Should we test Clostridium difficile for antimicrobial resistance? by author

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1 Should we test Clostridium difficile for antimicrobial resistance? Paola Mastrantonio Department of Infectious Diseases Istituto Superiore di Sanità, Rome,Italy

2 Clostridium difficile infection (CDI) (first steps leading to colonization) antibiotic use disturbance of the intestinal flora exogenous source colonization by C.difficile endogenous source

3 Main effects of antibiotics they kill or inhibit the targeted pathogen they affect the host microbiota endogenous microbiota microbiota antibiotic

4 Relationship between hospital exposure, intestinal microbiota and risk factors for CDI

5 Main antimicrobials inducing CDI Macrolides and lincosamides Broad-spectrum penicillins Third generation cephalosporins Fluoroquinolones **

6 Does the choice of drug for treatment of CDI matter? Which patients should be treated? Which antibiotic should be used?

7 Actions traditionally recommended Discontinue therapy with the inciting antimicrobial agent as soon as possible When severe or complicated CDI is suspected, initiate empirical treatment Metronidazole as the drug of choice for the first episode of mildto-moderate CDI Vancomycin as the drug of choice for a first episode of severe CDI Treatment of the first recurrence is usually with the same regimen as for the first episode but should be stratified by disease severity Treatment of the second or later recurrence with vancomycin using a tapered and or pulse regimen is the preferred strategy Suggested guidelines: M. P. Bauer, E. J. Kuijper and J. T. van Dissel. Clin.Microbiol Infect 2009; 15:

8 Antimicrobial therapy for the management of CDI is often empirical and culture results when available are reported to the clinician some time after the beginning of antimicrobial therapy low frequency of testing in the clinical laboratories is due in part to: the lack of expertise the lack of systematic culture in many labs the lack of appropriate clinical breakpoints results are unlikely to influence treatment

9 Current issues MZ and Vanco resistance was considered anedoctal for a long time but in the middle of 90s an alarm was sounded from Spain with 6% of MZ resistant strains A few reports underline the detection of isolates with an increased MIC value to metronidazole or showing heteroresistance, but the clinical significance is unknown For vancomycin, a very limited but persistent number of strains have been described with a reduced susceptibility

10 T. Pela ez,et al. Metronidazole Resistance in Clostridium difficile is Heterogeneous J. Clin Microbiol, 2008, 46,(9), Presence of pinpoint colonies around a 5 μg MZ disk or Etest strip

11 By CLSI-recommended reference agar dilution method for anaerobes(m11-a7) MZ breakpoints are: < 8 μg/ml susceptible 16 μg/ml intermediate > 32 μg/ml resistant Vanco breakpoints are not provided for anaerobes but there is a wide consensus on the following MIC values: < 2 μg/ml susceptible 4 to 16 μg/ml intermediate > 16 μg/ml resistant

12 EUCAST MIC distribution for Clostridium difficile Agent MIC (mg/l) Amoxicillin Amoxicillinclavulanic acid Cefuroxime Ciprofloxacin Clindamycin Daptomycin Ertapenem Erythromycin Fusidic acid Imipenem Linezolid Meropenem Metronidazole Moxifloxacin Piperacillin Piperacillintazobactam Rifampicin Teicoplanin Tetracycline Tigecycline Vancomycin Susceptible Resistant ECOFF (mg/l) (mg/l) (mg/l) Comment Metronidazole 2 >2 2 Breakpoint based on ECOFF. Vancomycin 2 >2 2 Breakpoint based on ECOFF. Fusidic acid No clinical breakpoint. Resistance develops rapidly. May be tested for epidemiological purposes only. Moxifloxacin No clinical breakpoint. May be tested for epidemiological purposes only. Rifampicin No clinical breakpoint. May be tested for epidemiological purposes only. Tentative ECOFF as few MIC distributions Tigecycline No clinical breakpoint. May be tested for epidemiological purposes only

13 Agar dilution (CLSI) E test The methods Need to harmonise breakpoints between CLSI and EUCAST and standardize susceptibility testing methods (link to the website with MIC distributions)

14 T. Pelàez et al Reassessment of C. difficile susceptibility to metronidazole and vancomycin Antimicrob. Agents Chemother. 46:

15 S. D. Baines et al Emergence of reduced susceptibility to metronidazole in C. difficile J. Antimicrob. Chemother.62: Changes in susceptibility pattern to MZ may be missed by some methods: 24.4% of PCR ribotype 001 isolates with a reduced susceptibility only by using the spiral gradient endpoint method 3.51 μg/ml for ribotype μg/ml for ribotype μg/ml for ribotype 027

16 MIC breakpoints for bacteria causing systemic infections are based upon levels of antibiotic in blood whereas in CDI MIC breakpoints should be based on faecal levels Increased MIC-values to metronidazole in vitro may be of clinical relevance as it is known that this drug may not achieve high concentrations in the gut lumen: mean concentrations range from 0.25 to 9.5 mg/l (Gut 1986,27: ) Decreased vancomycin susceptibility is considered less of a clinical issue as high drug concentrations are normally achieved in the gut lumen after oral administration (BMC Infect. Dis 2010,10:363) **

17 1. Should we test Clostridium difficile for antimicrobial resistance? for the patient s therapy? to which antibiotics?

18 Antibiotics for therapy Metronidazole bactericidal Vancomycin bacteriostatic Rifaximin (nonabsorbable oral antibiotic used for primary and recurrent episodes) broad spectrum Fusidic acid ( a bacterial protein syntesis inhibitor) broad spectrum Tigecycline (a glycylcycline structurally related to minocycline) broad spectrum Ramoplanin (poorly absorbed glycolipodepsipeptide) broad spectrum Tinidazole (structural analogue of Mz ) broad spectrum Nitazoxanide (a thiazolide derivative) broad spectrum Fidaxomicin (an 18-membered macrocycle with a narrow spectrum of activity) bactericidal, narrow-spectrum

19 In vitro susceptibility to 17 antimicrobials of clinical C. difficile isolates collected in in Sweden T. Norén et al. Clin. Microbiol. Infect 2010,16:

20 Pros and Cons of susceptibility testing Increased circulation of strains with MIC to MZ above 2μg/ml Detection of strains with heteroresistance to MZ Increased failure rates with the standard metronidazole therapy Recognition of rifaximin resistance x Late answers from the labs (at least 72h) x Results of a list of antibiotics may be confounding for the choice by the clinician

21 Perform the test : suggestions When the CDI is severe and antibiotic other than vancomcyin are considered If the clinical course does not improve during treatment In presence of an outbreak In the recurrences In a select sample of C. difficile isolates to monitor year by year the trend of antibiotic susceptibility in the hospital & **

22 2. Should we test Clostridium difficile for antimicrobial resistance? to the main antibiotic inducers of CDI? to which aims?

23 Main Inciting Antibiotics MLSB antibiotics: - Erythromycin - Clindamycin β-lactam antibiotics : - Cephalosporins - Amoxicillin + clavulanic acid - Piperacillin/tazobactam - Penicillin Fluoroquinolones: - Ciprofloxacin - Moxifloxacin - Levofloxacin

24 Percentages of resistance in 354 C. difficile strains isolated from 38 different hospitals in 14 EU countries in the Prospective Study (Barbut F et al. Clin Microbiol Infect 2007; 13: ) 44, Breakpoints of resistance: EM, CM, MX >4 mg/l; TC > 8 mg/l 9.2

25 Antimicrobial susceptibility in Chinese C. difficile strains collected in the years (Anaerobe 2010,16:633-35) **

26 Is there a role of antimicrobial resistance in the spread of epidemic PCR ribotypes of Clostridium difficile?

27 Table 3. Frequencies of resistance (%) in the 10 most common ribotypes and other rare ribotypes (1613 isolates tested). (Wiuff C. et al. J. Infect , ) % Resistance clindamycin erythromycin levofloxacin moxifloxacin cefotaxime 106 (n = 475) (n = 355) (n = 204) (n = 101) (n = 57) (n = 52) (n = 46) (n = 45) (n = 39) (n = 27) Other (rare) (n = 212) All isolates (breakpoints of resistance: EM, CM, MX,LE >8 mg/l) **

28 suggestions monitor the resistance patterns of select samples of strains for the correlation with specific antibiotic policy in the hospital (antibiotic stewardship) perform the susceptibility tests time to time to detect changes in the circulation of specific genotypes

29 Conclusions on antibiotic susceptibility testing on C. difficile 1. The importance of culturing C. difficile 2. The need to apply standardized methods 3. Selection of those cases of CDI for which the susceptibility test is useful to choose the most appropriate treatment 4. Samples of strains to be tested to monitor the resistance trend should be representative of CDI throughout the hospital setting and over time