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

Update on Antibiotic Treatment of Emergency Department InfectionsUpdate on Antibiotic Treatment of Emergency Department Infections

David A. Talan, MD, FACEP, FIDSADavid A. Talan, MD, FACEP, FIDSA

Professor and ChairProfessor and Chair

UCLA School of MedicineUCLA School of Medicine

Olive View-UCLA Dept. of Emergency Medicine Olive View-UCLA Dept. of Emergency Medicine

and Division of Infectious Diseasesand Division of Infectious Diseases

David A. Talan, MD, FACEP, FIDSADavid A. Talan, MD, FACEP, FIDSA

Professor and ChairProfessor and Chair

UCLA School of MedicineUCLA School of Medicine

Olive View-UCLA Dept. of Emergency Medicine Olive View-UCLA Dept. of Emergency Medicine

and Division of Infectious Diseasesand Division of Infectious Diseases

Adjusted Mortality Odds Ratio P

Initial abx < 8 hrs 0.85 (0.75-0.96) <0.001 (75.5%)

Meehan TP. JAMA 1997;278:2080.

Adjusted Mortality Odds Ratio P

Initial abx < 8 hrs 0.85 (0.75-0.96) <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)ED Abx (n=473)

LOS <9 days 71% 51% (OR 0.31*)

(ED 3.5 + 1.4 vs. after 9.5 + 3.0 hrs) Battleman DS. Arch Intern Med 2002:162:682.

LOS <9 days 71% 51% (OR 0.31*)

(ED 3.5 + 1.4 vs. after 9.5 + 3.0 hrs) Battleman DS. Arch Intern Med 2002:162:682.

LOS >9 days(n=136)

LOS >9 days(n=136)

What's New in 2003?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 (500-1000 mg QD)

Levofloxacin (Levaquin) Moxifloxacin (Avelox) Gatifloxacin (Tequin) Ertapenam (Invanz) Augmentin XR (1000 mg amoxicillin,

dose: 2 tabs Q 12 hours) Cipro XR (500-1000 mg QD)

Newer AntibioticsNewer Antibiotics

QuinolonesQuinolones withwith

enhancedenhanced pneumococcalpneumococcal

activityactivity

QuinolonesQuinolones withwith

enhancedenhanced pneumococcalpneumococcal

activityactivity

Azithromycin (Zithromax) Cefadroxil (Duricef) AminoglycosidesCefixime (Suprax) Ceftriaxone (Rocephin)Ceftibuten (Cedax) Ertapenam (Invanz)Cefdinir (Omnicef)Levofloxacin (Levaquin) Moxifloxacin (Avelox)Gatifloxacin (Tequin)Clarithromycin ER (Biaxin XL)

Azithromycin (Zithromax) Cefadroxil (Duricef) AminoglycosidesCefixime (Suprax) Ceftriaxone (Rocephin)Ceftibuten (Cedax) Ertapenam (Invanz)Cefdinir (Omnicef)Levofloxacin (Levaquin) Moxifloxacin (Avelox)Gatifloxacin (Tequin)Clarithromycin ER (Biaxin XL)

Once-Per-Day AntibioticsOnce-Per-Day Antibiotics

Oral Parenteral

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 ResistanceEmerging 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 ConceptsAcute Otitis Media: New Concepts

Wait and See Approach for Acute Otitis Media in British Children

Wait and See Approach for Acute Otitis Media in British Children

Days of earache 2.6 3.6

Nights disturbed 1.6 2.5

Days school missed 2.0 2.1

Diarrhea (%) 19 9

Very satisfied (%) 91 77

Would need MD in future (%) 83 63

Days of earache 2.6 3.6

Nights disturbed 1.6 2.5

Days school missed 2.0 2.1

Diarrhea (%) 19 9

Very satisfied (%) 91 77

Would need MD in future (%) 83 63

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.Little P. BMJ 2001:322:336.

Acute Otitis Media: 1999 US CDC Working Group

Acute Otitis Media: 1999 US CDC Working Group

1st line - HD amoxicillin - 80-90 mg/kg/day (BID, - HD amoxicillin - 80-90 mg/kg/day (BID, to 2 grams, up to 1 grams TID)to 2 grams, up to 1 grams TID)

2nd line - HD amoxicillin/clavulanate, cefuroxime, - 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

1st line - HD amoxicillin - 80-90 mg/kg/day (BID, - HD amoxicillin - 80-90 mg/kg/day (BID, to 2 grams, up to 1 grams TID)to 2 grams, up to 1 grams TID)

2nd line - HD amoxicillin/clavulanate, cefuroxime, - 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.Dowell SF. Pediatr Infect Dis J 1999;18:1. Avoid: cefaclor, cefprozil, Avoid: cefaclor, cefprozil, cefixime, ceftibuten b/o DRSP activitycefixime, ceftibuten b/o DRSP activity

Avoid: cefaclor, cefprozil, Avoid: cefaclor, cefprozil, cefixime, ceftibuten b/o DRSP activitycefixime, ceftibuten b/o DRSP activity

A/C >AZ bac and clin. curePed Infect Dis J 2000:19:95.

3 days > 1 day (DRSP)Ped Infect Dis J 2000:19:1040.

Community-Acquired PneumoniaCommunity-Acquired Pneumonia

US Study to Predict Low-Risk Pneumonia Patients

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 < 125, RR < 30, BP > 90, T 35-40oC

Less than 50 years of age

No history of cancer, CHF, cerebrovascular, HIV, renal or liver disease

Normal mental status

P < 125, RR < 30, BP > 90, T 35-40oC

Fine MJ. NEJM 1997;336:243.Fine MJ. NEJM 1997;336:243.

CAP Mortality Prediction RuleCAP Mortality Prediction Rule

Demographic: Exam:Age (-10 women) MS, RR >30, BP< 90 20 Nursing home 10 HR >125 15

T < 35o or > 40oC 10Co-morbidity: Lab:Cancer 30 pH < 7.35 30CHF 20 BUN > 30, Na < 130 20CVA, renal, liver 10 Glu>250, Hct <30, 10

pO2 <60, pleural effusion

Fine MJ. NEJM 1997;336:243.

Demographic: Exam:Age (-10 women) MS, RR >30, BP< 90 20 Nursing home 10 HR >125 15

T < 35o or > 40oC 10Co-morbidity: Lab:Cancer 30 pH < 7.35 30CHF 20 BUN > 30, Na < 130 20CVA, renal, liver 10 Glu>250, Hct <30, 10

pO2 <60, pleural effusion

Fine MJ. NEJM 1997;336:243.

CAP Risk Classes, Mortality, and Management

CAP Risk Classes, Mortality, and Management

Risk Class - score 30 Day Mortality (%) Rec. Care

I <0.5 Outpatient II <70 0.5-1 Outpatient III 71-90 1-4 Inpatient (brief) IV 91-130 4-10 Inpatient V >130 >10 Inpatient

Fine MJ. NEJM 1997;336:243.

Risk Class - score 30 Day Mortality (%) Rec. Care

I <0.5 Outpatient II <70 0.5-1 Outpatient III 71-90 1-4 Inpatient (brief) IV 91-130 4-10 Inpatient V >130 >10 Inpatient

Fine MJ. NEJM 1997;336:243.

Canadian CAP Clinical Pathway TrialCanadian CAP Clinical Pathway Trial

ED Dx Pneumonia22 hospitals, 1,743 patients

ED Dx Pneumonia22 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 homeStandard careStandard care

Inpatient care - 31%Inpatient care - 31% Inpatient care - 49%Inpatient care - 49%

2 &6 week QOL scores37 & 43

2 &6 week QOL scores37 & 43

2 &6 week QOL scores38 & 41

2 &6 week QOL scores38 & 41

Marrie TJ. JAMA 2000;283:749.Marrie TJ. JAMA 2000;283:749.

US CAP Antimicrobial StrategiesUS 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)

MacrolideDoxycycline

MacrolideDoxycycline

New fluoroquinolones2nd-3rd GC/Macrolide

New fluoroquinolones2nd-3rd GC/Macrolide

Azithromycin 500/250 mg QD (5 d)

Clarithromycin 500 mg BIDDoxycycline 100 mg BID

-lactam (HD amox, amox/clav, ceftriaxone -cefpodoxime /cefuroxime) with aboveLevofloxacin 500 mg QD

Moxifloxacin 400 mg QD Gatifloxacin 400 mg QD

Azithromycin 500/250 mg QD (5 d)

Clarithromycin 500 mg BIDDoxycycline 100 mg BID

-lactam (HD amox, amox/clav, ceftriaxone -cefpodoxime /cefuroxime) with aboveLevofloxacin 500 mg QD

Moxifloxacin 400 mg QD Gatifloxacin 400 mg QD

CAP: Outpatient Treatment in USCAP: Outpatient Treatment in US

Oral regimens10-14 days

Oral regimens10-14 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 failureshigh-riskdocumented DRSP

treatment failureshigh-riskdocumented DRSP

Worldwide OutpatientCAP Guidelines

Worldwide OutpatientCAP Guidelines

Country/Org/YearCountry/Org/Year RecommendationRecommendation

ACEP 2001 See US IDSAUS IDSA 2000 Macrolide or doxycycline or FQCanadian ID/TS 2000 Macrolide or doxycycline

mod. factor – FQUS ATS 2001 “ or BLI+ macrolideFrance 1991 AmoxicillinItaly 1995 BLI + macrolideSpain 1992 Penicillin or erythromycinUK BTS 2001 Amoxicillin HD or macrolide

ACEP 2001 See US IDSAUS IDSA 2000 Macrolide or doxycycline or FQCanadian ID/TS 2000 Macrolide or doxycycline

mod. factor – FQUS ATS 2001 “ or BLI+ macrolideFrance 1991 AmoxicillinItaly 1995 BLI + macrolideSpain 1992 Penicillin or erythromycinUK BTS 2001 Amoxicillin HD or macrolide

CAP: Inpatient Treatment in USCAP: Inpatient Treatment in US

2nd/3rd gen. cephalosporin plus azithro or doxy Levofloxacin 500 mg Q24o

Gatifloxacin 400 mg Q24o

Moxifloxacin 400 mg Q24o

2nd/3rd gen. cephalosporin plus azithro or doxy Levofloxacin 500 mg Q24o

Gatifloxacin 400 mg Q24o

Moxifloxacin 400 mg Q24o

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

FloorFloor ICUICU

Consider vancomycin ifquinolone exposure

Consider vancomycin ifquinolone exposure

3rd gen. ceph plus macrolide 0.66 (0.51-0.86)

Fluoroquinolone only 0.64 (0.36-1.14)

-lactamase inh. plus macrolide 1.61 (1.08-2.39)

3rd gen. cephalosporin only reference

3rd gen. ceph plus macrolide 0.66 (0.51-0.86)

Fluoroquinolone only 0.64 (0.36-1.14)

-lactamase inh. plus macrolide 1.61 (1.08-2.39)

3rd gen. cephalosporin only reference

US Study of Relative 30-Day Mortality by Initial Antibiotic Regimen for CAP

US Study of Relative 30-Day Mortality by Initial Antibiotic Regimen for CAP

Gleason PP. Arch Intern Med 1999;159:2562.Gleason PP. Arch Intern Med 1999;159:2562.

Adjusted hazard ratio (95% CI)Adjusted hazard ratio (95% CI)9,751 patients > 65 yrs, regimen9,751 patients > 65 yrs, regimenwithin 48 hrs of admissionwithin 48 hrs of admission9,751 patients > 65 yrs, regimen9,751 patients > 65 yrs, regimenwithin 48 hrs of admissionwithin 48 hrs of admission

Cystitis Pathogen Antimicrobial Resistance - Seattle 1992-6

Cystitis Pathogen Antimicrobial Resistance - Seattle 1992-6

92 93 94 95 96

AMP

CEPH

NITRO

T/S

CIPRO

%%%%

Gupta K. Gupta K. JAMAJAMA 1999;281:736. 1999;281:736.Gupta K. Gupta K. JAMAJAMA 1999;281:736. 1999;281:736.

10101010

20202020

30303030

40404040

Shift to quinolones/nitrofurantoin/3rd gen. cephs.

Cystitis: Effect of T/S Resistance on Clinical Success in T/S-Treated Patients In Israel

Cystitis: Effect of T/S Resistance on Clinical Success in T/S-Treated Patients In Israel

0

10

20

30

40

50

60

70

80

90

100

Susceptible Resistant

%%

Raz R. Clin Infect Dis 2002;34:1165. (follow-up 4-6 weeks)Raz R. Clin Infect Dis 2002;34:1165. (follow-up 4-6 weeks)

Resistance mattersLow morbidity disease

Resistance mattersLow 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 RegimensThree-Day Cystitis Regimens

Hooton TM. JAMA 1995;273:41.Hooton TM. JAMA 1995;273:41.

% Cure 2 weeks% 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), 3rd 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), 3rd GC Culture if no symptom resolution in 2 days

Therapy for Uncomplicated CystitisTherapy for Uncomplicated Cystitis

Cost-effectiveness modelsupports 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

Acute Uncomplicated Pyelonephritis in US: Cipro 7 Days vs. TMP/SMX 14

Days

0102030405060708090

100

PO +/- IVCipro

PO T/S +/-IV Ceftri-axone

%%

p =.004 99%(113) 89%

(101) 85% (111) 74%

(108)

p =.08

Talan DA. Talan DA. JAMA JAMA 2000;283:1583.Talan DA. Talan DA. JAMA JAMA 2000;283:1583.

91%(106)

77%(106)

96%(113)

83%(111)

p =.002p =.015

4-11 days 22-48 days 4-11 days 22-48 days4-11 days 22-48 days 4-11 days 22-48 days

Bacteriologic cureBacteriologic cure Clinical cureClinical cure

Effect of TMP/SMX Resistance in TMP/SMX-Treated AUP Patients

Effect of TMP/SMX Resistance in TMP/SMX-Treated AUP Patients

0

10

20

30

40

50

60

70

80

90

100

Susceptible Resistant

Bacterio-logiccure

Clinicalcure

%%

92%(76/83)

p < 0.0001 (both) p < 0.0001 (both)

96%(73/76)

50%(7/14)

35%(6/17)

Talan DA. Talan DA. JAMA JAMA 2000;283:1583.Talan DA. Talan DA. JAMA JAMA 2000;283:1583.

Resistance mattersHigh morbidity disease

Resistance mattersHigh morbidity disease

Cost/patient Cipro $510 TMP/SMX $725 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

Outpatient ED Treatment of Acute Uncomplicated Pyelonephritis

Initial PO/IV Dose

Oral regimens

QREC Spain 17% ’96Garau J. AAC 1999;43:2736.

QREC Spain 17% ’96Garau 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 Treatment of Urethritis and Cervicitis

GonorrheaGonorrhea

ChlamydiaChlamydia

Female sex workersBangladesh-GCcervicitis

micro. successCipro susc. (62%) 97.5% Cipro resist. (38%) 8.3 %

Rahman M. Clin Infect Dis 2001;32:884)

Female sex workersBangladesh-GCcervicitis

micro. successCipro susc. (62%) 97.5% Cipro resist. (38%) 8.3 %

Rahman M. Clin Infect Dis 2001;32:884)

Not where QRNGNot where QRNG

Widespread QRNG – SE Asia, India, Israel,othersWidespread QRNG – SE Asia, India, Israel,others

Acute Cellulitis / LymphangitisAcute Cellulitis / Lymphangitis

Kontiainen S. Eur J Clin Microbiol 1987;6 :420.Kontiainen S. Eur J Clin Microbiol 1987;6 :420.

Staphylococcus aureus Streptococcus pyogenes

First-generation cephalosporinsLong acting - ceftriaxoneprobenecid/cefazolinazithromycin/linezolid

Staphylococcus aureus Streptococcus pyogenes

First-generation cephalosporinsLong acting - ceftriaxoneprobenecid/cefazolinazithromycin/linezolid

Canadian Study of Effect of Probenecid on Cefazolin Concentrations

Canadian Study of Effect of Probenecid on Cefazolin Concentrations

0 4 8 12 16 20 24

Cefazolin +Probenecid(1 gr each)

Cefazolin1gr alone10101010

100100100100

1000100010001000

Cef

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lin

(u

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efaz

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efaz

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HoursHoursHoursHours

Brown G. J Antimicrob Chemother 1993;31:1009. Grayson ML. Clin Infect Dis 2002;34:1440.

1111

Now clinically confirmed!

Community-Associated MRSACommunity-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. Naimi TS. Clin Infect DisClin Infect Dis 2001;33:990. 2001;33:990.Naimi TS. Naimi TS. Clin Infect DisClin Infect Dis 2001;33:990. 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 PointsTake Home Points