Update on Antibiotic Treatment of Emergency Department Infections David A. Talan, MD, FACEP, FIDSA Professor and Chair UCLA School of Medicine Olive View-UCLA Dept. of Emergency Medicine and Division of Infectious Diseases David A. Talan, MD, FACEP, FIDSA Professor and Chair UCLA School of Medicine Olive View-UCLA Dept. of Emergency Medicine and Division of Infectious Diseases

Adjusted Mortality Odds Ratio P Initial abx < 8 hrs 0.85 ( ) <0.001 (75.5%) Meehan TP. JAMA 1997;278:2080. Adjusted Mortality Odds Ratio P Initial abx < 8 hrs 0.85 ( ) <0.001 (75.5%) Meehan TP. JAMA 1997;278:2080. Time to Antibiotics for CAP: Mortality and Length of Stay Time to Antibiotics for CAP: Mortality and Length of Stay ED Abx (n=473) LOS <9 days 71% 51% (OR 0.31*) (ED vs. after hrs) Battleman DS. Arch Intern Med 2002:162:682. LOS <9 days 71% 51% (OR 0.31*) (ED vs. after hrs) Battleman DS. Arch Intern Med 2002:162:682. LOS >9 days (n=136) LOS >9 days (n=136)

What's New in 2003?  Emerging bacterial resistance   New antibiotics  Short-course regimens  Outpatient management  Practice guidelines  Restricting diagnoses/antibiotic use  Emerging bacterial resistance   New antibiotics  Short-course regimens  Outpatient management  Practice guidelines  Restricting diagnoses/antibiotic use

 Levofloxacin (Levaquin)  Moxifloxacin (Avelox)  Gatifloxacin (Tequin)  Ertapenam (Invanz)  Augmentin XR (1000 mg amoxicillin, dose: 2 tabs Q 12 hours)  Cipro XR ( mg QD)  Levofloxacin (Levaquin)  Moxifloxacin (Avelox)  Gatifloxacin (Tequin)  Ertapenam (Invanz)  Augmentin XR (1000 mg amoxicillin, dose: 2 tabs Q 12 hours)  Cipro XR ( mg QD) Newer Antibiotics Quinolones with with enhanced enhanced pneumococcal pneumococcal activity activityQuinolones with with enhanced enhanced pneumococcal pneumococcal activity activity

Azithromycin (Zithromax) Cefadroxil (Duricef)Aminoglycosides Cefixime (Suprax) Ceftriaxone (Rocephin) Ceftibuten (Cedax)Ertapenam (Invanz) Cefdinir (Omnicef) Levofloxacin (Levaquin) Moxifloxacin (Avelox) Gatifloxacin (Tequin) Clarithromycin ER (Biaxin XL) Azithromycin (Zithromax) Cefadroxil (Duricef)Aminoglycosides Cefixime (Suprax) Ceftriaxone (Rocephin) Ceftibuten (Cedax)Ertapenam (Invanz) Cefdinir (Omnicef) Levofloxacin (Levaquin) Moxifloxacin (Avelox) Gatifloxacin (Tequin) Clarithromycin ER (Biaxin XL) Once-Per-Day Antibiotics OralParenteral

 DRSP (including QR-DRSP)  Macrolide-res. S. pneumoniae/pyogenes  TMP/SMX/FG ceph./Quinolone-res. E. coli  Quinolone-res. N. gonorrheae (QRNG)  Community-acquired (CA-MRSA)  DRSP (including QR-DRSP)  Macrolide-res. S. pneumoniae/pyogenes  TMP/SMX/FG ceph./Quinolone-res. E. coli  Quinolone-res. N. gonorrheae (QRNG)  Community-acquired (CA-MRSA) Emerging Bacterial Resistance

 Dx: inflamed and immobile TM  New higher dose, shorter duration  No treatment OK - 2 day follow-up  Dx: inflamed and immobile TM  New higher dose, shorter duration  No treatment OK - 2 day follow-up Acute Otitis Media: New Concepts

Wait and See Approach for Acute Otitis Media in British Children Days of earache Nights disturbed Days school missed Diarrhea (%) 19 9 Very satisfied (%) Would need MD in future (%) Days of earache Nights disturbed Days school missed Diarrhea (%) 19 9 Very satisfied (%) Would need MD in future (%) Immediate Rx (98% used, n=135) Immediate Rx (98% used, n=135) Pick up Rx in 3 day (24% used, n=150) Pick up Rx in 3 day (24% used, n=150)  Non-blind, randomized  6 months to 10 years  Pain & erythema, bulging or perforation  Non-blind, randomized  6 months to 10 years  Pain & erythema, bulging or perforation Little P. BMJ 2001:322:336.

Acute Otitis Media: 1999 US CDC Working Group Acute Otitis Media: 1999 US CDC Working Group  - HD amoxicillin mg/kg/day (BID,  1st line - HD amoxicillin mg/kg/day (BID, to 2 grams, up to 1 grams TID) to 2 grams, up to 1 grams TID) - HD amoxicillin/clavulanate, cefuroxime, 2nd line - HD amoxicillin/clavulanate, cefuroxime, IM ceftriaxone (50 mg/kg) IM ceftriaxone (50 mg/kg)  Risk groups - day care, prior abx, < 2 years  Refractory cases - IM ceftriaxone QD X3, clindamycin, tympanocentesis  - HD amoxicillin mg/kg/day (BID,  1st line - HD amoxicillin mg/kg/day (BID, to 2 grams, up to 1 grams TID) to 2 grams, up to 1 grams TID) - HD amoxicillin/clavulanate, cefuroxime, 2nd line - HD amoxicillin/clavulanate, cefuroxime, IM ceftriaxone (50 mg/kg) IM ceftriaxone (50 mg/kg)  Risk groups - day care, prior abx, < 2 years  Refractory cases - IM ceftriaxone QD X3, clindamycin, tympanocentesis Dowell SF. Pediatr Infect Dis J 1999;18:1. Avoid: cefaclor, cefprozil, cefixime, ceftibuten b/o DRSP activity Avoid: cefaclor, cefprozil, cefixime, ceftibuten b/o DRSP activity A/C >AZ bac and clin. cure Ped Infect Dis J 2000:19:95. 3 days > 1 day (DRSP) Ped Infect Dis J 2000:19:1040.

Community-Acquired Pneumonia

US Study to Predict Low-Risk Pneumonia Patients  Less than 50 years of age  No history of cancer, CHF, cerebrovascular, HIV, renal or liver disease  Normal mental status  P 90, T o C  Less than 50 years of age  No history of cancer, CHF, cerebrovascular, HIV, renal or liver disease  Normal mental status  P 90, T o C Fine MJ. NEJM 1997;336:243.

CAP Mortality Prediction Rule Demographic: Exam: Age (-10 women) MS, RR >30, BP< 9020 Nursing home 10 HR > T 40 o C10 Co-morbidity: Lab: Cancer 30 pH < CHF 20 BUN > 30, Na < CVA, renal, liver 10 Glu>250, Hct <30, 10 pO 2 <60, pleural effusion Fine MJ. NEJM 1997;336:243. Demographic: Exam: Age (-10 women) MS, RR >30, BP< 9020 Nursing home 10 HR > T 40 o C10 Co-morbidity: Lab: Cancer 30 pH < CHF 20 BUN > 30, Na < CVA, renal, liver 10 Glu>250, Hct <30, 10 pO 2 <60, pleural effusion Fine MJ. NEJM 1997;336:243.

CAP Risk Classes, Mortality, and Management Risk Class - score30 Day Mortality (%) Rec. Care I <0.5 Outpatient II < Outpatient III Inpatient (brief) IV Inpatient V >130 >10 Inpatient Fine MJ. NEJM 1997;336:243. Risk Class - score30 Day Mortality (%) Rec. Care I <0.5 Outpatient II < Outpatient III Inpatient (brief) IV Inpatient V >130 >10 Inpatient Fine MJ. NEJM 1997;336:243.

Canadian CAP Clinical Pathway Trial ED Dx Pneumonia 22 hospitals, 1,743 patients ED Dx Pneumonia 22 hospitals, 1,743 patients Pneumonia score (+Pox) given to MD by nurse <90 recommended d/c home Pneumonia score (+Pox) given to MD by nurse <90 recommended d/c home Standard care Inpatient care - 31% Inpatient care - 49% 2 &6 week QOL scores 37 & 43 2 &6 week QOL scores 37 & 43 2 &6 week QOL scores 38 & 41 2 &6 week QOL scores 38 & 41 Marrie TJ. JAMA 2000;283:749.

US CAP Antimicrobial Strategies Pneumococcal Etiology (Degree of Illness) Pneumococcal Etiology (Degree of Illness) DRSP (Prevalence, prior Abx/ hosp.) DRSP (Prevalence, prior Abx/ hosp.) Atypical Etiology (Young age) Atypical Etiology (Young age) Macrolide Doxycycline Macrolide Doxycycline New fluoroquinolones 2nd-3rd GC/Macrolide New fluoroquinolones 2nd-3rd GC/Macrolide

Azithromycin 500/250 mg QD (5 d) Clarithromycin 500 mg BID Doxycycline 100 mg BID  -lactam (HD amox, amox/clav, ceftriaxone -cefpodoxime /cefuroxime) with above Levofloxacin 500 mg QD Moxifloxacin 400 mg QD Gatifloxacin 400 mg QD Azithromycin 500/250 mg QD (5 d) Clarithromycin 500 mg BID Doxycycline 100 mg BID  -lactam (HD amox, amox/clav, ceftriaxone -cefpodoxime /cefuroxime) with above Levofloxacin 500 mg QD Moxifloxacin 400 mg QD Gatifloxacin 400 mg QD CAP: Outpatient Treatment in US Oral regimens days Oral regimens days American Thoracic Society. Am J Respir Crit Care Med 2001;163:1730. Bartlett JG. Clin Infect Dis 2000;31:347. CDC. Arch Intern Med 2000;160:1399. American Thoracic Society. Am J Respir Crit Care Med 2001;163:1730. Bartlett JG. Clin Infect Dis 2000;31:347. CDC. Arch Intern Med 2000;160:1399. treatment failures high-risk documented DRSP treatment failures high-risk documented DRSP

Worldwide Outpatient CAP Guidelines Worldwide Outpatient CAP Guidelines Country/Org/Year Recommendation ACEP 2001See US IDSA US IDSA 2000Macrolide or doxycycline or FQ Canadian ID/TS 2000Macrolide or doxycycline mod. factor – FQ US ATS 2001 “ or BLI+ macrolide France 1991Amoxicillin Italy 1995BLI + macrolide Spain 1992Penicillin or erythromycin UK BTS 2001Amoxicillin HD or macrolide ACEP 2001See US IDSA US IDSA 2000Macrolide or doxycycline or FQ Canadian ID/TS 2000Macrolide or doxycycline mod. factor – FQ US ATS 2001 “ or BLI+ macrolide France 1991Amoxicillin Italy 1995BLI + macrolide Spain 1992Penicillin or erythromycin UK BTS 2001Amoxicillin HD or macrolide

CAP: Inpatient Treatment in US  2nd/3rd gen. cephalosporin plus azithro or doxy  Levofloxacin 500 mg Q24 o  Gatifloxacin 400 mg Q24 o  Moxifloxacin 400 mg Q24 o  2nd/3rd gen. cephalosporin plus azithro or doxy  Levofloxacin 500 mg Q24 o  Gatifloxacin 400 mg Q24 o  Moxifloxacin 400 mg Q24 o ATS. Am J Respir Crit Care Med 2001;163:1730. Bartlett JG. Clin Infect Dis 2000;31:347. CDC. Arch Intern Med 2000;160:1399. Finch R. Antimicrob Agents Chemother 2002;1746. ATS. Am J Respir Crit Care Med 2001;163:1730. Bartlett JG. Clin Infect Dis 2000;31:347. CDC. Arch Intern Med 2000;160:1399. Finch R. Antimicrob Agents Chemother 2002;1746.  Ceftriaxone plus either New Quinolone or Macrolide and aminoglycoside  Ceftriaxone plus either New Quinolone or Macrolide and aminoglycoside Floor ICU Consider vancomycin if quinolone exposure Consider vancomycin if quinolone exposure

3 rd gen. ceph plus macrolide 0.66 ( ) Fluoroquinolone only 0.64 ( )  -lactamase inh. plus macrolide 1.61 ( ) 3 rd gen. cephalosporin only reference 3 rd gen. ceph plus macrolide 0.66 ( ) Fluoroquinolone only 0.64 ( )  -lactamase inh. plus macrolide 1.61 ( ) 3 rd gen. cephalosporin only reference US Study of Relative 30-Day Mortality by Initial Antibiotic Regimen for CAP Gleason PP. Arch Intern Med 1999;159:2562. Adjusted hazard ratio (95% CI) 9,751 patients > 65 yrs, regimen within 48 hrs of admission 9,751 patients > 65 yrs, regimen within 48 hrs of admission

Cystitis Pathogen Antimicrobial Resistance - Seattle % Gupta K. JAMA 1999;281: Shift to quinolones/nitrofurantoin/3 rd gen. cephs.

Cystitis: Effect of T/S Resistance on Clinical Success in T/S-Treated Patients In Israel % % Raz R. Clin Infect Dis 2002;34:1165. (follow-up 4-6 weeks) Resistance matters Low morbidity disease Resistance matters Low morbidity disease 54% (81/151) 88% (293/333)

TMP/SMX BS BID (n=39) 82* Nitrofurantoin 100 mg QID (n=36) 61 Cefadroxil 500 mg BID (n=32) 66 Amoxicillin 500 mg QID (n=42) 67 TMP/SMX BS BID (n=39) 82* Nitrofurantoin 100 mg QID (n=36) 61 Cefadroxil 500 mg BID (n=32) 66 Amoxicillin 500 mg QID (n=42) 67 Three-Day Cystitis Regimens Hooton TM. JAMA 1995;273:41. % Cure 2 weeks At least 7 days At least 7 days

 Routine culture not recommended  3 days -more effective than 1 dose less side effects than 7 days TMP/SMX DS BID (if < 20% resistance) Levofloxacin 250 mg QD Ciprofloxacin XR 500 mg QD Ofloxacin 200 mg BID Gatifloxacin 400 mg QD  7 days – Nitrofuratoin (low-cost/resistance) Cephalexin (resistance), 3 rd GC  Culture if no symptom resolution in 2 days  Routine culture not recommended  3 days -more effective than 1 dose less side effects than 7 days TMP/SMX DS BID (if < 20% resistance) Levofloxacin 250 mg QD Ciprofloxacin XR 500 mg QD Ofloxacin 200 mg BID Gatifloxacin 400 mg QD  7 days – Nitrofuratoin (low-cost/resistance) Cephalexin (resistance), 3 rd GC  Culture if no symptom resolution in 2 days Therapy for Uncomplicated Cystitis Cost-effectiveness model supports at 22% T/S resistance rate Clin Infect Dis 2002:33:615.

Acute Uncomplicated Pyelonephritis in US: Cipro 7 Days vs. TMP/SMX 14 Days % % p = % (113) 89% (101) 85% (111) 74% (108) p =.08 Talan DA. JAMA Talan DA. JAMA 2000;283: % (106) 77% (106) 96% (113) 83% (111) p =.002 p = days days Bacteriologic cure Clinical cure

Effect of TMP/SMX Resistance in TMP/SMX-Treated AUP Patients % % 92% (76/83) p < (both) 96% (73/76) 50% (7/14) 35% (6/17) Talan DA. JAMA Talan DA. JAMA 2000;283:1583. Resistance matters High morbidity disease Resistance matters High morbidity disease Cost/patient Cipro $510 TMP/SMX $725

Ciprofloxacin 400 mg Levofloxacin 250 mg Gentamicin 5-7 mg/kg Ceftriaxone 1 gram Cipro XR 1000 mg QD (7days)Levofloxacin 250 mg QD Ciprofloxacin 400 mg Levofloxacin 250 mg Gentamicin 5-7 mg/kg Ceftriaxone 1 gram Cipro XR 1000 mg QD (7days)Levofloxacin 250 mg QD Outpatient ED Treatment of Acute Uncomplicated Pyelonephritis Initial PO/IV Dose Oral regimens QREC Spain 17% ’96 Garau J. AAC 1999;43:2736. QREC Spain 17% ’96 Garau J. AAC 1999;43:2736.

Cefixime 400 mg Ceftriax. 125/cefotax. 500 mg IM Ciprofloxacin 500 mg* Ofloxacin 400 mg* Levofloxacin 250 mg* Azithro 1 gram Doxy 100 mg BID X 7 d Cefixime 400 mg Ceftriax. 125/cefotax. 500 mg IM Ciprofloxacin 500 mg* Ofloxacin 400 mg* Levofloxacin 250 mg* Azithro 1 gram Doxy 100 mg BID X 7 d Treatment of Urethritis and Cervicitis Gonorrhea Chlamydia Female sex workers Bangladesh- GCcervicitis micro. success Cipro susc. (62%) 97.5% Cipro resist. (38%) 8.3 % Rahman M. Clin Infect Dis 2001;32:884) Female sex workers Bangladesh- GCcervicitis micro. success Cipro susc. (62%) 97.5% Cipro resist. (38%) 8.3 % Rahman M. Clin Infect Dis 2001;32:884) Not where QRNG Widespread QRNG – SE Asia, India, Israel,others

Acute Cellulitis / Lymphangitis Kontiainen S. Eur J Clin Microbiol 1987;6 :420.  Staphylococcus aureus Streptococcus pyogenes  First-generation cephalosporins Long acting - ceftriaxone probenecid/cefazolin azithromycin/linezolid  Staphylococcus aureus Streptococcus pyogenes  First-generation cephalosporins Long acting - ceftriaxone probenecid/cefazolin azithromycin/linezolid

Canadian Study of Effect of Probenecid on Cefazolin Concentrations Cefazolin (ug/ml) HoursHours Brown G. J Antimicrob Chemother 1993;31:1009. Grayson ML. Clin Infect Dis 2002;34: Now clinically confirmed!

Community-Associated MRSA  Methicillin-resistant Staphylococcus aureus  Also resistant to all penicillins/cephalosporins  Increasing proportion of staph isolates  30% of skin infections at Olive View-UCLA  Susceptible to clindamycin, quinolones, TMP/SMX,rifampin, tetracylcne, vancomycin  Methicillin-resistant Staphylococcus aureus  Also resistant to all penicillins/cephalosporins  Increasing proportion of staph isolates  30% of skin infections at Olive View-UCLA  Susceptible to clindamycin, quinolones, TMP/SMX,rifampin, tetracylcne, vancomycin Naimi TS. Clin Infect Dis 2001;33:990.

 Otitis- high-dose amoxicillin/Augmentin, consider wait and see approach  CAP - scoring helps, guidelines work, quinolones very effective, even as ICU monotherapy  UTI - short-course and TMP/SMX resistance  STDs - quinolone resistance in West, no cefixime, consider flagyl for PID regimens  Infectious diarrhea - antibiotics work  CA-MRSA - biggest new problem  Otitis- high-dose amoxicillin/Augmentin, consider wait and see approach  CAP - scoring helps, guidelines work, quinolones very effective, even as ICU monotherapy  UTI - short-course and TMP/SMX resistance  STDs - quinolone resistance in West, no cefixime, consider flagyl for PID regimens  Infectious diarrhea - antibiotics work  CA-MRSA - biggest new problem Take Home Points