.7 h. At 2 h, free serum telithromycin concentrations achieved a 1.0-1.9 log(10) reduction in inoculum compared with a 3.0-3.3 log(10) reduction with free ELF versus macrolide-susceptible and macrolide-resistant S. pneumoniae. Free telithromycin serum and ELF concentrations simulating C(max)/MIC > or =14.1 and area under the curve to MIC (AUC(0-24)/MIC) > or =100 [time above the MIC (t > MIC) of 100%], were bactericidal (> or =3 log(10) killing) at 4, 6, 12, 24 and 48 h versus macrolide-susceptible and macrolide-resistant S. pneumoniae. CONCLUSION: Telithromycin serum and ELF concentrations rapidly eradicated macrolide-susceptible and macrolide-resistant S. pneumoniae regardless of resistance phenotype. Achieving C(max)/MIC > or =14.1 and AUC(0-24)/MIC > or =100 resulted in bactericidal activity at 4 h with no regrowth over 48 h.

Anti-Bacterial Agents↗

PubMed2004

Tetracycline and macrolide co-resistance in Streptococcus pyogenes: co-selection as a reason for increase in macrolide-resistant S. pyogenes?

In Denmark, tetracycline resistance in Streptococcus pyogenes is frequent (>30%) whereas macrolide resistance is low (<5%). The aim of this study was to investigate the genetic background of tetracycline- and macrolide resistance in macrolide-resistant S. pyogenes (MRSP) and to investigate the correlation between the use of macrolide and tetracycline and macrolide resistance using international data. A total of 133 MRSP isolates were received at Statens Serum Institut from nine Danish clinical microbiology laboratories between. November 2000, and November 2002. The macrolide-resistance genes, erm(B), erm(A), and mef(A) were detected in 46%, 18%, and 32% of the tested MRSP isolates, respectively. In 4% of MRSP isolates, none of the MR genes were detected. Tetracycline resistance was found in 52% of MRSP. Tetracycline resistance was encoded by either tet(M) or tet(O). erm(B) and mef(A) were associated with tet(M). Sixteen different T types were detected among the 133 MRSP. Analysis of the importance of antibiotic use for development of macrolide resistance in S. pyogenes showed no correlation with macrolide use alone (p = 0.15) but a significant correlation (p = 0.03) for the combination of macrolide and tetracycline use. The frequency of macrolide resistance in Danish S. pyogenes was low and mainly due to erm genes. A high frequency of macrolide-tetracycline coresistance in S. pyogenes is found in many countries including Denmark, hence tetracycline use must be considered as a co-factor in selection of MRSP.

Anti-Bacterial Agents↗

PubMed2005

Expression of the mef(E) gene encoding the macrolide efflux pump protein increases in Streptococcus pneumoniae with increasing resistance to macrolides.

Active macrolide efflux is a major mechanism of macrolide resistance in Streptococcus pneumoniae in many parts of the world, especially North America. In Canada, this active macrolide efflux in S. pneumoniae is predominantly due to acquisition of the mef(E) gene. In the present study, we assessed the mef(E) gene sequence as well as mef(E) expression in variety of low- and high-level macrolide-resistant, clindamycin-susceptible (M-phenotype) S. pneumoniae isolates (erythromycin MICs, 1 to 32 microg/ml; clindamycin MICs, < or = 0.25 microg/ml). Southern blot hybridization with mef(E) probe and EcoRI digestion and relative real-time reverse transcription-PCR were performed to study the mef(E) gene copy number and expression. Induction of mef(E) expression was analyzed by Etest susceptibility testing pre- and postincubation with subinhibitory concentrations of erythromycin, clarithromycin, azithromycin, telithromycin, and clindamycin. The macrolide efflux gene, mef(E), was shown to be a single-copy gene in all 23 clinical S. pneumoniae isolates tested, and expression post-macrolide induction increased 4-, 6-, 20-, and 200-fold in isolates with increasing macrolide resistance (erythromycin MICs 2, 4, 8, and 32 microg/ml, respectively). Sequencing analysis of the macrolide efflux genetic assembly (mega) revealed that mef(E) had a 16-bp deletion 153 bp upstream of the putative start codon in all 23 isolates. A 119-bp intergenic region between mef(E) and mel was sequenced, and a 99-bp deletion was found in 11 of the 23 M-phenotype S. pneumoniae isolates compared to the published mega sequence. However, the mef(E) gene was fully conserved among both high- and low-level macrolide-resistant isolates. In conclusion, increased expression of mef(E) is associated with higher levels of macrolide resistance in macrolide-resistant S. pneumoniae.

Azithromycin↗

PubMed2006

Macrolide and azithromycin use are linked to increased macrolide resistance in Streptococcus pneumoniae.

The connection between regional rates of antimicrobial resistance in Streptococcus pneumoniae and regional antimicrobial use in Finland was investigated. During the 6-year study period of 1997 to 2002, a total of 31,609 S. pneumoniae isolates were tested for penicillin resistance and a total of 23,769 isolates were tested for macrolide resistance in 18 central hospital districts in Finland. The regional macrolide resistance rates were compared with the local use of (i) all macrolides pooled and (ii) azithromycin. The penicillin resistance levels were compared with the consumption data for (i) penicillins, (ii) cephalosporins, (iii) all beta-lactams pooled, and (iv) all macrolides pooled. A statistically significant association between macrolide resistance and total use of macrolides and the use of azithromycin was found. Moreover, total use of beta-lactams and total use of cephalosporins were significantly connected to low-level penicillin resistance. A statistically significant association between penicillin-nonsusceptible isolates and penicillin or total macrolide consumption was not found. In conclusion, total macrolide use and azithromycin use are associated with increased macrolide resistance, and beta-lactam use and cephalosporin use are connected to increased low-level penicillin resistance in S. pneumoniae. Unnecessary prescribing of macrolides and cephalosporins should be avoided.

Anti-Bacterial Agents↗

PubMed2006

Effects of macrolides on pneumolysin of macrolide-resistant Streptococcus pneumoniae.

To clarify the discrepancy between increasing resistance and conservative clinical effects of macrolides on macrolide-resistant Streptococcus pneumoniae, the authors evaluated the effects of sub-minimum inhibitory concentrations of macrolides on pneumolysin. In vitro, S. pneumoniae was incubated with 1, 2 and 4 microg.mL(-1) of clarithromycin (CLR) and azithromycin (AZM) for 8 h. Western blot analysis and haemolytic assay were performed to examine the production and activities of pneumolysin. In vivo, mice were infected with S. pneumoniae intra-nasally and treated with CLR (40 or 200 mg.kg(-1) twice daily) or AZM (40 or 200 mg.kg(-1) once daily) orally for 7 days. After 72 h post-infection, western blot analysis was performed to examine pneumolysin production in lungs. Survival rates were observed for 10 days. In vitro, every concentration of macrolide inhibited pneumolysin production more than the control. CLR (2 and 4 microg.mL(-1)) and AZM (4 microg.mL(-1)) reduced the pneumolysin activities more than the control. In vivo, macrolides (200 mg.kg(-1)) reduced pneumolysin in murine lungs more than the control. CLR (40 and 200 mg.kg(-1)) and AZM (200 mg.kg(-1)) improved the survival rates more than the control. The study results show that sub-minimum inhibitory concentrations of macrolides reduced pneumolysin. This might be related to the effectiveness of macrolides against pneumonia caused by high-level macrolide-resistant Streptococcus pneumoniae. Further investigations are necessary to evaluate the effects of macrolides on macrolide-resistant Streptococcus pneumoniae.

Bacterial Proteins↗

PubMed2006

Macrolide resistance rates in respiratory pathogens in Slovenia following reduced macrolide use.

The aim of this study was to investigate the association between decreased use of macrolides and resistance of common respiratory pathogens in Slovenia from 1999 to 2004. Over a 6-year period the consumption of macrolides in Slovenia decreased by 21.3%, from 3.81 defined daily doses/1000 inhabitants per day (DID) to 3.0 DID. The use of short-acting, intermediate-acting and long-acting subclasses of macrolides decreased by 50%, 18% and 13%, respectively. In the same period, resistance of invasive strains of Streptococcus pneumoniae increased from 4.6% to 11.1% and resistance of non-invasive strains of S. pneumoniae and Streptococcus pyogenes increased from 12.8% to 20.2% and from 7.4% to 12.5%, respectively. Resistance increased significantly more in children than in adults (P=0.05) and was significantly correlated with increased use of intermediate-acting macrolides (r=0.94 for non-invasive S. pneumoniae and r=0.96 for S. pyogenes) in children. Resistance of Haemophilus influenzae and Moraxella catarrhalis was low and did not change. In children and adults, the emergence and spread of multidrug-resistant strains of invasive S. pneumoniae was observed. The decline in total macrolide use was not paralleled by reduced macrolide resistance rates of S. pyogenes and S. pneumoniae during the 6-year period. There was a strong correlation between the use of intermediate-acting macrolides and macrolide resistance of S. pyogenes and S. pneumoniae in children. Further reduction in the use of intermediate- and long-acting macrolides should be encouraged.

Adolescent↗

PubMed2004

Distribution across the USA of macrolide resistance and macrolide resistance mechanisms among Streptococcus pneumoniae isolates collected from patients with respiratory tract infections: PROTEKT US 2001-2002.

BACKGROUND: Resistance to the macrolides has increased rapidly among isolates of Streptococcus pneumoniae from community-acquired respiratory tract infections (CARTIs). METHODS: A total of 10 012 S. pneumoniae isolates were submitted from 46 US states and the territory of Puerto Rico in the PROTEKT US Year 2 (2001-2002) surveillance study. Antimicrobial susceptibilities were determined according to NCCLS guidelines and genes encoding common macrolide resistance mechanisms were sought by PCR. RESULTS: Overall, 27.9% (n=2793) of S. pneumoniae isolates were macrolide (erythromycin) resistant; the highest prevalence was recorded in Louisiana (48.2%). Of the 2738 genotyped macrolide-resistant S. pneumoniae, 68.7% possessed mef(A) (state range: Delaware 40.0%-Georgia 84.8%), 16.8% of isolates harboured erm(B) (Georgia 6.1%-Idaho and Rhode Island both 36.4%) and 12.2% possessed erm(B) + mef(A) (Arkansas and Rhode Island 0%-South Dakota 32.9%). Five isolates possessed an erm(A) subclass erm(TR) gene (from California, Illinois, Missouri, Pennsylvania and Virginia), while the mechanisms for 56 isolates were not definable by the methods used in this study. Susceptibility to telithromycin was high, irrespective of macrolide resistance mechanism, with > or =96.4% of the macrolide-resistant isolates susceptible. CONCLUSIONS: The prevalence of macrolide resistance and the resistance mechanisms among S. pneumoniae isolates are highly variable among the US states. Telithromycin may represent an effective treatment option for CARTIs caused by macrolide-resistant pneumococci.

Anti-Bacterial Agents↗

PubMed1989

New macrolides active against Streptococcus pyogenes with inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance.

Macrolide-resistant bacteria can be classified as inducibly resistant or constitutively resistant. Inducibly resistant bacteria are resistant to 14-membered macrolides, such as erythromycin and clarithromycin (A-56268), but are susceptible to the 16-membered macrolides, such as tylosin and spiramycin, as well as to clindamycin. Constitutively resistant bacteria are resistant to macrolide-lincosamide-streptogramin B antibiotics. In this study, the MICs of several erythromycin and clarithromycin analogs against macrolide-susceptible and macrolide-resistant Streptococcus pyogenes strains were determined. Four 11,12-carbamate analogs of clarithromycin had lower MICs than erythromycin did against S. pyogenes with the inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance. Five 11,12-carbonate analogs of erythromycin with modifications at the 4" position of cladinose had lower MICs than did erythromycin against S. pyogenes with the constitutive type of resistance, and one of these compounds, which had a naphthyl-glycyl substitution at the 4" position, had a lower MIC than erythromycin against both the inducibly resistant and constitutively resistant strains. Two analogs of erythromycin with a modification on the 4" position of cladinose had lower MICs than erythromycin did against the constitutively resistant organisms but not against the inducibly resistant organisms. Thus, 14-membered macrolides can be modified so as to confer a low MIC when tested in vitro.

Aminoglycosides↗

PubMed2002

Rokitamycin: bacterial resistance to a 16-membered ring macrolide differs from that to 14- and 15-membered ring macrolides.

Rokitamycin is the latest semi-synthetic 16-membered ring macrolide introduced into clinical practice. It is characterized by greater hydrophobicity, better bacterial uptake and a slower release, more cohesive ribosomal binding, and a longer post-antibiotic-effect (PAE) than can be observed with other available 14-, 15- and 16-membered ring macrolides. Rokitamycin exerts its activity on strains that harbor inducible erm genes or the efflux gene, mef(A). It has also been reported to be more active in vitro than other 16-membered ring macrolides. However, these recognized features are not fully exploited yet because current automated test procedures used in many microbiological laboratories determine susceptibility only to erythromycin or clarithromycin. Resistance to 16-membered ring macrolides cannot be predicted solely on the basis of known resistance to erythromycin or clarithromycin as revealed by an automated susceptibility assay. At least equally important is the knowledge of the bacterial resistance phenotype. This is underlined by the existence of Gram-positive coccal strains resistant to erythromycin and other 14-,15-membered ring macrolides but susceptible to 16-membered ring macrolides. Since the local prevalence of erythromycin phenotypes is generally unknown but might determine the outcome of treatment, the procedure for identifying the phenotypes in erythromycin-resistant strains (which can be easily and cheaply performed using the two- or three-disk assay) should become routine, at least in the countries in which 16-membered ring macrolides are used. This approach should help to optimize the use of macrolides, improve our knowledge of the local prevalence of phenotypes resistant to erythromycin, and offer the possibility of treating infections caused by certain types of erythromycin-resistant pathogens.

Anti-Bacterial Agents↗

PubMed2006

Macrolide use identified as risk factor for macrolide-resistant Streptococcus pneumoniae in a 17-center case-control study.

The objective of the case-control study presented here was to examine the risk factors for macrolide-resistant Streptococcus pneumoniae. As part of a 44-center U.S. surveillance study, 1,817 unique isolates of S. pneumoniae were collected from November 2002 through April 2003. Seventy-five randomly selected macrolide-resistant isolates (cases) were each matched with one susceptible control. Macrolide use in the 6 weeks prior to sample collection was reported for seven cases and one control. The final conditional logistic regression model identified two statistically significant variables: a history of alcohol abuse was protective, while macrolide use in the 6 weeks prior to sample collection was a significant risk factor for macrolide-resistant S. pneumoniae. Macrolide resistance was associated with use of any antibiotic during the prior 6 weeks, and was most strongly associated with previous macrolide use.

Adolescent↗

PubMed1999

Influence of increased macrolide consumption on macrolide resistance of common respiratory pathogens.

The impact of increased macrolide consumption on the resistance of common respiratory pathogens to erythromycin and azithromycin was evaluated. The study focused mainly on azithromycin. During the period from 1991 to 1996, a 3.5-fold increase in macrolide prescriptions for outpatients was observed in Slovenia. Compared to 1994, when no macrolide resistance was evident in Streptococcus pyogenes and noninvasive Streptococcus pneumoniae, a significant increase in macrolide resistance was observed in these two pathogens in 1997. Moraxella catarrhalis remained uniformly susceptible to macrolides. Close monitoring of macrolide resistance of common respiratory pathogens is thus necessary.

Anti-Bacterial Agents↗

PubMed1997

Macrolide resistance in Helicobacter pylori: rapid detection of point mutations and assays of macrolide binding to ribosomes.

Resistance of Helicobacter pylori to macrolides is a major cause of failure of eradication therapies. Single base substitutions in the H. pylori 23S rRNA genes have been associated with macrolide resistance in the United States. Our goal was to extend this work to European strains, to determine the consequence of this mutation on erythromycin binding to H. pylori ribosomes, and to find a quick method to detect the mutation. Seven pairs of H. pylori strains were used, the parent strain being naturally susceptible to macrolides and the second strain having acquired an in vivo resistance during a treatment regimen that included clarithromycin. The identity of the strains was confirmed by random amplified polymorphic DNA testing with two different primers, indicating that resistance was the result of the selection of variants of the infecting strain. All resistant strains were found to have point mutations at position 2143 (three cases) or 2144 (four cases) but never on the opposite DNA fragment of domain V of the 23S rRNA gene. The mutation was A-->G in all cases except one (A-->C) at position 2143. Using BsaI and BbsI restriction enzymes on the amplified products, we confirmed the mutations of A-->G at positions 2144 and 2143, respectively. Macrolide binding was tested on purified ribosomes isolated from four pairs of strains with [14C]erythromycin. Erythromycin binding increased in a dose-dependent manner for the susceptible strain but not for the resistant one. In conclusion we suggest that the limited disruption of the peptidyltransferase loop conformation, caused by a point mutation, reduces drug binding and consequently confers resistance to macrolides. Finally, the macrolide resistance could be detected without sequencing by performing restriction fragment length polymorphism with appropriate restriction enzymes.

Anti-Bacterial Agents↗

PubMed2001

The relationship between trends in macrolide use and resistance to macrolides of common respiratory pathogens.

The correlation between increased macrolide consumption and the resistance of Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis to macrolides in Slovenia from 1994 to 1999 was evaluated. The outpatient consumption of macrolides increased from 1.89 to 3.84 defined daily doses (DDD)/1000 inhabitants/day during the observation period. This increase in macrolide consumption was paralleled by a steady increase in macrolide resistance in S. pyogenes (from 0 to 7.4%, r = 0.90, P = 0.014) and upper respiratory S. pneumoniae isolates (from 0 to 9%, r = 0.82, P = 0.044). In other pathogens studied, no significant increase was detected.

Ambulatory Care↗

PubMed1992

Inducible resistance to a 16-membered macrolide, mycinamicin, in Staphylococcus aureus resistant to 14-membered macrolides and streptogramin B antibiotics.

Staphylococcus aureus 8325(pEP2104), a transductant derived from S. aureus PM2104 isolated clinically in Hungary (L. Janosi, and E. Ban, Acta Microbiol. Acad. Sci. Hung., 29: 187-200, 1982), exhibited an inducible resistance to the 14-membered macrolides [erythromycin (EM) and oleandomycin (OL)] and streptogramin B (MKM-B) antibiotics, but not to the 16-membered macrolides and lincosamides. This resistance was referred to as PMS-resistance phenotype (L. Jánosi, Y. Nakajima, and H. Hashimoto, Microbiol. Immunol., 34: 723-735, 1990). In addition to EM, OL, and MKM-B, however, the strain was recently and first observed to have inducible resistance to mycinamicin, a 16-membered ring macrolide. Thereby, we propose that the reference stated just above as PMS-resistance has to be extended to such 16-membered macrolides as mycinamicin. An optimum concentration of erythromycin or oleandomycin for induction of PMS-resistance was 1.35 mu g/ml in the strain 8325(pEP2104). The concentration was about 30 times as great as that (0.05 mu g/ml) required for induction of well-known co-resistance to macrolide-lincosamide-streptogramin B antibiotics in S. aureus ISP447.

Anti-Bacterial Agents↗

PubMed1992

Purification and characterization of macrolide 2'-phosphotransferase type II from a strain of Escherichia coli highly resistant to macrolide antibiotics.

The resistance mechanism of Escherichia coli BM2506 to macrolides was found to be due to inactivation. Inactivated oleandomycin was identified as oleandomycin 2'-phosphate by thin-layer chromatography. A new type of macrolide-phosphorylating enzyme, macrolide 2'-phosphotransferase type II (MPH(2')II), was detected, purified 95-fold and its enzymological properties investigated. MPH(2')II was a constitutive intracellular enzyme which showed high levels of activity with both 14-member-ring and 16-member-ring macrolides. The optimum pH for the inactivation of oleandomycin was 8.2 and the optimum temperature of the reaction was 40 degrees C. Enzyme activity was lost by heat treatment at 60 degrees C for 1 min. The isoelectric point and M(r) of the enzyme were 5.3 and 48,000, respectively. Purine nucleotides, such as ITP, GTP and ATP, were effective as cofactors in the inactivation of macrolides. An inhibitory effect of iodine, EDTA, or divalent cations on MPH(2')II activity was observed.

Anti-Bacterial Agents↗

PubMed2005

In vitro selection of mutants of Streptococcus pneumoniae resistant to macrolides and linezolid: relationship with susceptibility to penicillin G or macrolides.

OBJECTIVES: To evaluate the rate of acquisition of resistance to linezolid and macrolides in Streptococcus pneumoniae isolates with different levels of susceptibility to penicillin and erythromycin. MATERIALS AND METHODS: Thirty strains of S. pneumoniae were tested by serial passages in subinhibitory concentrations of each antibiotic by the spiral method. The four copies of the 23S rRNA rrl gene of parent strains and linezolid-resistant mutants were amplified and sequenced. RESULTS: The rate of acquisition of macrolide resistance did not differ when C-14 and C-16 macrolides were tested. Resistance to linezolid in strains susceptible to penicillin and erythromycin was difficult to produce. For mutants with low-level resistance to linezolid the cut-off value of the MIC was between 6 and 8 mg/L depending on the strain. All linezolid-resistant mutants displayed a mutation in 2-4 copies of the 23S rRNA rrl gene, mainly the G2576U mutation (27/30) with an additional C2610U mutation observed in certain mutants. Two new mutations were also noted, namely C2612A and C2571G. In three linezolid-resistant mutants no mutation was identified within the studied domain, suggesting another mechanism of resistance. CONCLUSIONS: Linezolid resistance in pneumococcal strains susceptible to penicillin and macrolides was more difficult to obtain than with macrolides. Increased resistance to these agents may therefore influence the clinical use of linezolid.

Acetamides↗