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Background

The clinical management of community-acquired respiratory tract infections (RTIs) is complicated by the increasing worldwide prevalence of antibacterial resistance, in particular, β-lactam and macrolide resistance, among the most common causative bacterial pathogens. This study aimed to determine the mechanisms and molecular- and sero-epidemiology of antibacterial resistance among the key paediatric respiratory pathogens in Japan.

Methods

Isolates were collected at 18 centres in Japan during 2002 and 2003 from children with RTIs as part of the PROTEKT surveillance programme. A proportion of Haemophilus influenzae isolates was subjected to sequencing analysis of the ftsI gene; phylogenetic relatedness was assessed using multilocus sequence typing. Streptococcus pneumoniae isolates were screened for macrolide-resistance genotype by polymerase chain reaction and serotyped using the capsular swelling method. Susceptibility of isolates to selected antibacterials was performed using CLSI methodology.

Results and Discussion

Of the 557 H. influenzae isolates collected, 30 (5.4%) were β-lactamase-positive [BL+], 115 (20.6%) were BL-nonproducing ampicillin-resistant (BLNAR; MIC ≥ 4 mg/L) and 79 (14.2%) were BL-nonproducing ampicillin-intermediate (BLNAI; MIC 2 mg/L). Dabernat Group III penicillin binding protein 3 (PBP3) amino acid substitutions in the ftsI gene were closely correlated with BLNAR status but phylogenetic analysis indicated marked clonal diversity. PBP mutations were also found among BL+ and BL-nonproducing ampicillin-sensitive isolates. Of the antibacterials tested, azithromycin and telithromycin were the most active against H. influenzae (100% and 99.3% susceptibility, respectively). A large proportion (75.2%) of the 468 S. pneumoniae isolates exhibited macrolide resistance (erythromycin MIC ≥ 1 mg/L); erm(B) was the most common macrolide resistance genotype (58.8%), followed by mef(A) (37.2%). The most common pneumococcal serotypes were 6B (19.7%), 19F (13.7%), 23F (13.5%) and 6A (12.8%). Telithromycin and amoxicillin-clavulanate were the most active antibacterials against S. pneumoniae (99.8% and 99.6% susceptibility, respectively).

Conclusion

Approximately one-third of H. influenzae isolates from paediatric patients in Japan are BLNAI/BLNAR, mainly as a result of clonally diverse PBP3 mutations. Together with the continued high prevalence of pneumococcal macrolide resistance, these results may have implications for the clinical management of paediatric RTIs in Japan.

The PROTEKT US (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin in the United States) surveillance program was established to determine the prevalence and mechanisms of antibacterial resistance among bacterial pathogens from patients with community-acquired respiratory tract infections. In year 1 of the PROTEKT US study, 10,103 isolates of Streptococcus pneumoniae, including 3,133 erythromycin-resistant strains and 81 levofloxacin-resistant strains, were collected from 206 centers. We report on the molecular analyses of these resistant strains. The resistance genotypes among the 3,044 typed macrolide-resistant isolates overall were mef(A) (n = 2,157; 70.9%), erm(B) (n = 530; 17.4%), mef(A) erm(B) (n = 304; 10.0%), and erm(A) subclass erm(TR) (n = 5; 0.2%). Fifty (1.6%) macrolide-resistant isolates were negative for the mef and the erm resistance genes. Seventy-eight (96.3%) of the 81 levofloxacin-resistant isolates analyzed possessed multiple mutations in the gyrA, gyrB, parC, and/or parE quinolone resistance-determining regions. A total of 43 known multilocus sequence typing (MLST) profiles (or single- or double-locus variants) accounted for 75 of 81 isolates. There was no evidence of dissemination of fluoroquinolone-resistant clones within the United States; however, 12 isolates with the same MLST profile were located in one center in Massachusetts. Almost 90% of the erythromycin-resistant isolates and approximately one-third of the levofloxacin-resistant isolates were multidrug resistant.

Background

Increasing antimicrobial resistance among the key pathogens responsible for community-acquired respiratory tract infections has the potential to limit the effectiveness of antibiotics available to treat these infections. Since there are regional differences in the susceptibility patterns observed and treatment is frequently empirical, the selection of antibiotic therapy may be challenging. PROTEKT, a global, longitudinal multicentre surveillance study, tracks the activity of telithromycin and comparator antibacterial agents against key respiratory tract pathogens.

Methods

In this analysis, we examine the prevalence of antibacterial resistance in 1,336 bacterial pathogens, isolated from adult and paediatric patients clinically diagnosed with acute bacterial sinusitis (ABS).

Results and discussion

In total, 58.0%, 66.1%, and 55.8% of S. pneumoniae isolates were susceptible to penicillin, cefuroxime, and clarithromycin respectively. Combined macrolide resistance and reduced susceptibility to penicillin was present in 200/640 (31.3 %) of S. pneumoniae isolates (128 isolates were resistant to penicillin [MIC >= 2 mg/L], 72 intermediate [MIC 0.12–1 mg/L]) while 99.5% and 95.5% of isolates were susceptible to telithromycin and amoxicillin-clavulanate, respectively. In total, 88.2%, 87.5%, 99.4%, 100%, and 100% of H. influenzae isolates were susceptible to ampicillin, clarithromycin, cefuroxime, telithromycin, and amoxicillin-clavulanate, respectively. In vitro, telithromycin demonstrated the highest activity against M. catarrhalis (MIC50 = 0.06 mg/L, MIC90 = 0.12 mg/L).

Conclusion

The high in vitro activity of against pathogens commonly isolated in ABS, together with a once daily dosing regimen and clinical efficacy with 5-day course of therapy, suggest that telithromycin may play a role in the empiric treatment of ABS.

In the United States, approximately 30% of Streptococcus pneumoniae isolates are macrolide (erythromycin [ERY]) resistant (ERSP), most commonly due to expression of the mef(A) gene previously associated with lower-level ERY resistance (ERYr; MIC = 1 to 4 μg/ml). The data from the PROTEKT US surveillance study were analyzed to evaluate the prevalence and antibacterial susceptibility of mef(A)-positive ERSP. In all, 26,634 isolates of S. pneumoniae were collected in the United States between 2000 and 2004 from centers common to all years. ERYr was stable at approximately 29% over the 4 years, but the proportion of ERSP isolates positive for mef(A) alone decreased (year 1 [2000 to 2001], 69.0%; year 4 [2003 to 2004], 60.7%), with the sharpest declines seen in isolates from patients from 0 to 2 years of age. Conversely, the proportion isolates positive for both erm(B) and mef(A) increased over the duration of the present study (year 1, 9.3%; year 4, 19.1%), a change that was again most marked in patients aged ≤2 years. The majority of ERSP isolates expressing mef(A) alone exhibited higher than previously reported levels of ERYr (MIC90 = 16 μg/ml). However, the ketolide antibacterial telithromycin consistently demonstrated in vitro activity against these isolates over the 4 years of the study (MIC90 = 0.5 to 1 μg/ml).

Streptococcus pneumoniae isolates (N = 31,001) were collected from patients with community-acquired respiratory tract infections during the PROTEKT US surveillance study (2000–2003). While the macrolide (erythromycin) resistance rate remained stable at ≈29%, the prevalence of resistant isolates containing both erm(B) and mef(A) increased from 9.7% in year 1 to 16.4% in year 3, with substantial regional variability. Almost all (99.2%) dual erm(B)+mef(A) macrolide-resistant isolates exhibited multidrug resistance, whereas 98.6% and 99.0% were levofloxacin- and telithromycin-susceptible, respectively. These strains were most commonly isolated from the ear or middle-ear fluid of children. Of 152 representative erm(B)+mef(A) isolates, >90% were clonally related to the multidrug-resistant international Taiwan19F-14 clonal complex 271 (CC271). Of 366 erm(B)+mef(A) isolates from the PROTEKT global study (1999–2003), 83.3% were CC271, with the highest prevalence seen in South Africa, South Korea, and the United States. This study confirms the increasing global emergence and rapidly increasing US prevalence of this multidrug-resistant pneumococcal clone.

The in vitro antibacterial activities of oral cephem antibiotics and ketolide telithromycin against major respiratory pathogens possessing β-lactam-resistant mutations (within the pbp gene) and/or macrolide-resistant genes (erm and mef) were examined in clinical isolates collected at 66 institutes in all over the Japan between 2002 and 2003. Telithromycin showed the strongest antibacterial activity against methicillin-susceptible Staphylococcus aureus strains with and without macrolide-resistant genes, such as ermA or ermC gene. All the cephem antibiotics showed potent antibacterial activity against Streptococcus pyogenes, with minimum inhibitory concentrations (MICs) of 0.015 mg/L or lower. Cefdinir had a much higher MIC90 against genotypic penicillin-resistant Streptococcus pneumoniae (gPRSP) than cefditoren and cefcapene (8 mg/L cefdinir vs. 1 mg/L cefditoren and cefcapene). The majority of gPRSP harbored either ermB or mefA, and the antibacterial activity of telithromycin against these strains was decreased however some susceptibility was still sustained. Cefditoren exerted the strongest antibacterial activity against β-lactamase-negative ampicillin-resistant Haemophilus influenzae, with an MIC90 of 0.5 mg/L. These results underline the importance of checking the susceptibility and selecting an appropriate antibiotic against target pathogens.

The global emergence of antibacterial resistance among common and atypical respiratory pathogens in the last decade necessitates the strategic application of antibacterial agents. The use of bactericidal rather than bacteriostatic agents as first-line therapy is recommended because the eradication of microorganisms serves to curtail, although not avoid, the development of bacterial resistance. Bactericidal activity is achieved with specific classes of antimicrobial agents as well as by combination therapy. Newer classes of antibacterial agents, such as the fluoroquinolones and certain members of the macrolide/lincosamine/streptogramin class have increased bactericidal activity compared with traditional agents. More recently, the ketolides (novel, semisynthetic, erythromycin-A derivatives) have demonstrated potent bactericidal activity against key respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Chlamydia pneumoniae, and Moraxella catarrhalis. Moreover, the ketolides are associated with a low potential for inducing resistance, making them promising first-line agents for respiratory tract infections.

Background

This study determined macrolide resistance genotypes in clinical isolates of Streptococcus pneumoniae from multiple medical centers in Lebanon and assessed the serotype distribution in relation to these mechanism(s) of resistance and the source of isolate recovery.

Methods

Forty four macrolide resistant and 21 macrolide susceptible S. pneumoniae clinical isolates were tested for antimicrobial susceptibility according to CLSI guidelines (2008) and underwent molecular characterization. Serotyping of these isolates was performed by Multiplex PCR-based serotype deduction using CDC protocols. PCR amplification of macrolide resistant erm (encoding methylase) and mef (encoding macrolide efflux pump protein) genes was carried out.

Results

Among 44 isolates resistant to erythromycin, 35 were resistant to penicillin and 18 to ceftriaxone. Examination of 44 macrolide resistant isolates by PCR showed that 16 isolates harbored the erm(B) gene, 8 isolates harbored the mef gene, and 14 isolates harbored both the erm(B) and mef genes. There was no amplification by PCR of the erm(B) or mef genes in 6 isolates. Seven different capsular serotypes 2, 9V/9A,12F, 14,19A, 19F, and 23, were detected by multiplex PCR serotype deduction in 35 of 44 macrolide resistant isolates, with 19F being the most prevalent serotype. With the exception of serotype 2, all serotypes were invasive. Isolates belonging to the invasive serotypes 14 and 19F harbored both erm(B) and mef genes. Nine of the 44 macrolide resistant isolates were non-serotypable by our protocols.

Conclusion

Macrolide resistance in S. pneumoniae in Lebanon is mainly through target site modification but is also mediated through efflux pumps, with serotype 19F having dual resistance and being the most prevalent and invasive.

A multicenter susceptibility surveillance (the S.A.U.C.E. project) including 2,721 Streptococcus pneumoniae, 3,174 Streptococcus pyogenes, and 2,645 Haemophilus influenzae consecutive isolates was carried out in 25 hospitals all over Spain from November 2001 to October 2002 to evaluate the current epidemiology of resistance of the main bacteria involved in community-acquired respiratory tract infections. Susceptibility testing was performed in a single centralized laboratory by a broth microdilution method. The prevalence of resistant S. pneumoniae strains was 0.4% for cefotaxime, 4.4% for amoxicillin and amoxicillin-clavulanic acid, 25.6% for cefuroxime-axetil, 34.5% for erythromycin, clarithromycin, and azithromycin, and 36.0% for cefaclor. Phenotypes of resistance to erythromycin were MLSB (macrolide-lincosamide-streptogramin B) in 89.9% (gene ermB) and M (macrolide) in 9.7% of cases (gene mefA). No strain harbored both genes simultaneously. Serotypes 19, 6, 23, 14, and 3 were the most prevalent, accounting for 54.6% of the total isolates. Resistance to macrolides seems to be the most alarming point, since among penicillin-susceptible isolates it reached 15.1% compared to 55.8% among penicillin-resistant strains. Geographically, a number of regions had rates of erythromycin resistance above 40% (even higher in children). Resistance to erythromycin was also high in S. pyogenes isolates: mean regional 33.2%, beta-lactamase-producing H. influenzae were 20%, whereas 4.4% had a beta-lactamase-negative, ampicillin-resistant phenotype. We highlight the importance of different geographical frequencies of coresistance (associations of resistance to different drugs within the same species) and coupled resistance (association of resistance between different species) probably resulting from different local coselective events.

Sixteen (1.5%) of the 1,043 clinical macrolide-resistant Streptococcus pneumoniae isolates collected and analyzed in the 1999-2000 PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) study have resistance mechanisms other than rRNA methylation or efflux. We have determined the macrolide resistance mechanisms in all 16 isolates by sequencing the L4 and L22 riboprotein genes, plus relevant segments of the four genes for 23S rRNA, and the expression of mutant rRNAs was analyzed by primer extension. Isolates from Canada (n = 4), Japan (n = 3), and Australia (n = 1) were found to have an A2059G mutation in all four 23S rRNA alleles. The Japanese isolates additionally had a G95D mutation in riboprotein L22; all of these originated from the same collection center and were clonal. Three of the Canadian isolates were also clonal; the rest were not genetically related. Four German isolates had A2059G in one, two, and three 23S rRNA alleles and A2058G in two 23S rRNA alleles, respectively. An isolate from the United States had C2611G in three 23S rRNA alleles, one isolate from Poland had A2058G in three 23S rRNA alleles, one isolate from Turkey had A2058G in four 23S rRNA alleles, and one isolate from Canada had A2059G in two 23S rRNA alleles. Erythromycin and clindamycin resistance gradually increased with the number of A2059G alleles, whereas going from one to two mutant alleles caused sharp rises in the azithromycin, roxithromycin, and rokitamycin MICs. Comparisons of mutation dosage with rRNA expression indicates that not all alleles are equally expressed. Despite their high levels of macrolide resistance, all 16 isolates remained susceptible to the ketolide telithromycin (MICs, 0.015 to 0.25 μg/ml).

Of a total of 1,043 macrolide-resistant Streptococcus pneumoniae isolates collected from 24 countries as part of PROTEKT 1999-2000, 71 isolates tested positive for both the mef(A) and erm(B) genes. Of 69 isolates subjected to further molecular investigations, all were resistant to tetracycline, 63 (91.3%) were resistant to penicillin, and 57 (82.6%) were resistant to trimethoprim-sulfamethoxazole. One isolate was also fluoroquinolone resistant, and another was resistant to quinupristin-dalfopristin. The ketolide telithromycin retained activity against all of the isolates. Of the 69 of these 71 isolates viable for further testing, 46 were from South Korea, 13 were from the United States, 8 came from Japan, and 1 each came from Mexico and Hungary. One major clonal complex (59 [85.5%] of 69 isolates) was identified by serotyping (with 85.5% of the isolates being 19A or 19F), pulsed-field gel electrophoresis, and multilocus sequence typing. The remaining isolates were less clonal in nature. Representative isolates were shown to carry the mobile genetic elements Tn1545 and mega, were negative for Tn1207.1, had tetracycline resistance mediated by tet(M), and contained the mef(E) variant of mef(A). All isolates were positive for mel, a homologue of the msr(A) efflux gene. These clones are obviously very efficient at global dissemination, and hence it will be very important to monitor their progress through continued surveillance. Telithromycin demonstrated high levels of activity (MIC for 90% of the strains tested, 0.5 μg/ml; MIC range, 0.06 to 1 μg/ml) against all isolates.

A nationwide multicenter susceptibility surveillance study (Susceptibility to the Antimicrobials Used in the Community in España [SAUCE] project), SAUCE-4, including 2,559 Streptococcus pneumoniae, 2,287 Streptococcus pyogenes, and 2,736 Haemophilus influenzae isolates was carried out from May 2006 to June 2007 in 34 Spanish hospitals. Then, the results from SAUCE-4 were compared to those from all three previous SAUCE studies carried out in 1996-1997, 1998-1999, and 2001-2002 to assess the temporal trends in resistance and the phenotypes of resistance over the 11-year period. In SAUCE-4, on the basis of the CLSI breakpoints, penicillin (parenteral, nonmeningitis breakpoint) and cefotaxime were the antimicrobials that were the most active against S. pneumoniae (99.8% and 99.6%, respectively). Only 0.9% of isolates had a penicillin MIC of ≥2 μg/ml. In S. pyogenes, nonsusceptibility to erythromycin was observed in 19.4% of isolates. Among the H. influenzae isolates, a β-lactamase-positive prevalence of 15.7% was found. A statistically significant temporal decreasing trend over the 11-year period was observed for nonsusceptibility (from 60.0% to 22.9%) and resistance (from 36.5% to 0.9%) to penicillin and for the proportion of erythromycin-resistant isolates of S. pneumoniae of the macrolide-lincosamide-streptogramin B (MLSB) phenotype (from 98.4% to 81.3%). A similar trend was observed for the prevalence of ampicillin resistance (from 37.6% to 16.1%), β-lactamase production (from 25.7% to 15.7%), and β-lactamase-negative ampicillin resistance (BLNAR) in H. influenzae (from 13.5% to 0.7%). Among erythromycin-resistant isolates of S. pyogenes, a significant increasing trend in the prevalence of MLSB was observed (from 7.0% to 35.5%). SAUCE-4 confirms a generalized decline in the resistance of the main respiratory pathogens to the antimicrobials as well as a shift in their resistance phenotypes.

Broth microdilution tests were carried out with 2,671 respiratory tract isolates from 19 medical centers throughout the continental United States. The tests compared a streptogramin (RP59500) to erythromycin, dirithromycin, clarithromycin, and azithromycin against Streptococcus pneumoniae, S. pyogenes, Haemophilus influenzae, and Moraxella catarrhalis. Against macrolide-susceptible strains, the potency of RP59500 was similar to that of the macrolides: the azalide, azithromycin, was two to four times more potent against H. influenzae. The azalide and three macrolides showed nearly complete cross-resistance. At 2.0 micrograms/ml or less, the streptogramin, RP59500, was active against both macrolide-resistant and -susceptible strains of S. pneumoniae (MIC for 50% of the strains tested, 0.25 microgram/ml; MIC for 90% of the strains tested, 0.5 microgram/ml).

To date, 86 of 7,746 macrolide-resistant Streptococcus pneumoniae isolates from 1999 to 2002 PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) surveillance studies were negative for methylase and efflux mechanisms. Mutations in 23S rRNA or the genes encoding riboprotein L4 or L22 were found in 77 of 86 isolates. Six isolates were resistant to quinupristin-dalfopristin and two were resistant to linezolid, while telithromycin demonstrated good activities against all isolates.

Norway has a low prevalence of antimicrobial resistance, including macrolide-resistant Streptococcus pneumoniae (MRSP). In a nationwide surveillance program, a total of 2,200 S. pneumoniae isolates were collected from blood cultures and respiratory tract specimens. Macrolide resistance was detected in 2.7%. M-type macrolide resistance was found in 60% of resistant isolates, and these were mainly mef(A)-positive, serotype-14 invasive isolates. The erm(B)-encoded macrolide-lincosamide-streptogramin B (MLSB) type dominated among the noninvasive isolates. One strain had an A2058G mutation in the 23S rRNA gene. Coresistance to other antibiotics was seen in 96% of the MLSB-type isolates, whereas 92% of the M-type isolates were susceptible to other commonly used antimicrobial agents. Serotypes 14, 6B, and 19F accounted for 84% of the macrolide-resistant isolates, with serotype 14 alone accounting for 67% of the invasive isolates. A total of 29 different sequence types (STs) were detected by multilocus sequence typing. Twelve STs were previously reported international resistant clones, and 75% of the macrolide-resistant isolates had STs identical or closely related to these clones. Eleven isolates displayed 10 novel STs, and 7/11 of these “Norwegian strains” coexpressed MLSB and tetracycline resistance, indicating the presence of Tn1545. The invasive serotype-14 isolates were all classified as ST9 or single-locus variants of this clone. ST9 is a mef-positive M-type clone, commonly known as England14-9, reported from several European countries. These observations suggest that the import of major international MRSP clones and the local spread of Tn1545 are the major mechanisms involved in the evolution and dissemination of MRSP in Norway.

Background

Bacterial infections of the central nervous system, especially acute infections such as bacterial meningitis require immediate, invariably empiric antibiotic therapy. The widespread emergence of resistance among bacterial species is a cause for concern. Current antibacterial susceptibility data among central nervous system (CNS) pathogens is important to define current prevalence of resistance.

Methods

Antimicrobial susceptibility of pathogens isolated from CNS specimens was analyzed using The Surveillance Database (TSN®) USA Database which gathers routine antibiotic susceptibility data from >300 US hospital laboratories. A total of 6029 organisms derived from CNS specimen sources during 2000–2002, were isolated and susceptibility tested.

Results

Staphylococcus aureus (23.7%) and Streptococcus pneumoniae (11.0%) were the most common gram-positive pathogens. Gram-negative species comprised approximately 25% of isolates. The modal patient age was 1 or <1 year for most organisms. Prevalence of MRSA among S. aureus from cerebrospinal fluid (CSF) and brain abscesses were 29.9–32.9%. Penicillin resistance rates were 16.6% for S. pneumoniae, 5.3% for viridans group streptococci, and 0% for S. agalactiae. For CSF isolates, ceftriaxone resistance was S. pneumoniae (3.5%), E. coli (0.6%), Klebsiella pneumoniae (2.8%), Serratia marcescens (5.6%), Enterobacter cloacae (25.0%), Haemophilus influenzae (0%). Listeria monocytogenes and N. meningitidis are not routinely susceptibility tested.

Conclusions

Resistance is commonly detected, albeit still at relatively low levels for key drugs classes such as third-generation cephalosporins. This data demonstrates the need to consider predominant resistance phenotypes when choosing empiric therapies to treat CNS infections.

JNJ-Q2, a novel fluorinated 4-quinolone, was evaluated for its antibacterial potency by broth and agar microdilution MIC methods in studies focused on skin and respiratory tract pathogens, including strains exhibiting contemporary fluoroquinolone resistance phenotypes. Against a set of 118 recent clinical isolates of Streptococcus pneumoniae, including fluoroquinolone-resistant variants bearing multiple DNA topoisomerase target mutations, an MIC90 value for JNJ-Q2 of 0.12 μg/ml was determined, indicating that it was 32-fold more potent than moxifloxacin. Against a collection of 345 recently collected methicillin-resistant Staphylococcus aureus (MRSA) isolates, including 256 ciprofloxacin-resistant strains, the JNJ-Q2 MIC90 value was 0.25 μg/ml, similarly indicating that it was 32-fold more potent than moxifloxacin. The activities of JNJ-Q2 against Gram-negative pathogens were generally comparable to those of moxifloxacin. In further studies, JNJ-Q2 exhibited bactericidal activities at 2× and 4× MIC levels against clinical isolates of S. pneumoniae and MRSA with various fluoroquinolone susceptibilities, and its activities were enhanced over those of moxifloxacin. In these studies, the activity exhibited against strains bearing gyrA, parC, or gyrA plus parC mutations was indicative of the relatively balanced (equipotent) activity of JNJ-Q2 against the DNA topoisomerase target enzymes. Finally, determination of the relative rates or frequencies of the spontaneous development of resistance to JNJ-Q2 at 2× and 4× MICs in S. pneumoniae, MRSA, and Escherichia coli were indicative of a lower potential for resistance development than that for current fluoroquinolones. In conclusion, JNJ-Q2 exhibits a range of antibacterial activities in vitro that is supportive of its further evaluation as a potential new agent for the treatment of skin and respiratory tract infections.

Background

In several European Countries, by the end of 2012, CLSI guidelines will be replaced by EUCAST. We compared antimicrobial susceptibility results of a large number of respiratory pathogens using both EUCAST and previously adopted CLSI criteria to evaluate the impact on susceptibility patterns and the possible consequences that could occur in clinical practice due to this replacement.

For S. pyogenes and S. aureus, the interpretation of susceptibility data using the EUCAST criteria did not produce relevant changes in comparison to CLSI.

Against S. pneumoniae, more restrictive EUCAST breakpoints could lead to increased benzylpenicillin and/or amoxicillin-clavulanate resistance rates, which in turn could translate in increased dosages of these antibiotics or usage of alternative agents for respiratory tract infections.

Against S. pneumoniae, M. catarrhalis and H. influenzae, cefuroxime-axetil and cefaclor produced the most divergent results depending on the breakpoints adopted and these striking differences could lead to the revision of those guidelines suggesting these two cephalosporins as alternatives in the management of upper respiratory tract infections.

Discussion

Many differences exist between CLSI and EUCAST breakpoints. However, only in a few cases do these differences translate in major interpretive category discrepancies. In countries adopting more restrictive EUCAST breakpoints, clinicians should be aware of these discrepancies and that they could be faced with antibiotic-resistant respiratory pathogens more frequently than before.

Summary

The interpretive discrepancies between EUCAST and CLSI suggest that the discussion on the management of community-acquired respiratory tract infections is still open and further studies are desirable to better define the role of some antibiotics.

SUMMARY

The Belgian data (2003–2010) for the European Antimicrobial Resistance Surveillance Network (EARS-Net) showed a significant decreasing trend in the proportion of penicillin non-susceptible Streptococcus pneumoniae (9·4% to <1%) from blood and CSF isolates. We found that 75% of this decrease was explained by a change in Clinical and Laboratory Standards Institute (CLSI) breakpoints as the trend disappeared if only the new breakpoints were applied. Applying only European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints also resulted in a relatively stable proportion of penicillin non-susceptibility (average 5%), but this proportion was 7–13 times higher than with the new CLSI breakpoints. When the new CLSI breakpoints alone are used, fewer than 1% of bacteraemia isolates were penicillin non-susceptible during the entire period, but the proportion of non-susceptible meningitis isolates rose from 6·3% in 2003 to 15·9% between 2003 and 2010. Changing breakpoints should lead to retrospective analysis of historical data to minimize wrongly interpreting resistance trends.

The in vitro activities of modithromycin against Gram-positive and -negative respiratory pathogens, including macrolide-resistant cocci with different resistance mechanisms, were compared with those of other macrolide and ketolide agents. MICs were determined by the broth microdilution method. All 595 test strains used in this study were isolated from Japanese medical facilities. The erm (ribosome methylase) and/or mef (efflux pump) gene, which correlated with resistance to erythromycin as well as clarithromycin and azithromycin, was found in 81.8%, 21.3%, and 23.2% of Streptococcus pneumoniae, Streptococcus pyogenes, and methicillin-susceptible Staphylococcus aureus (MSSA) strains, respectively. Modithromycin showed MIC90s of 0.125 μg/ml against these three cocci, including macrolide-resistant strains. In particular, the MIC of modithromycin against ermB-carrying S. pyogenes was ≥32-fold lower than that of telithromycin. The activities of modithromycin as well as telithromycin were little affected by the presence of mefA or mefE in both streptococci. Against Gram-negative pathogens, modithromycin showed MIC90s of 0.5, 8, and 0.031 μg/ml against Moraxella catarrhalis, Haemophilus influenzae, and Legionella spp., respectively. The MICs of modithromycin against M. catarrhalis and H. influenzae were higher than those of telithromycin and azithromycin. However, modithromycin showed the most potent anti-Legionella activity among the macrolide and ketolide agents tested. These results suggested that the bicyclolide agent modithromycin is a novel class of macrolides with improved antibacterial activity against Gram-positive cocci, including telithromycin-resistant streptococci and intracellular Gram-negative bacteria of the Legionella species.

Antimicrobial resistance continues to increase worldwide among isolates of Streptococcus pneumoniae and other species of streptococci. Increasing rates of penicillin resistance, particularly in viridans group streptococci, and resistance to multiple classes of antimicrobial agents, including β-lactams, macrolides, and fluoroquinolones, in pneumococci have increased the importance of having accurate antimicrobial susceptibility testing results for guiding therapy. One commercial method of assessing resistance in streptococci is the PASCO Strep Plus panel. This broth microdilution-based method has recently been expanded to include a variety of newer antimicrobial agents. Therefore, we compared the results of the new PASCO Strep Plus panels for 26 antimicrobial agents against the results generated using the National Committee for Clinical Laboratory Standards (NCCLS) broth microdilution reference method for 75 pneumococci and 68 other streptococcal isolates. Only 4 (0.2%) very major errors (all with pneumococci and each with a different antimicrobial agent) were observed. There were 5 (0.3%) major errors observed with pneumococci (each with a different antimicrobial agent), but only 1 major error with nonpneumococcal streptococci. All of the very major and major errors resolved on retesting. Of the 65 (3.9%) and 17 (1.6%) minor errors observed with pneumococci and other streptococci, respectively, all were within 1 dilution of the broth microdilution reference MIC result. Thus, the PASCO Strep Plus panel has comparable accuracy to the NCCLS broth microdilution reference method.

ABT-773 is a novel ketolide effective against antibacterial-resistant respiratory tract pathogens. The pharmacokinetic profile of ABT-773 was studied in rats and consisted of a mean peak concentration in plasma of 1.07 μg/ml and an area under the concentration-time curve (AUC) of 12.03 μg · h/ml when the compound was delivered at a dose of 25 mg/kg of body weight. It concentrated in rat lung tissue, with a lung tissue-to-plasma ratio of 29 based on the AUC. In acute systemic infections in mice, ABT-773 showed efficacy against macrolide-susceptible strains of Staphylococcus aureus, Streptococcus pneumoniae, S. pyogenes, and Listeria monocytogenes. Additionally, ABT-773 improved the survival of mice infected with resistant S. pneumoniae containing either the ermB gene, the mefE gene, or altered penicillin binding protein genes. In a rat lung model of infection, ABT-773 demonstrated 50% effective doses lower than those of comparator macrolides when evaluated against the following strains of S. pneumoniae: a macrolide-lincosamide-streptogramin B-susceptible strain, an ermB strain, and an mefE strain. ABT-773 was also effective against Haemophilus influenzae lung infections in rats. Thus, ABT-773 may prove to be a useful new antibacterial agent for the treatment of respiratory tract infections.

Similarities between Streptococcus pneumoniae and viridans group streptococci may result in misidentification of these organisms. In surveillance programs which assess antimicrobial resistance rates among respiratory tract pathogens, such identification errors could lead to overestimates of pneumococcal resistance rates. DNA probe analysis (Gen-Probe, San Diego, CA), the bile solubility test, optochin susceptibility, colony morphology, and the capsular swelling reaction with Omni serum (Staten Serum Institut, Copenhagen, Denmark) were used to characterize 1,733 organisms provisionally identified as S. pneumoniae in a 2004 to 2005 antimicrobial resistance surveillance program. These organisms were obtained in 41 U.S. medical centers. Among these, 1,647 (95%) were determined to be S. pneumoniae by DNA probe. Elimination of those isolates found not to be S. pneumoniae resulted in 1 to 2% decreases in resistance rate estimates with penicillin, erythromycin, tetracycline, and trimethoprim-sulfamethoxazole. With AccuProbe as a reference standard, the sensitivities and specificities of each phenotypic method for the identification of S. pneumoniae were, respectively, 98.8% and 82.6% for bile solubility, 99.3% and 74.4% for the capsular swelling reaction with Omni serum, and 87.9% and 59.3% for optochin susceptibility. Colony morphology was of limited value, as 391 (23.7%) isolates lacked the typical button or mucoid colony appearance of S. pneumoniae.

Taiwan has one of the highest levels of antibiotic-resistant pneumococcus in the world. Pneumococcal isolates not susceptible to penicillin first appeared in Taiwan in 1986; in 1995 an increase in the prevalence of nonsusceptibility to penicillins, extended-spectrum cephalosporins, trimethoprim-sulfamethoxazole, and macrolides as well as multidrug resistance began to be recognized. With the persistence of antibiotic selective pressure, resistance in some antibiotics reached a high plateau (β-lactam antibiotics) or continued to increase (macrolides), while novel resistance (fluoroquinolones) emerged in the last 3 years. Widespread distribution of some novel resistant 23F and 19F clones (and the international epidemic of 23F clones) contributes further to the rapid increase of resistance. Because Streptococcus pneumoniae is a major pathogen that causes community-acquired lower respiratory tract infections and meningitis in adults and children, antibiotic-resistance in this organism is a serious problem.

Background

Pneumococcal diseases remain a major cause of morbidity and mortality worldwide. Updated data on drug-resistance from different populations may be important to recognize changes in disease patterns. This study assessed current levels of penicilin resistance among Streptococcus Pneumoniae causing pneumonia in Spanish middle age and older adults.

Methods

Antimicrobial susceptibility was tested for 104 consecutive isolates of Streptococcus pneumoniae recovered from patients 50 years or older with radiographically confirmed pneumonia in the region of Tarragona (Spain) between 2002 and 2007. According to the minimum inhibitory concentration of tested antimicrobials (penicillin, erythromycin, cefotaxime and levofloxacin) strains were classified as susceptible or resistant. Antimicrobial resistance was determined for early cases (2002–2004) and contemporary cases (2005–2007).

Results

Twenty-seven (25.9%) were penicillin-resistant strains (19 strains with intermediate resistance and 8 strains with high resistance). Penicillin-resistance was higher in 2002–2004 than in 2005–2007 (39.5% vs 18.2%, p = 0.017).

Of 27 penicillin-resistant strains, 10 (37%) were resistant to erythromycin, 8 (29.6%) to cefotaxime, 2 (7.4%) to levofloxacin, and 4 (14.8%) were identified as multidrug resistant. Case-fatality rate was higher among those patients who had an infection caused by any penicillin susceptible strain (16.9%) than in those with infections due to penicillin-resistant strains.

Conclusion

Resistance to penicillin among Streptococcus pneumoniae remains high, but such resistance does not result in increased mortality in patients with pneumococcal pneumonia.