Giving the Proper Dose: How Can The Clinical and Laboratory Standards Institute(CLSI)Help?

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1 Giving the Proper Dose: How Can The Clinical and Laboratory Standards Institute(CLSI)Help? Pranita D. Tamma, M.D., M.H.S. Director, Pediatric Antimicrobial Stewardship Johns Hopkins University School of Medicine Baltimore, Maryland, USA

2 Disclosures Current grant support Centers for Disease Control and Prevention Antibacterial Resistance Leadership Group Fisher Center Thrasher Research Foundation Pfizer Merck

3 Adapted from Bouchet HW, et al. Clin Infect Dis ;1684

4 Drugs on the Horizon for MDRGNs (Phase 2 or 3) Product ESBLs CREs MDR-PSA MDR- Acinetobacter Ceftolozane-tazobactam Ceftazidime-avibactam Ceftaroline-avibactam Imipenem-MK-7655 Plazomicin Eravacycline Brilacidin Green- Active; Red- Not active; Orange- Active against KPCs but not other CREs; Gray- Unknown

5 What can Antibiotic Stewards do? X Sit around and wait for new antibiotics? Optimize the use of existing antibiotics Ensure clinicians are prescribing the best drug, dose, interval, and duration (if antibiotics are actually needed for a particular patient).

6 What can the CLSI do? Continue to enhance our understanding of optimal drug dosing and interval through simulation studies Use prevailing (and higher and more frequent) antimicrobial dosage regimens for analysis. When possible, PK data should be derived from the population of interest. When possible, PK data should be derived from the body source the drug is predominantly used for. Lodise TP, et al. Antimicrob Ag Chemo 2004;48:4718.

7 Piperacillin-Tazobactam

8 Lodise TP, et al. Antimicrob Ag Chemo 2004;48:4718.

9 Comparison of target attainment profiles of grams of PIP-TAZ administered every 6 or 4 hours as a 0.5 h infusion for hospitalized patients Lodise TP, et al. Antimicrob Ag Chemo 2004;48:4718.

10 Comparison of target attainment profiles of grams of PIP-TAZ administered every 6 or 4 hours as a 0.5 h infusion for healthy patients Lodise TP, et al. Antimicrob Ag Chemo 2004;48:4718.

11 What Was Particularly Helpful About This Study? They used dosing strategies that mimic what practitioners use in practice. They looked at intervals more frequent than normally utilized to highlight other potential administration strategies. They illustrated the importance of using PK data from the target patient population whenever possible.

12 Confirming the Results With Clinical Outcomes Studies Tam VH, et al. 34 adult bacteremia patients with PIP MIC 32 μg/ml: 4 times higher 30-day mortality in PIP group compared to non-pip group Yamagashi Y, et al. 78 adult patients with bacteremia or pneumonia receiving PIP: 95% cure with MICs <16 μg/ml and 33% when MIC was μg/ml Tamma PD, et al. 170 bacteremic children receiving PIP-TAZ: 3 times higher mortality if MIC µg/ml compared to 16 µg/ml Tam VH et al, Clin Infect Dis 2008; 46:862. Yamagishi Y, et al. J Infect Chemother 2012;18:127. Tamma PD, et al. Clin Infect Dis. 2012; 55:799.

13 Prolonged Infusion PIP-TAZ Lorente et al. For patients with Gram-negative VAP with MICs 16 ug/ml, clinical cure was approximately 10 times greater using extended-infusion PIP-TAZ compared to standard dosing Lorente L, et al. Int J Antimicrob Ag 2009; 33:464. Lorente L, et al. Int J Antimicrob Agents 2009;33:464.

14 PIP-TAZ Dosing: What Did We Do in Response? Recommended g every 6 hours Our Practice MICs 8 µg/ml: g every 6 hours MICs 16 µg/ml: Consider extended infusion PIP-TAZ MICs >16 µg/ml: Use alternative agent

15 Future Work Related to PIP-TAZ Consider evaluating role of susceptible dose-dependent strategies for PIP-TAZ against MICs of 16 ug/ml Evaluate simulation studies using 4.5 grams of PIP-TAZ Lorente L, et al. Int J Antimicrob Ag 2009; 33:464. Lorente L, et al. Int J Antimicrob Agents 2009;33:464.

16 Cefepime

17 What does the Package Insert Say? FDA Approved Indications Moderate to severe pneumonia: 1-2 grams every 12h Empiric therapy for F&N: 2 grams every 8h Mild to moderate UTI: grams every 12h Complicated UTI: 2 grams every 12h Moderate to severe SSSI: 2 grams every 12h Complicated IAI (+ metronidazole): 2 grams every 12h attachment-03-vol1.pdf

18 What Dose of Cefepime are Most Clinicians Prescribing? Data from 120 US hospitals Source: CLSI cefepime ad hoc working group with original data from Vikas Gupta, PharmD, BC-PS, Director of CareFusion Medmined Services

19 Dudley MN, et al. Clin Infect Dis 2013;56:1301.

20 Dudley MN, et al. Clin Infect Dis 2013;56:1301.

21 Source: CLSI cefepime ad hoc working group analysis in 2004

22 Available Clinical Data Bhat et al Evaluated 204 episodes of Gram-negative bacteremia treated with 1-2 g q12h of cefepime o55% of patients with MIC 8 µg/ml died o25% of patients with MIC <8 µg/ml died Bhat SV, et al. Antimicro Ag Chemo 2007;51:4390.

23 CLSI Recommendations for Cefepime Before 2014 Enterobacteriaceae with MICs 8 µg/ml were considered susceptible (regardless of dose or interval). Since 2014, MICs of 4-8 µg/ml considered susceptible depending on dose of cefepime prescribed. Performance Standards for antimicrobial susceptibility testing. Twenty-fourth supplement. CLSI Document M100-S24. Wayne, PA 2014.

24 Susceptible-Dose Dependent Implies susceptibility of an isolate is dependent on the dosing regimen used. Growing need to refine susceptibility reporting to maximize clinicians use of available drugs SDD conveys that a higher dose can be considered for isolates with MICs that fall into a specific MIC range. ASPs can enhance clinician understanding of SDD.

25 Enterobacter cloacae Cefepime is susceptible but dose dependent (SDD). If normal renal function, adults should receive 2 grams every 8 hours at this MIC value; for pediatrics, use 50 mg/kg/dose every 8 hours. Antibiotics MIC Interpretation Cefazolin >16 R Cefoxitin >16 R Cefepime 8 S Ceftriaxone >32 R

26 Enterobacter cloacae Cefepime is susceptible but dose dependent (SDD). If normal renal function, adults should receive 1 gram every 8 hours at this MIC value; for pediatrics, use 50 mg/kg/dose every 8 hours. Antibiotics MIC Interpretation Cefazolin >16 R Cefoxitin >16 R Cefepime 4 S Ceftriaxone >32 R

27 Cefazolin

28 Turnridge JD, et al. Clin Infect Dis 2011;52:917.

29 Previous MIC Breakpoints (µg/ml) Revised MIC Breakpoints (µg/ml) S Int R S Int R Cefazolin 8 16 > 32 < 2 4 > 8

30 Monte Carlo Simulation Results % Target Attainment (50% T>MIC) Nightingale et al % Target Attainment (50% T>MIC) Scheld et al MIC 1 gram q8h 1.5 grams q6h 2 grams q8h 1 gram q8h 1.5 grams q6h 2 grams q8h Nightingale CH, et al. J Pharm Sci 1975; 64:1899. Scheld WM, et al. Antimicrob Agents Chemother 1981; 19:613.

31 Monte Carlo Simulation Results % Target Attainment (50% T>MIC) Nightingale et al % Target Attainment (50% T>MIC) Scheld et al MIC 1 gram q8h 1.5 grams q6h 2 grams q8h 1 gram q8h 1.5 grams q6h 2 grams q8h *Both studies performed in healthy volunteers and focusing on bacteremia

32 Clinical Outcomes Data Study Dose Indication Cefazolin MIC Iversen et al 1981 N=58 Millar et al 1995 N=120 Sanchez- Ramos et al 1995 N=178 Wing et al 1998 N=179 1 g q8h IM 1 g q8h IV 2 g q8h IV 2 g q8h IV Outcome Pyelonephritis MICs 8 97% cure in both cefuroxime and cefazolin arms Pyelonephritis MICs 16 Recurrent pyelonephritis in 3 patients in each arm (ceftriaxone/cefazolin vs. oral cephalexin) Pyelonephritis MICs 8 No difference in days of fever, LOS, treatment failure between ceftriaxone or cefazolin Pyelonephritis MICs 16 No difference in days of fever, clinical cure, LOS in amp/gent vs. ceftriaxone vs. cefazolin arms Iversen P, et al. Clin Ther 1981;4:302. Millar LK, et al. Obstet Gynecol 1995;86:560. Sanchez-Ramos L, et al. Am J Obstet Gynecol 1995;172:129. Wing DA, et al Obstet Gynecol 1998;92:249.

33 13 patients with E. coli pyelonephritis with bacteremia Treated with cefazolin 2g every 8 h Only 7 of 13 isolates had MICs in susceptible range Using breakpoint of 2µg/ml All patients had clinical cure and no relapses Lewis JS & Jorgensen JH. Presented at Infectious Diseases Society of America Annual Meeting. Vnacouver BC, Canada: IDSA, 2010.

34 Unintended Consequences

35 Unintended Consequences Organism N Cefazolin (S 8 µg/ml) E. coli K. pneumoniae P. mirabilis Cefazolin breakpoints of 8µg/ml and 2µg/ml were used by 76% and 24% of 43 included institutions, respectively. Tamma PD, et al. Clin Infect Dis 2014, Advanced Access: May 13 th, 2014.

36 Unintended Consequences Organism N Cefazolin (S 8 µg/ml) N Cefazolin (S 2 µg/ml) N Ceftriaxone E. coli K. pneumoniae P. mirabilis Cefazolin breakpoints of 8µg/ml and 2µg/ml were used by 76% and 24% of 43 included institutions, respectively. Tamma PD, et al. Clin Infect Dis 2014, Advanced Access: May 13 th, 2014.

37 Unintended Consequences Organism N Cefazolin (S 8 µg/ml) N Cefazolin (S 2 µg/ml) N Ceftriaxone E. coli K. pneumoniae P. mirabilis Cefazolin breakpoints of 8µg/ml and 2µg/ml were used by 76% and 24% of 43 included institutions, respectively. Cephalothin was active against 56% of E. coli. Tamma PD, et al. Clin Infect Dis 2014, Advanced Access: May 13 th, 2014.

38 What did the CLSI do in 2014? A revised breakpoint was established for cefazolin for urinary isolates. Discouraged clinical microbiology laboratories from using cephalothin as a proxy for susceptibility to other oral cephalosporins Serum Breakpoints (µg/ml) Urine Breakpoints (µg/ml) S Int R S Int R Cefazolin < 2 4 > 8 < > 32

39 Where is there room for further improvement?

40 Ceftriaxone

41 Dudley MN, et al. Clin Infect Dis 2013;56:1301.

42 Ceftriaxone PK-PD decision influencing breakpoint changes of 8 µg/ml to 1 µg/ml for ceftriaxone relied on dosing of 1 gram q24 h In reality clinicians use up to 2 grams q12 h Breakpoint data for ceftazidime based on PK-PD data using 1 gram q8 h 2 grams q8h often used in practice Breakpoint data for aztreonam based on PK-PD data using 1 gram q8 h 2 grams q8h used in practice

43 Organism Old Resistance Breakpoint 64 µg/ml Revised Resistance Breakpoint 4 µg/ml Relative Percent Increase Citrobacter spp. 3 (8.6%) 16 (45.7%) 531.4% Escherichia coli 5 (2.6%) 42 (22.0%) 846.2% Enterobacter spp. 39 (20.7%) 82 (43.6%) 210.6% Klebsiella spp. 25 (8.3%) 63 (20.9%) 251.8% Serratia spp. 4 (6.5%) 24 (38.7%) 595.4% Proteus spp. 0 2 (33.3%) -- Total 76 (9.7%) 229 (29.2%) 301.3% Tamma PD, et al. Peds Infect Dis 2013;32:965

44 The Distribution of MICs by ESBL and Non-ESBL Producing Organisms Huang Y, et al. J Clin Microbiol 2014;52:2228.

45 Ceftriaxone Wish List PK-PD data using different dosing strategies PK-PD data in hospitalized patients Clinical outcomes data

46 Ciprofloxacin

47 Use of Ciprofloxacin in Clinical Practice Treatment of Pyelonephritis Cipro 500 mg PO Q12h for 7 days TMP/SMX 1DS tab PO Q12h for 14 days RCT Evidence Talan JAMA 2000, Sandberg Lancet 2012 Cipro 1000 mg ER Q24h for 7 days Talan J Urol 2004 Levofloxacin 750 mg Q24 h for 5 days Peterson Urol 2008 Talan DA, et al. JAMA 2000;283:1583. Sandberg T, et al. Lancet 2012; 380:484. Talan DA, et al. J Urol 2004; 171: 734. Peterson J, et al. 2008; 71: 17.

48 Use of Ciprofloxacin in Clinical Practice Current breakpoint of 1µg/ml Based on PK-PD data for bloodstream infections Rates of resistance to ciprofloxacin against the most common uropathogens is challenging use of ciprofloxacin for UTIs. Resistance >25% in US based on data from mid-2000s

49 Would Ciprofloxacin still be Effective for UTIs Caused by E. coli with Higher MICs? Clinical resolution of a woman with a UTI when prescribed ciprofloxacin for E. coli with MIC >4 ug/ml A recent study examined urine bactericidal activity of levofloxacin 750 mg against fluoroquinolone-resistant uropathogens Levofloxacin 750 mg dose effective against pathogens with MICs as high as 32 μg/ml- same true for ciprofloxacin? Ciprofloxacin 1000 mg shown to have prolonged bactericidal activity in urine Chien SC, Antimicrob Agents Chemother 1998;42:885. Klausner HA, et al. Curr Med Res Opin 2007;23:2637. Wagenlehner FM, et al. Int J Antimicrob Agents 2006; 27:7-14.

50 Future Work Needed for Ciprofloxacin Ciprofloxacin for the treatment of urinary pathogens with MICs > 1 µg/ml needs to be evaluated based on prudent PK-PD studies focusing on urine and a range of dosing strategies. More relevant clinical studies are needed to determine whether the results of in vitro susceptibility testing can predict clinical outcomes.

51 My Vision PK-PD studies are conducted in hospitalized patients using the optimal dosing and interval in body sites of interest to set breakpoints. Antimicrobial stewardship teams encourage clinicians to use optimal dosing and interval when prescribing antibiotics. Automated laboratory systems are able to easily interface with breakpoint recommendations and laboratory software. CLSI encourages follow-up clinical studies to evaluate clinical outcomes and unintended consequences.

52 Thank you for your attention!