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JAC Advance Access originally published online on June 26, 2007
Journal of Antimicrobial Chemotherapy 2007 60(3):587-593; doi:10.1093/jac/dkm232
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

A survey of antibiotic resistance in Streptococcus pneumoniae and Haemophilus influenzae in Turkey, 2004–2005

Burçin Sener1, Ferda Tunçkanat1, Sercan Ulusoy2, Alper Tünger3, Güner Söyletir4, Lütfiye Mülazimoglu5, Nezahat Gürler6, Lütfiye Öksüz6, Iftihar Köksal7, Kemalettin Aydin7, Ata Nevzat Yalçin8, Dilara Ögünç9, Asli Acar10 and Jörg Sievers11,*

1 Department of Microbiology and Clinical Microbiology, Faculty of Medicine, Hacettepe University, Ankara, Turkey 2 Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Ege University, Izmir, Turkey 3 Department of Microbiology and Clinical Microbiology, Faculty of Medicine, Ege University, Izmir, Turkey 4 Department of Microbiology and Clinical Microbiology, Faculty of Medicine, Marmara University, Istanbul, Turkey 5 Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Marmara University, Istanbul, Turkey 6 Department of Microbiology and Clinical Microbiology, Istanbul Medical Faculty, Istanbul University, Çapa-Istanbul, Turkey 7 Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey 8 Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Akdeniz University, Antalya, Turkey 9 Department of Microbiology and Clinical Microbiology, Faculty of Medicine, Akdeniz University, Antalya, Turkey 10 GlaxoSmithKline, Istanbul, Turkey 11 GlaxoSmithKline, Brentford, UK

* Corresponding author. Tel: +44-208047-5807; Fax: +44-208047-0666; E-mail: jorg.x.sievers{at}gsk.com

Received 23 February 2007; returned 16 April 2007; revised 10 May 2007; accepted 5 June 2007


   Abstract
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Objectives: To determine the prevalence of antimicrobial resistance among Streptococcus pneumoniae and Haemophilus influenzae isolated in Turkey as part of Survey Of Antibiotic Resistance, a surveillance programme in the Africa and Middle East region examining the antimicrobial susceptibility of key bacterial pathogens involved in community-acquired respiratory tract infections (CARTIs).

Methods: Susceptibility was evaluated against a range of antimicrobial agents using disc diffusion and Etest methods.

Results: Six centres in five cities collected 301 S. pneumoniae and 379 H. influenzae isolates between October 2004 and November 2005. Among S. pneumoniae, the prevalence of isolates with intermediate susceptibility (MICs 0.12–1 mg/L) and resistance to penicillin (MICs ≥2 mg/L) was 24.6% and 7.6%, respectively; there was a wide variation between cities (2.4% to 36.9% intermediate and 0% to 23.8% resistant phenotypes). Macrolide-azalide resistance rates exceeded those of penicillin resistance in all cities. Overall, 5.0% of isolates were co-resistant to penicillin and erythromycin and 10.0% were multidrug-resistant (joint resistance to erythromycin, co-trimoxazole and tetracycline). Agents tested to which over 90% of countrywide S. pneumoniae isolates remained susceptible were amoxicillin/clavulanate (98.7%), chloramphenicol (94.7%) and cefprozil (90.6%). Overall, the percentage of H. influenzae isolates producing ß-lactamase was 5.5%, differing widely across the country with the highest prevalence of ß-lactamase production detected in Trabzon (14.0%) and no ß-lactamase-positive isolates found in Izmir. H. influenzae had the highest per cent susceptibility to amoxicillin/clavulanate (99.5%) and ofloxacin (99.2%) while >20% were resistant to co-trimoxazole.

Conclusions: Prevalence of penicillin and macrolide–azalide resistance among S. pneumoniae appears to be on the increase in Turkey while overall ß-lactamase production in H. influenzae remains relatively low. To adequately monitor the spread of drug-resistant phenotypes among these two important CARTI pathogens, ongoing collection of resistance surveillance data is required—where possible locally as resistance patterns can vary substantially between cities and institutions.

Keywords: pneumococci , surveillance , community-acquired respiratory tract infections


   Introduction
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Streptococcus pneumoniae and Haemophilus influenzae are the key bacterial pathogens implicated in community-acquired respiratory tract infections (CARTIs), which occur frequently and account for significant morbidity and mortality.1–4 Because of the time required to establish the significance, identity and susceptibility of bacterial isolates from patients with CARTIs, antimicrobial therapeutic choices are usually empirical. The increasing prevalence of resistant organisms, however, complicates this choice and poses a serious threat to current and future treatment of these infections.5–8 Surveillance studies provide an important tool for determining local and regional susceptibility patterns and guiding empirical antimicrobial therapy.9

S. pneumoniae exhibits resistance to penicillins and several other classes of antimicrobials including macrolides, co-trimoxazole and also fluoroquinolones, although levels of resistance to the latter remain low in most countries.10–13 Among H. influenzae, increasing aminopenicillin resistance, usually occurring as the result of ß-lactamase production, and co-trimoxazole resistance further underline the need for effective surveillance.8,14,15 During the first Survey Of Antibiotic Resistance (SOAR) in S. pneumoniae and H. influenzae in 2002–2003, penicillin non-susceptibility among S. pneumoniae was documented in 25.3% of Turkish isolates (24.0% intermediate and 1.3% resistant) and, overall, 14.7% were non-susceptible to macrolides/azalides.16 Penicillin non-susceptibility rates of up to 50% have been reported in Turkey in recent years, with prevalence of penicillin-resistant S. pneumoniae (PRSP) ranging from 0.7% to 19.4%.17–21 In these studies, the prevalence of macrolide resistance in S. pneumoniae varied from 2.1% to 21.1%. In the SOAR study from 2002 to 2003, 4.5% of H. influenzae isolates from Turkey were ß-lactamase positive.16 Similar rates of ß-lactamase production in clinical isolates of H. influenzae (3.8–7.0%) have been reported by other surveillance programmes.17,21–24

In October 2004, the second phase of SOAR was initiated in the Africa and Middle East region to provide contemporary antimicrobial susceptibility data for the key respiratory pathogens S. pneumoniae and H. influenzae. Here we report findings from the programme in Turkey during 2004–2005.


   Materials and methods
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Collaborating centres

The following centres took part in the study: Ankara, Hacettepe University; Antalya, Akdeniz University; Istanbul, Istanbul University and Marmara University; Izmir, Ege University; Trabzon, Karadeniz Technical University.

Bacterial isolates and antimicrobial susceptibility testing

Isolates of S. pneumoniae and H. influenzae were obtained from fresh clinical material taken primarily from adult and paediatric patients with clinical indications of community-acquired respiratory tract infections using routine clinical collection methods. Duplicate isolates from the same patient were not accepted.

Organisms were identified using conventional methods (optochin susceptibility for S. pneumoniae and X and V factor requirement for H. influenzae). Organisms were stored frozen at –70°C until tested. ß-Lactamase production of H. influenzae isolates was determined by a chromogenic cephalosporin (nitrocefin) disc method.25 ß-Lactamase-negative, ampicillin-resistant isolates were defined as those organisms having a negative ß-lactamase result and an ampicillin MIC of ≥4 mg/L.26

MICs were determined using the Etest susceptibility testing method according to the manufacturer's instructions (AB Biodisk, Solna, Sweden). Disc susceptibility testing was performed according to CLSI (formerly NCCLS) guidelines.27 Briefly, frozen isolates were subcultured twice on blood-supplemented Mueller–Hinton agar (S. pneumoniae) or Haemophilus Test Medium (H. influenzae) before susceptibility testing was performed. For susceptibility testing, a 0.5 McFarland standard dilution of each isolate was prepared by direct colony suspension and inoculated onto appropriate agar plates to produce a confluent lawn of growth. Etests and antibiotic discs were applied and plates incubated for 20–24 h (16–18 h for H. influenzae agar disc diffusion) at 35°C in a 5% CO2 atmosphere. For azithromycin and clarithromycin Etests, S. pneumoniae isolates were incubated in ambient air due to the adverse effect of CO2 on the activity of macrolide/azalide antibiotics. Etest MICs and inhibition zone diameters were read in accordance with AB Biodisk's instructions and CLSI guidelines for disc susceptibility testing, respectively.27

The antimicrobials tested using Etest included: penicillin (S. pneumoniae only), ampicillin (H. influenzae only), amoxicillin/clavulanate (2/1), cefaclor, cefprozil, clarithromycin, azithromycin and ofloxacin. In addition, susceptibility to erythromycin and clindamycin (S. pneumoniae only), tetracycline, co-trimoxazole (trimethoprim/sulfamethoxazole, 1/19) and chloramphenicol was determined by agar disc diffusion.

Quality control and data analysis

Quality control strains recommended by CLSI were used on each day of testing, and results of isolate testing were accepted if results of the control strains were within published limits.

Any Etest MIC results that were between doubling dilutions were rounded up to the next doubling dilution MIC for data analysis. MICs and zone diameters were interpreted qualitatively using CLSI interpretive standards; MICs were also analysed using pharmacokinetic/pharmacodynamic (PK/PD) breakpoints helping to predict the clinical and bacteriologic efficacy of antimicrobial dosing regimens (Table 1).8,26,28 To interpret azithromycin and clarithromycin MICs for H. influenzae, revised breakpoints were used to account for incubation in a CO2 atmosphere (AB Biodisk Etest package insert, Table 1 ‘Summary of performance, interpretive criteria and quality control ranges’). The respective PK/PD breakpoints were adjusted accordingly, i.e. raised by one doubling dilution, for interpretation of H. influenzae susceptibility. Statistical significance was determined by {chi}2 or Fisher's exact test analysis and P values of ≤0.05 were regarded as significant.


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  		Table 1. Breakpoints (mg/L) used to determine susceptible (S), intermediate (I) and resistant (R) categories based on PK/PD and CLSI interpretive breakpoints8,26,28

 

   Results
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Discussion
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A total of 301 isolates of S. pneumoniae and 379 isolates of H. influenzae were collected largely from patients with indications of community-acquired respiratory tract infections from October 2004 to November 2005. Isolates were from sputum (66.3%), bronchoalveolar lavage (10.1%), throat (5.9%), tracheal aspirate (4.6%), blood (2.4%), CSF (2.1%) and other sources. The patient age was known in 95.0% of cases; of these, 38.2% were paediatric patients (<18 years). Overall gender distribution was 60.4% male and 39.6% female with the proportion of females being higher in the paediatric than in the adult group (47.8% versus 35.1%).

S. pneumoniae

Antimicrobial susceptibility and MIC50/90s of all 301 isolates of S. pneumoniae are shown in Table 2. Overall, 32.2% of isolates were non-susceptible to penicillin, 24.6% were intermediate (PISP) and 7.6% were resistant to penicillin (PRSP). Based on CLSI breakpoints, the most active antimicrobial tested against S. pneumoniae was amoxicillin/clavulanate with 98.7% susceptibility. Of the cephalosporins tested, cefprozil was more active than cefaclor (90.6% versus 78.7% susceptibility). Substantial resistance was observed with azithromycin and clarithromycin (17.2% and 17.3%, respectively), and susceptibility to azithromycin was as low as 40.2% when PK/PD breakpoints were applied. Overall susceptibility to azithromycin was lower than to clarithromycin due to 14 isolates (4.7%; 13 from Istanbul and one from Ankara) that tested azithromycin-intermediate by Etest although disc susceptibility results indicated that these isolates were azithromycin-susceptible (data not shown). Within the country and in each city, resistance levels to macrolide/azalide antibiotics exceeded the prevalence of penicillin resistance (penicillin MIC >1 mg/L). Cross-resistance between clindamycin and erythromycin can be used as an approximation of prevalence of the erm(B)-mediated methylation mechanism (MLSB-phenotype) of S. pneumoniae macrolide resistance versus the mef(A)-mediated efflux mechanism (M-phenotype). Based on disc diffusion data, cross-resistance between erythromycin and clindamycin was 72.3% (34/47). Resistance to co-trimoxazole was very high (43.2%) and only 72.1% of S. pneumoniae were susceptible to ofloxacin, with the vast majority of non-susceptible isolates being ofloxacin-intermediate. The eight ofloxacin-resistant isolates, four of which surprisingly were from paediatric patients (<18 years), were not tested against newer fluoroquinolones or examined for potential quinolone resistance-determining region mutations. All ofloxacin-resistant isolates were susceptible to amoxicillin/clavulanate.


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  		Table 2. Susceptibility of all S. pneumoniae and H. influenzae isolates from Turkey to 13 antimicrobials based on CLSI26 and PK/PD8,28 interpretive breakpoints and MIC50s and MIC90s

 
In vitro activity was also analysed based on penicillin susceptibility category of the isolates (Table 3). Using CLSI breakpoints, generally higher levels of resistance to cephalosporins, macrolides and other antibiotics were detected in penicillin non-susceptible compared with penicillin-susceptible S. pneumoniae. Of PRSP, 87.0% remained susceptible to amoxicillin/clavulanate. Only 34.8% of PRSP and 59.5% of PISP were susceptible to erythromycin, and overall 5.0% of isolates were co-resistant to penicillin and erythromycin. Joint resistance to erythromycin, co-trimoxazole and tetracycline was 10.0%; one-third of these isolates were also resistant to penicillin. For isolates where patient age information was available, a higher prevalence of PISP/PRSP were detected in paediatric patients (<18 years) than in adults (29.4%/10.8% versus 21.0%/5.9%; P = 0.05) while there was no difference in macrolide–azalide resistance rates between these two patient groups. There were no notable differences in penicillin and macrolide non-susceptibility associated with the gender of the patient.


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  		Table 3. Susceptibility (%) of penicillin-susceptible (PSSP), -intermediate (PISP) and -resistant (PRSP) S. pneumoniae to 12 antimicrobials using CLSI interpretive breakpoints

 
Table 4 shows susceptibility of S. pneumoniae to all antimicrobials tested for each centre. Penicillin resistance was highest in Ankara (13.8%) and Antalya (23.8%) although only 21 isolates were tested in Antalya. The proportion of penicillin-intermediate and penicillin-resistant strains in these two cities (50.8% and 47.6%, respectively) was significantly higher than in Trabzon where intermediate resistance was 2.4% and no PRSP were isolated (P < 0.001 and P < 0.01, respectively). Susceptibility to amoxicillin/clavulanate was 100% in Antalya, Istanbul and Trabzon. Cephalosporin resistance prevalence was mirrored by the levels of penicillin non-susceptibility, and cefaclor was less active than cefprozil in all centres. Macrolide susceptibility was lowest in Ankara with only 72.8%, 73.8% and 73.8% of isolates susceptible to azithromycin, clarithromycin and erythromycin, respectively. Macrolide–azalide susceptibility was significantly higher in Trabzon at 97.6% compared with the other four cities. The unusually low level of azithromycin susceptibility of isolates collected in Istanbul is due to 13 isolates tested azithromycin-intermediate by Etest (see above). Except for ofloxacin and co-trimoxazole, susceptibility levels were high (>90%) in Trabzon.


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  		Table 4. Susceptibility (%) of S. pneumoniae to 12 antimicrobials [susceptible (S), intermediate (I) and resistant (R) shown for penicillin] by city using CLSI interpretive breakpoints

 
H. influenzae

Antimicrobial susceptibility data for all 379 isolates of H. influenzae and MIC50/90s are shown in Table 2. Of these, 5.5% produced ß-lactamase and 4.7% were resistant to ampicillin (>2 mg/L). Of the ß-lactamase producers, five isolates were found to be intermediate-resistant to ampicillin; two isolates were tested ß-lactamase-negative and ampicillin-resistant (BLNAR) (0.5%). In vitro activity was high for most antimicrobials tested, with susceptibility of >99% detected for amoxicillin/clavulanate and ofloxacin; only susceptibility to tetracycline and co-trimoxazole was <90%. Although CLSI breakpoints for cefaclor, azithromycin and clarithromycin show 96.3%, 98.9% and 95.2% of H. influenzae susceptible to these agents, respectively, based on PK/PD breakpoints, the susceptibility was <10%. Prevalence of ß-lactamase production and antimicrobial susceptibility of H. influenzae isolates from Ankara, Antalya, Istanbul, Izmir and Trabzon are shown in Table 5. The highest prevalence of ß-lactamase-positive isolates was detected in Trabzon (14.0%) and Istanbul (6.2%). In Istanbul, we saw a notable difference between the two participating centres (10.3% at Istanbul University versus 2.4% at Marmara University). No ß-lactamase-positive H. influenzae were isolated in Izmir, which was significantly lower than in Trabzon (P < 0.001). Based on CLSI breakpoints, susceptibility was >90% for most antibiotics although considerable non-susceptibility was seen against co-trimoxazole (up to 33.3%) and tetracycline (up to 52.0%) in some cities.


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  		Table 5. ß-Lactamase production (%) and susceptibility (%) of H. influenzae to 10 antimicrobials by city using CLSI interpretive breakpoints

 

   Discussion
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The increasing prevalence of antimicrobial resistance among the major pathogens responsible for CARTI is a serious global problem that complicates the management of these infections. SOAR was established to provide information on local resistance patterns among the two most common pulmonary pathogens, S. pneumoniae and H. influenzae, in African and Middle Eastern countries for some of which resistance surveillance data have been poorly documented. The Turkish SOAR programme provides contemporary surveillance data from six centres in five cities for the years 2004 and 2005. Penicillin non-susceptibility is common among S. pneumoniae; overall, 32.2% of strains were penicillin non-susceptible. However, there were marked differences in prevalence of penicillin non-susceptible isolates varying from 2.4% to ~50% highlighting the need to obtain and monitor local susceptibility data. Similar differences in penicillin susceptibility between centres and cities were detected in a study conducted in 1996–1997: the prevalence of penicillin non-susceptible S. pneumoniae was higher in Istanbul and Ankara than in Trabzon.17 Overall penicillin resistance (>1 mg/L) nearly doubled from 3.9% in 1996–1997 to 7.6% in 2004–2005. However, lower as well as higher penicillin resistance rates have been reported in other recent surveillance studies conducted in Turkey.29 As found in other programmes, higher penicillin non-susceptibility levels were detected in S. pneumoniae isolated from paediatric patients compared with those from adult patients.30 Macrolide–azalide resistance also appears to be on the increase with only 2.1% of S. pneumoniae resistant to azithromycin in 1996–1997 compared with 17.2% in this study.17 Based on co-resistance to erythromycin and clindamycin, S. pneumoniae macrolide resistance was predominantly due to the erm(B)-mediated methylation mechanism as also shown by a recent analysis of erythromycin-resistant S. pneumoniae collected during 1994–2002 in Ankara.31 The overall prevalence of resistance to cefaclor, co-trimoxazole and tetracycline was high (19.3%, 43.2% and 16.9%, respectively) but the majority of isolates remained susceptible to amoxicillin/clavulanate (98.7%). The problem of multidrug resistance is an increasing worry although multidrug-resistant S. pneumoniae may be still relatively uncommon in Turkey compared with some other regions and countries.12 In this study, combined resistance to erythromycin, co-trimoxazole and tetracycline was 10.0% while 3.3% of isolates were also resistant to penicillin.

Ofloxacin resistance, a marker for fluoroquinolone resistance, was at a low prevalence (2.7%) although intermediate resistance was common. The first treatment failure due to fluoroquinolone-resistant S. pneumoniae was reported in Turkey in 2003.32 Among invasive S. pneumoniae isolated during 2000–2001, only 3.5% of isolates were ofloxacin non-susceptible, all of the intermediate-resistant type.18

ß-Lactamase production in H. influenzae remains below 10% and seems to have been relatively stable over recent years as our data were comparable with prevalence rates found by other surveillance programmes. However, ß-lactamase production and corresponding ampicillin resistance rates varied considerably between cities, with the high rates detected in Trabzon. BLNAR strains of H. influenzae were rare (0.5%) which is consistent with other surveillance studies.17,23,24 Using CLSI breakpoints, susceptibility was >90% for all tested antibiotics except co-trimoxazole and tetracycline. However, <10% of H. influenzae were susceptible to cefaclor, azithromycin and clarithromycin based on PK/PD breakpoints.

Overall, the data presented here are consistent with other surveillance projects conducted during recent years in Turkey. Ongoing collection of resistance surveillance data is however required to provide further data especially for those cities and areas where only low numbers of isolates were collected such as Antalya and to adequately monitor the spread of drug-resistant phenotypes among CARTI pathogens, including penicillin, macrolide and multidrug-resistant S. pneumoniae and ß-lactamase-positive H. influenzae. This study also highlights the need to collect and utilize local susceptibility data wherever possible as resistance patterns can vary substantially between cities and even institutions within the same city.


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This study was supported by GlaxoSmithKline Turkey.


   Transparency declarations
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The authors of this study received consumables, including Etest strips, discs and testing media, as well as financial support for conducting susceptibility testing of S. pneumoniae and H. influenzae isolates (US$10/isolate) from GlaxoSmithKline Turkey.


   Acknowledgements
 
We thank Deniz Gür and Neval Ergörmüs for their contributions to this study.


   References
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