Objec7ves. Disclosures. Managing Complicated Outpa7ent Infec7ons Prac7cal Considera7ons for the Primary Care Clinician 4/26/12

Transcription

1 Managing Complicated Outpa7ent Infec7ons Prac7cal Considera7ons for the Primary Care Clinician Conan MacDougall, PharmD, MAS Associate Professor of Clinical Pharmacy UCSF School of Pharmacy Objec7ves Given a pa7ent with an infec7on requiring outpa7ent intravenous therapy, select an effec7ve and prac7cal agent for home administra7on. Differen7ate between bioavailability and equivalence in the context of switching an7microbials from IV to PO Iden7fy four common drug- drug interac7ons between an7microbials and other drugs and provide management recommenda7ons Discuss the pros and cons of oral agents used for an7bio7c- resistant urinary tract infec7ons Disclosures I have no relevant conflicts of interest to disclose Some off- label discussion JL is a 58 year- old poorly controlled Type II diabe7c pa7ent of yours who was recently admised to a local hospital with a severe diabe7c foot infec7on of the heel. Surgical debridement was performed and the pa7ent was started on piperacillin/tazobactam 4.5g IV q6h. Deep 7ssue cultures grew Enterococcus faecalis (ampicillin- suscep7ble), E. coli (pan- suscep7ble), and Bacteroides fragilis. Six days into treatment JL has responded well and the hospitalist calls you to discuss an7bio7c therapy for JL when he is discharged 1

2 Which of the following drug regimens would you recommend for JL as an outpa7ent? a) Piperacillin/tazobactam b) Ertapenem c) Linezolid + Moxifloxacin d) Amoxicillin + Cefpodoxime + Metronidazole Challenges in Transi7oning Pa7ents to Outpa7ent An7microbial Therapy Outpa&ent Parenteral An&microbial Therapy (OPAT) Frequency/complexity of IV an7microbial administra7on Stability of IV an7microbials for prolonged infusions Monitoring drug levels & labs Retaining adequate spectrum of ac7vity Switch to PO an&microbials Retaining adequate spectrum of ac7vity Achieving adequate drug levels Frequency of administra7on Food considera7ons Drug interac7ons Prac7ce Models for OPAT Delivery OPAT best op7on Select appropriate sebng on basis of availability, needs, Insurance status Home: Self- admin. Medically stable IV- PO switch feasible Change to PO Home: Visi7ng nurse Pa7ent presents with infec7on that requires IV ABX therapy OPAT contraindicated or poor compliance Medically unstable Hospitalize OPAT indicated (e.g. pa7ent stabilized) Infusion center MD office Nursing home Prac7cal Considera7ons for OPAT Frequency of administra7on 1/day = ), 2 7mes/day =, >2 7mes/day = { Complexity Recons7tu7on, dura7on of infusion Drug stability Concentra7on & temperature Infusion- related effects Vancomycin, amphotericin, quinupris7n/ dalfopris7n Adapted from: Paladino JA, Poretz D. Outpatient Parenteral Antimicrobial Therapy. CID 2010;51(S2):S198-S208 Slide courtesy Brett Heintz, PharmD 2

3 Prac7cal Considera7ons for OPAT Access issues PICC, tunnelled, or implanted catheter Excep7on: post- HD dosing only? Vancomycin, cefazolin, cefepime Delivery method Gravity feed & tubing Programmable IV pump Computerized ambulatory drug delivery (CADD) medwow.com joeypouch.co.uk Drug Intermi>ent Frequency Con&nuous Infusion Prac&cal choice for intermi>ent infusions Celriaxone 1-2g IV q12-24h - - Ertapenem 1g IV q24h - - Daptomycin 6+ mg/kg IV q24h - - Gent/tobramycin 5-7mg/kg IV q24h - - Vancomycin 0.5-2g IV q8-12h - - Tigecycline 50mg IV q12h - - Imprac&cal choice for intermi>ent infusion, stable for con&nuous infusions Pip/tazo g IV q4-8h g IV/day Cefazolin 1-2g IV q8h 3-6g IV/day Nafcillin 1-2g IV q4-6h 6-12g IV/day Penicillin G 3-4 MU IV q4-6h MU/day Celazidime/Cefepime* 1-2g IV q8-12h 3-6g IV/day Imprac&cal choice for intermi>ent infusion, likely unstable for con&nuous infusions Ampicillin* 1-2g IV q4-6h unstable Imipenem/meropenem 0.5g IV q6h/1-2g IV q8h unstable Practice Guidelines for Outpatient Parenteral Antimicrobial Therapy Alan D. Tice, 1 Susan J. Rehm, 2 Joseph R. Dalovisio, 3 John S. Bradley, 4 Lawrence P. Martinelli, 5 Donald R. Graham, 6 R. Brooks Gainer, 7 Mark J. Kunkel, 8 Robert W. Yancey, 9 and David N. Williams 10 1 John A. Burns School of Medicine, University of Hawaii, Honolulu; 2 Department of Infectious Diseases, Cleveland Clinic Foundation, Cleveland, Ohio; 3 Ochsner Clinic, Department of Infectious Diseases, New Orleans, Louisiana; 4 Division of Infectious Diseases, Children s Hospital of San Diego, San Diego, California; 5 Consultants in Infectious Diseases, Lubbock, Texas; 6 Springfield Clinic, Springfield, Illinois; 7 Morgantown Internal Medicine Group, Morgantown, West Virginia; 8 Pfizer, Inc.; 9 Florida Infection Physicians, Gainsville; 10 Hennepin County Medical Center, Minneapolis, Minnesota Tice AD, et al. Clin Infect Dis 2004;38: IDSA GUIDELINES 3

4 IV- PO Switch Considera7ons Retaining adequate spectrum of ac7vity Celriaxone cefpodoxime? levofloxacin? Piperacillin/tazobactam amox/clav? moxifloxacin? Achieving adequate drug levels Good bioavailability isn t everything Administra7on considera7ons Frequency of administra7on With/without food Gastric acidity Drug chela7on Drug % Absorbed Typical IV dose Typical PO dose Drugs with High Bioavailability and IV- PO ~ Equivalence Metronidazole % 500mg IV q8 500mg PO q8 Levofloxacin % mg IV q mg PO q8 Linezolid % 600mg IV q8 600mg PO q8 Fluconazole % mg IV qd mg PO qd Doxycycline % 100mg IV q12 100mg PO q12 TMP/SMX % 10mg/kg/day IV 1 DS PO q12h* Ciprofloxacin ~80% 400mg IV q12h 500mg PO q12h Drugs with High Bioavailability BUT IV- PO Nonequivalence Amoxicillin ~90% 1-2g IV q4-6h (amp) 500mg- 1g PO TID Cephalexin ~90% 1-2g IV q8h (cefaz) 500mg PO QID Drugs with Low Bioavailability AND IV- PO Nonequivalence Azithromycin ~40% mg IV q24h mg PO q24h Cefuroxime ~40% 750mg IV q8h 500mg PO BID Antimicrobial Class Frequency of Testing (per week) Comments / Other CBC SCr Lytes LFTs Aminoglycosides Monitor weekly troughs, ototoxicity Beta-lactams Nafcillin Fluoroquinolones Phototoxicity, CNS symptoms Clindamycin S/sxs C. difficile Linezolid S/sxs neuropathy, optic neuritis Daptomycin Baseline and weekly CK, myalgias Synercid Monitor for arthralgias TMP/SMX Monitor for rash Vancomycin Weekly trough levels Pentamidine Infusion clinic recommended Amphotericin B Infusion clinic recommended Fluconazole Acyclovir Consider valacyclovir Ganciclovir Consider valganciclovir Foscarnet, Cidofovir Infusion clinic recommended Slide adapted from BreS Heintz, PharmD IV or PO? Take- homes Pick an7bio7cs that can be given daily or BID or via a con7nuous infusion pump Think about total drug exposure when switching from IV to PO Have a lab & symptom monitoring plan for pa7ents on long- term an7bio7cs 4

5 Which of the following drug regimens would you recommend for JL as an outpa7ent? a) Piperacillin/tazobactam Not prac)cal as q6h; reasonable if give as con)nuous infusion b) Ertapenem Prac)cal daily dosing; doesn t cover Enterococcus c) Linezolid + Moxifloxacin Levels equivalent to IV; +/- ac)vity vs B. fragilis a) Amoxicillin + Cefpodoxime + Metronidazole Amox & cefpodoxime lower total drug exposure vs IV TL is a 37 year old female with recurrent MRSA sol 7ssue infec7ons. She comes into clinic with a new 1 x 3 cm abscess with some associated celluli7s. Aler performing minor incision & drainage, you decide to provide adjunc7ve an7bacterial therapy. Based on her prior MRSA isolates, all of the regimens listed would be likely to have in vitro ac7vity. She has no history of drug allergies. TL s Current Medica7ons: Warfarin Paroxe7ne Ferrous sulfate Mul7vitamin Calcium carbonate Ortho Tri- cyclen Which would be your preferred therapy? a) TMP/SMX b) Levofloxacin + Rifampin c) Linezolid d) Doxycycline An7microbial Drug Interac7ons Most commonly used an7microbials (beta- lactams) have few interac7ons Commonly used agents with significant interac7ons TMP/SMX, metronidazole, fluoroquinolones, linezolid, macrolides, fluconazole Pharmacists responsible for iden7fying interac7ons BUT: Pa7ents receive drugs from mul7ple pharmacies Popup fa7gue Can t always reach you 5

6 Metabolic Drug Interac7ons Metabolic Drug Interactions Inhibi7on Drug A inhibits the ac7on of the enzyme that metabolizes drug B Concentra7ons of drug B rise quickly aler drug A started Adverse effects associated with higher levels of drug B Concentra7ons drug B quickly return to normal aler drug A stopped Induc7on Drug A causes an increase in the number of enzymes that metabolize drug B Concentra7ons of drug B decrease slowly aler drug A started Poten7al therapeu7c failure associated with lower levels of drug B Concentra7ons drug B increase slowly aler drug A stopped Normal Metabolism Bloodstream 1A2 S S S S 1A2 2C9 2C9 2C19 2C19 2D6 Hepatocyte 2D6 2E1 2E1 Enzymatic Inhibition Hepatocyte Bloodstream Inh Inh 1A2 1A2 2C9 2C9 2C19 Chemical Interac7ons S S S S Enzymatic Induction Bloodstream Ind S S S S 1A2 1A2 2C9 2C19 2D6 2E1 2D6 2E1 Hepatocyte 2C9 2C9 2C19 2C19 2D6 2E1 2C9 2D6 2E1 Chela7on Fluoroquinolones/tetracyclines & divalent/trivalent ca7ons Calcium, iron, zinc, aluminum, magnesium Ca7ons bind to quinolone/tetracycline forma7on non- absorbable complex absorp7on blood levels therapeu7c failure/resistance? 6

7 Modifica7on of GI Flora Clobng factor precursor synthesis Vitamin K produced by GI flora An7bio7cs bacteria vitamin K INR bleeding? Enterohepa7c recycling Liver conjugates hormonal contracep7ves excreted into gut Gut bacteria hydrolyze conjugate reabsorp7on An7bio7cs bacteria hydrolysis reabsorp7on contracep7ve failure? An7microbials - - Warfarin More potent S- isomer metabolized by CYP 2C9 TMP/SMX, metronidazole, fluconazole Less potent R- isomer by CYP & 1A2 clarithromycin, ciprofloxacin rifampin Reduced vitamin K produc7on Any an7microbial (?) An7microbial - - Warfarin Interac7ons: Risk Retrospec7ve cohort study Pa7ents on stable warfarin dose INR change aler drug ini7a7on Drug Absolute change % > therapeu&c p- value vs terazosin Terazosin % - - Azithromycin % <0.05 Levofloxacin % <0.01 TMP/SMX % <0.001 Glasheen JJ, et al. J Gen Intern Med 2005;20: Popula7on- based case- control study in Canada >66 years old outpts receiving warfarin Case=hospital admission for GI hemorrhage Age- & sex- matched controls An7bio7c exposure <14 days of index date Drug % Cases Exposed % Controls Exposed Adjusted OR (95% CI) TMP/SMX 1.2% 0.3% 3.84 ( ) Amoxicillin 1.4% 1.0% 1.37 ( ) Ciprofloxacin 1.4% 0.6% 1.94 ( ) Nitrofurantoin 0.5% 0.3% 1.40 ( ) Ocular abx 0.5% 0.4% 0.99 ( ) Fischer HD, et al. Arch Intern Med 2010;170:

8 Cohort study from US PDM Medical claim for hemorrhage <7 days aler warfarin fill or refill Prevalence of hemorrhage w/ or w/o co- prescrip7on Co- prescrip&on % Hemorrhage Adjusted OR (95% CI) None 14.2% 1.57 ( ) Metronidazole 22.7% 1.16 ( ) Cephalosporins 17.2% 1.94 ( ) Amiodarone 14.8% 0.98 ( ) NSAIDs 14.3% 0.90 ( ) Zhang K, et al. J Managed Care Pharm 2006;12: Lee CR, et al. Pharmacotherapy 2001;21: Used with permission. An7microbial - - Warfarin Interac7ons: Management Select lower- risk an7bio7c if possible TMP/SMX, ciprofloxacin cephalexin, cefpodoxime, amox/clav, nitrofurantoin, fosfomycin, levofloxacin Metronidazole clindamycin Clarithromycin azithromycin, doxycycline Fluconazole topical (if appropriate) Rifampin rifabu7n An7microbial Warfarin Interac7ons: Management Increase monitoring of warfarin Empiric dose reduc7on/increase Ahmad A, et al. J Thromb Thrombolysis 2008;26: Used with permission. 8

9 Linezolid - - An7depressants Monoamine oxidase: metabolism of serotonin, norepinephrine Linezolid modest inhibitor of monoamine oxidase Linezolid + SSRI/SNRI/TCA/triptans/buspirone monoamines serotonin syndrome? Coadministra7on contraindicated per PI Studies of linezolid- sero&nergic drug coadministra&on Study Methodology Cases(effects) N Risk Go et al Taylor et al Lorenz et al Lawrence et al Linezolid An7depressant Interac7ons: Risks Single- center review; Hunter criteria Single- center review; Sternbach/Boyer criteria Single- center review; Naranjo scale FDA AERS review; Hunter criteria 1 (prolonged hospitaliza7on) 2 (myoclonus, altered mental status) 24 4% 52 4% 1 (myoclonus) 53 2% 29 (3 deaths, 6 hospitaliza7ons) n/a n/a Linezolid An7depressant Interac7ons: Management Use alterna7ve an7microbial Daptomycin, 7gecycline, celaroline, telavancin, clindamycin, doxycycline D/c or taper serotenergic drug Risk serotonin withdrawal syndrome Coadminister with careful monitoring S/sx serotonin syndrome: tremor, hyperreflexia, muscle rigidity, fever, mental status changes, myoclonus, diaphoresis Fluoroquinolones/Tetracyclines Ca7ons: Risks % decrease in total drug exposure Drug Ca Fe Mg/Al Zn Ciprofloxacin 20-40% 25-60% 80% 20-50% Levofloxacin 20% 20% 22% - - Moxifloxacin 5% 40% 60% - - Doxycycline ~50% 50-90% 90% - - Dairy products/ca- for&fied orange juice: - ciprofloxacin: up to 50% reduc7on in exposure - levofloxacin: no effect - moxifloxacin: no effect - doxycycline: 20-30% reduc7on in exposure Piscitelli SC (ed) Drug Interac7ons in Infec7ous Diseases

10 Fluoroquinolones/Tetracyclines Ca7ons: Risks Fluoroquinolones/Tetracyclines Ca7ons: Risks Cohort study 725- bed medical center % of levofloxacin courses w/coadministra7on Subsequent isola7on of levo- R organism 3134 courses of levofloxacin 895 (29%) levo- ca7on concomitant all doses 606 (19%) levo- ca7on concomitant 1 dose Co- administra7on likelihood levo- R 1.5x risk of levo- R organism (p=0.005) MacDougall C. Data on file Cohen KA, et al. Infect Control Hosp Epidemiol 2008;29: Fluoroquinolones/Tetracyclines Ca7ons: Management Separate FQs/TCNs from ca7ons/antacids/mvis Most conserva7ve recs: 2 hr before/6 hr aler Reasonable: 1 hr before/2 hr aler May need to hold tube feeds before/aler Consider holding mineral supplements for dura7on of FQ therapy An7microbials Hormonal Contracep7ves Metabolic interac7ons Rifampin, rifabu7n drug concentra7on failure (very well- documented) Must use backup method including 1 cycle aler Modifica7on of GI flora An7bacterials kill GI flora reduced enterohepa7c recycling drug concentra7on? failure? (sporadic reports) Use backup method? 10

11 Drug Interac7ons: Take- homes Many common drugs have poten7ally serious interac7ons with an7bio7cs Warfarin, SSRIs, mineral supplements, oral contracep7ves Get pa7ent s FULL medica7on history Enlist pharmacist help in iden7fying & managing interac7ons Which would be your preferred therapy? a) TMP/SMX Risk of over- an)coagula)on; consider empiric warfarin dose decrease & increase monitoring b) Levofloxacin + Rifampin Avoid; very difficult to an)coagulate w/rifampin c) Linezolid Risk of serotonin syndrome; careful monitoring/ counseling; stop SSRI? a) Doxycycline Reasonable choice; separate from ca)ons; increase INR monitoring BR is a 56 year- old female with diabetes and end- stage renal dysfunc7on on dialysis, who presents to your office for the third 7me in three months with symptoms of UTI. The prior two episodes were treated empirically first with TMP/SMX 1 DS tab po BID and then with ciprofloxacin (250mg po BID). For this episode of cys77s you ini7ate ciprofloxacin at a higher dosage (500mg po BID) and send a urine culture. Two days later the results of the urine culture come back. >100,000 E.coli: Ciprofloxacin: resistant Ampicillin: resistant Ampicillin/sulbactam: suscep7ble TMP/SMX: resistant Cefazolin: resistant Celriaxone: suscep7ble Nitrofurantoin: suscep7ble Which of the an7microbials below would you switch BR to? a) Fosfomycin b) Nitrofurantoin c) Cefpodoxime d) Amoxicillin/clavulanate e) Celriaxone IV/IM 11

12 100 Ac&vity versus ESBL- producing E. coli Urinary Isolates Percent Sensa&ve % sensi7ve Fosfomycin Nitrofurantoin Gentamicin Ciprofloxacin TMP/SMX Guillermo V, et al. An7microb Agents Chemother 2012;56: Auer SA, et al. An7microb Agents Chemother 2010;54: Only FDA- approved for uncomplicated UTI Nitrofurantoin Only FDA- approved for uncomplicated UTI Fosfomycin Pros Very good ac7vity vs E. coli, Klebsiella, Enterococcus (some VRE) Accumulates in urine Usually tested by micro Narrow- spectrum; lisle collateral damage Data on long- term use Cons Only for lower UTI urine concentra7ons with CrCl <50 ml/min Reduced effec7veness? No difference in cure rates in 300- pa7ent series* Mean CrCl 40 ml/min Pros Excellent ac7vity vs E. coli, Klebsiella, Enterococcus (some VRE) Accumulates in urine Narrow- spectrum; lisle collateral damage Well- tolerated Cons Only for lower UTI Suscep7bility tes7ng not rou7nely performed Only approved for single- dose in U.S. Given 3g QOD x 3 doses; 94% clinical cure, 79% eradica7on Hard to obtain/insurance approval? *Bains A, et al. Can Pharm J 2009;142: *Pullucku H, et al. Int J An7microb Agents 2007;29:

13 Not all oral cephalosporins FDA- approved for UTI Oral Cephalosporins Amoxicillin/clavulanate Pros Modest- good ac7vity vs E. coli, Klebsiella Well- tolerated Accumulates in urine Cons Suscep7bility interpreta7on Cefazolin cephalexin Celriaxone cefpodoxime? ac7vity vs ESBL Broad- spectrum, collateral damage Less effec7ve than ciprofloxacin for uncomplicated UTI* Pros Good ac7vity vs E. coli, Klebsiella, Enterococcus (not VRE) Accumulates in urine Cons Suscep7bility interpreta7on Amox/clav > amp/ sulbactam? ac7vity vs ESBL GI adverse effects Less effec7ve than ciprofloxacin for uncomplicated UTI* *Hooton TF, et al. JAMA 2012;307: *Hooton TF, et al. JAMA 2005;293: Your pa7ents will hate you but Intramuscular an7bio7c administra7on? Celriaxone 1g IM Ertapenem 1g IM Gentamicin 7mg/kg IM An7bio7c- Resistant UTIs: Take- homes Resistance increasing but representa7ve data difficult to obtain PO op7ons Lower UTI only: nitrofurantoin & fosfomycin Lower efficacy: cefpodoxime & amox/clav Return of IM administra7on? 13

14 Which of the an7microbials below would you switch BR to? a) Fosfomycin No; likely ineffec)ve with ESRD b) Nitrofurantoin No; likely ineffec)ve with ESRD c) Cefpodoxime Reasonable, but exact suscep)bility unknown & less effec)ve a) Amoxicillin/clavulanate Reasonable, but exact suscep)bility unknown & less effec)ve b) Celriaxone IV/IM Likely effec)ve but unpopular 14