Tetracycline Rationale for the EUCAST clinical breakpoints, version th November 2009

Transcription

1 Tetracycline Rationale for the EUCAST clinical breakpoints, version th November 2009 Introduction The natural tetracyclines, including tetracycline, chlortetracycline, oxytetracycline and demethylchlortetracycline are derived from Streptomyces spp. They have broad spectrum activity against many aerobic and anaerobic Gram-positive and Gram-negative bacteria. Tetracyclines are bacteriostatic and inhibit protein synthesis by binding to the 30S ribosomal subunit. Resistance may be mediated by efflux, ribosomal protection and ribosomal modification. In Bacteroides spp. an inactivation mechanism has been described. Tetracycline use is limited by poor absorption, resistance and the availability of more active and better tolerated alternatives. Tetracyclines have a wide range of potential clinical indications such as infections caused by chlamydiae, mycoplasmas and rickettsiae, and as alternative agents for respiratory tract and sexually transmitted infections, acne vulgaris, skin and skin structure infection and pelvic inflammatory disease. They are also used for treatment of brucellosis and infections with Yersinia spp., Burkholderia pseudomallei and Leptospira spp. Tetracycline is available for oral administration.

2 1. Dosage BSAC CA-SFM CRG DIN NWGA SRGA Most common dose 250 mg x mg x mg x mg x mg x mg x 4 Maximum dose schedule 500 mg x mg x mg x mg x mg x mg x 4 Available formulations Oral Oral Oral Oral Oral Oral

3 2. MIC distributions and epidemiological cut-off (ECOFF) values ECOFF Acinetobacter spp Campylobacter coli Campylobacter jejuni Citrobacter spp Clostridium difficile ND Enterobacter aerogenes Enterobacter aerogenes Enterobacter agglomerans ND Enterobacter cloacae Enterobacter cloacae Enterobacter dissolvens ND Enterobacter spp ND Enterococcus faecalis Enterococcus faecium Enterococcus hirae Enterococcus spp Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Hafnia alvei ND Helicobacter pylori Klebsiella oxytoca Klebsiella pneumoniae Klebsiella spp ND Kluyvera spp ND Listeria monocytogenes Mannheimia haemolytica

4 ECOFF Moraxella catarrhalis Morganella morganii ND Neisseria gonorrhoeae ND Neisseria meningitidis ND Pasteurella multocida Proteus mirabilis Proteus spp ND Raoultella spp ND Salmonella spp Serratia liquefaciens ND Serratia spp Staphylococcus aureus Staphylococcus aureus MRSA Staphylococcus aureus MSSA Staphylococcus coagulase-negative Staphylococcus coagulase-negative MRSE Staphylococcus epidermidis ND Staphylococcus epidermidis ND Staphylococcus haemolyticus ND Staphylococcus saprophyticus ND Stenotrophomonas maltophilia ND Streptococcus agalactiae Streptococcus anginosus ND Streptococcus group G ND Streptococcus oralis Streptococcus pneumoniae Streptococcus pyogenes Streptococcus viridans ND Yersinia spp ND

5 The table includes MIC distributions available at the time breakpoints were set. They represent combined distributions from multiple sources and time periods. The distributions are used to define the epidemiological cut-offs (ECOFF) and give an indication of the MICs for organisms with acquired or mutational resistance mechanisms. They should not be used to infer resistance rates. When there is insufficient evidence (IE) no epidemiological cut-off has been determined.

6 3. Breakpoints prior to harmonisation (mg/l) S< R> BSAC CA-SFM CRG DIN NWGA SRGA CLSI General breakpoint 4/8 1/4 1/4-2/2 Species specific breakpoints: Enterobacteriaceae 1/1 4/8 4/8 4/8 Pseudomonas spp. 1/1 4/8 Acinetobacter spp. 1/1 4/8 4/8 Staphylococcus spp. 1/1 4/8 1/2 2/2 4/8 Streptococcus spp. 1/1 4/8 2/2 2/2 2/4 Streptococcus pneumoniae 1/1 4/8 2/2 2/2 2/4 Enterococcus spp. 4/8 1/1 4/8 Haemophilus influenzae 1/1 2/4 2/2 2/2 2/4 Moraxella catarrhalis 1/1 2/4 2/2 2/2 Corynebacteria Neisseria meningitidis 1/1 0.25/1 Neisseria gonorrhoeae 1/1 1/4 0.12/1 0.12/1 0.25/1 Pasteurella multocida Anaerobes, Gram-positive 4/4 Anaerobes, Gram-negative 4/4 Campylobacter spp. 4/8 Helicobacter pylori 4/4 2/2 2/2

7 4. Pharmacokinetics Dosage (mg) 250 mg 500 mg Cmax (mg/l) Cmin (mg/l) - - Total body clearance (L/h) - - T ½ (h), mean (range) AUC24h (mg.h/l) - - Fraction unbound (%) Volume of distribution (L/kG) Comments Two values are given where references differ. Cells are left empty when data are not readily available. The drug is 80-90% absorbed from the small intestine, and is 30% excreted in the urine Peak serum concentrations are achieved in 1-3.5h References Bryskier A. In Antimicrobial Agents ASM; Finch R. In Antibiotic and Chemotherapy Churchill-Livingstone; Agwuh KN, MacGowan A. J. Antimicrobial Chemotherapy , 1-10.

8 5. Pharmacodynamics fauc/mic for bacteriostasis - fauc/mic for 2 log reduction - fauc/mic from clinical data - Comments Free drug AUC/MIC is the dominant pharmacodynamic index; there is insufficient data to determine its size for bacteriostatic or bactericidal effects in pre-clinical models and no supporting clinical data. References Review by Agwuh KN, MacGowan A. 2006, J. Antimicrob Chemother, 61, 1-10.

9 6. Monte Carlo simulations and Pk/Pd breakpoints No data

10 7. Clinical data There is little recent clinical experience with the use of tetracycline and no contemporary randomised controlled trials to support its use.

11 8. Clinical breakpoints Non-species-related breakpoints There is insufficient evidence to set non-species-related breakpoints. Breakpoints were based on Pk data, microbiological data and clinical experience. Species-related breakpoints For Staphylococcus spp., group A,B,C,G streptococci, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis the breakpoints are 1/2 mg/l. For Neisseria gonorrhoeae breakpoints are 0.5/1 mg/l. For Pasteurella multocida breakpoints are 2/4 mg/l. Species without breakpoints Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp., Enterococcus spp., and Streptococcus spp. other than Group A,B,C,G streptococci and S. pneumoniae were considered poor targets for tetracycline therapy and for that reason did not receive breakpoints. For anaerobic bacteria there is clinical evidence of activity in mixed intra-abdominal infections, but no correlation between MIC values, Pk/Pd and clinical outcome. Therefore no breakpoint is given. Breakpoints are given for Neisseria meningitidis only for use as an indicator of minocycline susceptibility for use in prophylaxis. Clinical qualifications Dosage Breakpoints apply to oral tetracycline dosage of mg x4/day. Additional comment

12 9. Tetracycline - EUCAST clinical MIC breakpoints These can be found at

13 10. Exceptions noted for individual national committees None