Marc Decramer 3. Respiratory Division, University Hospitals Leuven, Leuven, Belgium

Transcription

1 AAC Accepts, published online ahead of print on April 0 Antimicrob. Agents Chemother. doi:./aac Copyright 0, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved. 1 Consumption Patterns and in vitro Resistance of S. pneumoniae to Fluoroquinolones Steven Simoens, 1 Jan Verhaegen, Pascal van Bleyenbergh, Willy E. Peetermans, Marc Decramer 1 1 Research Centre for Pharmaceutical Care and Pharmaco-economics, Katholieke Universiteit Leuven, Leuven, Belgium Belgian Pneumococcal Reference Laboratory, Department of Microbiology, Katholieke Universiteit Leuven, Leuven, Belgium Respiratory Division, University Hospitals Leuven, Leuven, Belgium Department of Internal Medicine, Katholieke Universiteit Leuven, Leuven, Belgium Running title: Consumption of and resistance to fluoroquinolones Corresponding author: Prof. Dr. Steven Simoens, Research Centre for Pharmaceutical Care and Pharmacoeconomics, Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven. Onderwijs en Navorsing, Herestraat, P.O. Box 1, 000 Leuven, Belgium. Tel: +-(0)-. Fax: +-(0)-. steven.simoens@pharm.kuleuven.be 1.

2 Abstract This article analyses consumption patterns of fluoroquinolones and documents in vitro resistance of S. pneumoniae to fluoroquinolones in ambulatory care in Belgium over time. The volume of fluoroquinolone consumption has fallen consistently since 00. Fluoroquinolones were primarily used in their registered indications (i.e. urinary tract infections and lower respiratory tract infections). The MIC distribution of moxifloxacin and levofloxacin in S. pneumoniae isolates remained stable during and resistance to moxifloxacin and levofloxacin was low ( 1%). 1 1 Keywords: fluoroquinolones, respiratory tract infections, Streptococcus pneumoniae, consumption, resistance

3 Fluoroquinolones are a class of antibiotics developed in the s. Fluoroquinolones initially demonstrated their effectiveness against Gram-negative bacteria (H. influenzae, Moraxella catarrhalis), whereas newer fluoroquinolones such as moxifloxacin have increased activity against Gram-positive bacteria, including S. pneumoniae and Staphylococcus aureus, anaerobes and against atypical micro-organisms (Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella pneumophila). This article aims to analyse consumption patterns of fluoroquinolones and to document in vitro resistance of S. pneumoniae to fluoroquinolones in ambulatory care in Belgium over time Data on fluoroquinolone consumption in ambulatory care in Belgium were derived from IMS Health during Volume of consumption was expressed in terms of the number of defined daily doses per 1,000 inhabitants per day (DID). Defined daily doses of fluoroquinolones originated from the World Health Organisation and evolved over the study time period, if applicable. Volume of consumption was valued at public prices pertaining to the month of consumption IMS Health consumption data by type of infection originated from a panel of 00 physicians of all specialities offering general medical services, except for hospital inpatients. The composition of the panel of physicians corresponded to the distribution of the Belgian population of physicians by speciality and by region. When extrapolating the number of fluoroquinolone prescriptions by type of infection issued by the panel of 00 physicians to consumption of fluoroquinolones in the Belgian population, care was taken that the frequency of results adheres to the Gauss curve as closely as possible..

4 1 1 The study analysed respiratory blood isolates taken from adults to test the in vitro susceptibility of S. pneumoniae to amoxicillin, cefuroxime, levofloxacin and moxifloxacin. The S. pneumoniae strains were isolated in 1 clinical laboratories throughout Belgium participating in the National Surveillance Programme and sent to the Belgian Pneumococcal Reference Laboratory. A hundred blood isolates per year were at random selected from the collection that the Reference Laboratory received from 00 to 00. Minimum inhibitory concentrations (MICs) were determined by the E test (AB Biodisk). MIC was the concentration of the antibiotic that inhibited completely the growth of the pneumococcus. Susceptibility and resistance of S. pneumoniae was expressed using the Clinical and Laboratory Standards Institute (CLSI) breakpoints, because these breakpoints represent the gold standard and are used internationally in trials The volume of consumption of fluoroquinolones in ambulatory care in Belgium increased from 1. DIDs in 1 to.00 DIDs in 00, but then fell to. DIDs in 00. The annual consumption of fluoroquinolones valued at public prices increased from.1 million in 1 to a maximum of. million in 00, and then decreased to.0 million in 00. The decrease in consumption since 00/00 originated from the falling consumption of norfloxacin and ofloxacin. In 00, consumption of fluoroquinolones consisted of 1.0 DIDs of ciprofloxacin (0% of fluoroquinolone consumption), 0. DIDs of moxifloxacin (%), 0. DIDs of levofloxacin (1%), 0. DIDs of norfloxacin (%), and 0.1 DIDs of ofloxacin (%). Fluoroquinolones.

5 represented % of the volume of antibiotic consumption in 00. The same trend was demonstrated by European Surveillance of Antimicrobial Consumption (ESAC) data. 1 1 Figure 1 presents monthly data on the volume of consumption of levofloxacin (introduced in July/August 000) and moxifloxacin (introduced in April 00). The pattern of seasonal variation observed for levofloxacin prior to the introduction of moxifloxacin almost disappeared after its introduction. On the other hand, consumption of moxifloxacin exhibited a typical pattern of seasonal variation. This may reflect the fact that levofloxacin was used for treating respiratory tract infections prior to the introduction of moxifloxacin, and remained one of the fluoroquinolones for treating gastro-intestinal and urinary tract infections after the introduction of moxifloxacin. Moxifloxacin, a fluoroquinolone typically used in the treatment of respiratory tract infections, followed the pattern of seasonal variation that would be expected A breakdown of the volume of consumption of fluoroquinolones by type of infection in Belgium in 00 is portrayed in Figure. This shows that the principal use of fluoroquinolones was in the treatment of urinary tract infections (% of consumption, volume of 0. DIDs) and lower respiratory tract infections (% of consumption, volume of 0.0 DIDs). This suggests that fluoroquinolones were primarily used in those indications where they have been shown to yield clinical benefit 1,. 1 Fluoroquinolones were used marginally in managing upper respiratory tract infections, with a share of consumption of % (volume of 0.1 DIDs). Upper respiratory tract.

6 infections were mainly managed by broad-spectrum penicillins (% of consumption in 00, volume of. DIDs), macrolides (1% of consumption, volume of 1. DIDs), and oral cephalosporins (% of consumption, volume of 0. DIDs). Therefore, this study recommends to identify those indications, such as upper respiratory tract infections, where the use of antibiotics is not recommended and introduce policy measures such as clinical guidelines, peer review with feedback, educational campaigns or financial incentives to discourage the use of antibiotics in the treatment of those infections The MIC distributions (MIC to MIC 0 ) in S. pneumoniae and susceptibility rates during are presented in Table 1 for moxifloxacin, levofloxacin, amoxicillin and cefuroxime. The resistance levels to moxifloxacin and levofloxacin were low ( 1%). The MIC distributions of moxifloxacin as well as levofloxacin remained stable during The percentage of S. pneumoniae that are not susceptible to amoxicillin was equal to or less than 1% for the six different years. Resistance of S. pneumoniae to cefuroxime was %-% in 00-00, but decreased to % in The in vitro results of this study indicate that moxifloxacin is the most potent fluoroquinolone available for treatment of S. pneumoniae infections in Belgium with MIC 0 of 0.1 mg/l. The use of new fluoroquinolones (levofloxacin, moxifloxacin) and the ongoing use of the older fluoroquinolones (mainly for urinary tract infections) has not led, to date, to an increase in the rate of pneumococcal resistance to fluoroquinolones. It remains at or below 1% for levofloxacin and moxifloxacin. In this multi-year surveillance study, a rightward shift in the distributions of MICs of the fluoroquinolones was not.

7 observed. This finding suggests that also first-step mutants have not yet become more prevalent in Belgian strains. Our results mirror the findings of a recent survey of antibiotic resistance in S. pneumoniae collected from, non-invasive clinical isolates in Belgium from 1 to 00. Resistance of S. pneumoniae to levofloxacin and to moxifloxacin was less than 1% and no rightward shift in the MIC distributions of the fluoroquinolones was noted. Even though worldwide resistance to moxifloxacin is low in general, resistance does appear in some regions with a high prevalence of multi-drug resistant S. pneumoniae. In Belgium, however, multi-drug resistance remains relatively low, with.% resistance to more than five drug classes and % of isolates resistant to any four drug classes

8 Acknowledgements Financial support for this research was received from Bayer Schering Pharma. The authors have no conflicts of interest that are directly relevant to the content of this manuscript. The authors would like to express their gratitude to Eric Mostrey (market research, Bayer Schering Pharma) for his assistance

9 Reference List 1. Bailey, R. R. 1. Quinolones in the treatment of uncomplicated urinary tract infections. Int.J.Antimicrob.Agents :1-.. Ball, P. 00. Efficacy and safety of levofloxacin in the context of other contemporary fluoroquinolones: a review. Diagn.Microbiol.Infect.Dis. :-1.. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; 0th informational supplement. Clinical and Laboratory Standards Institute Ref Type: Electronic Citation. European Surveillance of Antimicrobial Consumption. Country sheet Belgium Ref Type: Internet Communication. Jacobs, M. R., D. Felmingham, P. C. Appelbaum, and R. N. Gruneberg. 00. The Alexander Project 1-000: susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents. J Antimicrob.Chemother. :-.. Vanhoof, R, Van Bossuyt, E, De Craeye, S, Van Eldere, J, Verhaegen, J., Kaufman, L, and The Belgian SP Study Group. Survey of antibiotic resistance in Streptococcus pneumoniae collected in Belgium during winter 00. Follow-up of resistance since 1 and possible effects of antibiotic campaigns. 1th ESCMID conference. 00. Helsinki Ref Type: Conference Proceeding.

10 Table 1. MIC (mg/l) distributions and susceptibility rates in S. pneumoniae 1A. Moxifloxacin MIC MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC ,0 0,1 0,1 0,1 0,1 0,1 0,1 0,1 0,1 00 0,0 0,1 0,1 0,1 0,1 0,1 0,1 0,1 0,1 00 0,1 0,1 0,1 0,1 0,1 0,1 0,1 0,1 0, 0, 00 0,1 0,1 0,1 0,1 0,1 0,1 0,1 0,1 0, 0, 00 0,0 0,1 0,1 0,1 0,1 0,1 0,1 0,1 0,1 00 0,0 0,0 0,1 0,1 0,1 0,1 0,1 0,1 0,1 0, S ( 1 mg/l) I ( mg/l) R ( mg/l) 00 % 1% 0 00 % 0 1% 00 0% % % 0 1% 00 0% 0 0 1B. Levofloxacin MIC MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC , 0, 0, , > 00 0, 0, 0, 0, > 00 0, 0, 0, 0, , 00 0, 0, 0, 0, , 1, 00 0, 0, 0, , > 00 0, 0, 0, 0, S ( 1 mg/l) I ( mg/l) R ( mg/l) 00 % 1% 1% 00 % 1% 1% 00 0% % % 0 1% 00 0% 0 0 1C. Amoxicillin MIC MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 00 <0,0 <0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 00 <0,0 <0,0 0,0 0,0 0,0 0,0 0,0 0,0 0, 1, 00 <0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 1, 00 <0,0 <0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 00 <0,0 <0,0 <0,0 0,0 0,0 0,0 0,0 0,0 0,0 1, 00 <0,0 <0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 1 S ( mg/l) I ( mg/l) R ( mg/l) 00 0% % % % 1% % % 0 0.

11 D. Cefuroxime MIC MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC 0 MIC ,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0, ,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 1, 00 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 00 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 00 <0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 00 <0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 0,0 S ( 0. mg/l) I (1 mg/l) R ( mg/l) 00 1% 0 % 00 % % % 00 % 1% % 00 % 0 % 00 % 1% % 00 % 0 % Note: MIC = minimum inhibitory concentrations; S = susceptible; I = intermediate resistant; R = resistant..

12 Figure 1. Consumption of levofloxacin / moxifloxacin in ambulatory care in Belgium 1, 1, 1, Consumption in DID 1, 1,0 0, 0, 0, 0, 0,0 aug/00 dec/00 apr/01 aug/01 dec/01 apr/0 aug/0 dec/0 apr/0 aug/0 dec/0 apr/0 aug/0 dec/0 apr/0 LEVOFLOXACIN Note: DID = defined daily dose per 1,000 inhabitants per day. aug/0 dec/0 MOXIFLOXACIN apr/0 aug/0 dec/0 apr/0 aug/0 dec/0 apr/0 aug/0 dec/0 apr/0 aug/0 dec/0 1.

13 Figure. Consumption of fluoroquinolones by type of infection in Belgium in 00 % % % 1% % % GASTRO-INTESTINAL TRACK INFECTION URINARY TRACK INFECTIONS UPPER RESPIRATORY TRACK INFECTIONS GENITAL TRACK INFECTIONS LOWER RESPIRATORY TRACK INFECTIONS OTHER INFECTIONS 1.