strategicmanagement of cap and hap caused by fluoroquinolone resistant pathogens

Risk Factors for MDR • High frequency of antibiotic resistance in the community or in the specific hospital unit • Immunosuppressive disease and/or therapy • Likely pathogens – MDR gr

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STRATEGIC MANAGEMENT OF CAP/HAP

CAUSED BY FLUOROQUINOLONE

RESISTANT PATHOGENS

• non smoker, no any chronic disease

– Fever, cough with scant sputum for one day

– Difficulty in taking full breath

businessman

Community Acquired Pneumonia

• Proper management reduces morbidity and cost

Fine MJ, et al Prognosis of CAP; JAMA 1996;275:134-141

Management of CAP

• Choosing the “right” antibiotic

• Respiratory and supportive care

What is the “right”

antibiotic?

• The ‘right’ antibiotic for CAP

– Active against likely etiologies

• What is the most likely etiology?

• What is its antibiotic susceptibility ( or resistant) ?

– Easy to administer

• Oral

• Once a day

– Good bioavailability (easy for i.v to p.o switch)

– No or little side effects

– Cheap

Bartlett JG, et al Guidelines for the management of CAP CID 2000;31:347-82

KEY BACTERIAL PATHOGENS IN CAP

Reimer and Carroll: Clin Infect Dis 26:742-748, 1998

Marrie: Infect Dis Clin North Am 12:723-740,1998.

Bartlett et al: Clin Infect Dis 26:811-838, 1998

Streptococcus pneumoniae is the primary recognized bacterial cause of

community respiratory infections

Etiologies of CAP

– Hundreds of organisms can

cause CAP

• BUT

– The majority of CAP are

caused by a group of few

Community Acquired Pneumonia

• The likely etiology cannot be accurately

predicted from clinical or radiological features.

• Extensive investigations usually not

cost-effective

– In up to 50% of CAP no etiology can be identified– The results always come too late

• Most patients can be treated successfully

without any knowledge of an infecting microorganism.

Bartlett et al: Community-Acquired Pneumonia NEJM 1995;333:1618-1624

Selection of Antibiotics in CAP

• More severe CAP should receive broader coverage

IDSA-ATS Consensus Guidelines on CAP; CID 2007:44 (Suppl 2) S27-S72

Drugs Resistant S pneumoniae is

Antibiotics Selection for CAP in

View of Increasing Drug

Resistance

• Choices

– Single antibiotic

• Respiratory fluoroquinolones

• β lactam ( not active against Mycoplasma, DRSP)

• Macrolides ( DRSP and DR H.flu worrisome)

– Combination

• β lactam + macrolides ( DRSP a problem)

• β lactam + fluoroquinolones ( no more effecive than FQ alone)

IDSA-ATS Consensus Guidelines on CAP; CID 2007:44 (Suppl 2) S27-S72

IDSA/ATS Guidelines: Outpatient

Treatment Recommendations for CAP

• Low risk for MDR

– Macrolides or

– doxycycline

• Increase risk for MDR

– Respiratory fluoroquinolones

Risk Factors for DRSP in Adult Patients With CAP

– Age >65 years

– Alcoholism

– Medical comorbidities

– Immunosuppressive illness or therapy

– Exposure to children in day care

IDSA-ATS Consensus Guidelines on CAP; CID 2007:44 (Suppl 2) S27-S72

IDSA/ATS Guidelines: Inpatient

Treatment Recommendations for CAP

Costs of antibiotic treatment varied

– DM, HT, DLP, CRF, ASHD, COPD, …

– Admitted for CHF requiring assisted ventilation

– Developed fever, purulence sputum, new lung infiltrates on day 4

on ventilator

Second Case

A 71 year old man

Burden of Nosocomial Pneumonia

(USA)

– Approximately 300,000 cases annually

– 10-15 cases per 1,000 admissions

– Up to 20 times more common in

ventilated patients

– Increases hospitalization costs

by up to $40,000 per patient

McEachern R, Campbell GD Infect Dis Clin North Am 1998;12:761-779; George DL Clin Chest Med 1995;1:29-44; Ollendorf D, et al

Poster presented at 41st annual Interscience Conference on Antimicrobial Agents and Chemotherapy September 22-25, 2001 Abstract K-1126; Warren DK, et al Poster presented at 39th annual conference of the Infectious Diseases Society of America October 25-28,

2001 Abstract 829.

Common Nosocomial Pneumonia

C albicans Others

Enterobacter spp

P aeruginosa

K pneumoniae

S aureus

• Late onset (5 days or more)

– A lot more gram negative bacilli

Antibiotic Resistant Bacteria are

Even More Common in HAP

Infect Control Hosp Epidemiol.2013;34(1);1-14

Risk Factors for MDR

• High frequency of antibiotic

resistance in the community or

in the specific hospital unit

• Immunosuppressive disease

and/or therapy

• Likely pathogens

– MDR gram negative bacilli

ATS/IDSA Guidelines Am J Respir Crit Care Med 2005;171:388-416

Critical Issues in the Treatment

of Nosocomial Pneumonia

• Choosing the correct empiric therapy once

nosocomial pneumonia is diagnosed

– Appropriate initial antibiotic therapy is

a vital factor in determining outcome

– Mortality decreases only when appropriate therapy is initiated immediately

– MDR bacteria make choosing

the appropriate empiric therapy difficult

ATS/IDSA Guidelines Am J Respir Crit Care Med 2005;171:388-416

Effect of Appropriate Antibiotic Treatment on Hospital Mortality

– 305 with adequate therapy

– 106 with inadequate therapy

Kollef MH et al Chest 1999;115:462–474.

0 10 20 30 40 50 60

All Hospital Causes

Infection-related Causes

Critical Issues in the Treatment

of Nosocomial Pneumonia

• Not all lung infiltrates are pneumonia

– Inappropriate antibiotics increase super infection

Antibiotics For HAP

Levofloxacin 750 mg Effective for

Early Onset HAP

• High-dose levofloxacin QD vs imipenem/cilastatin 3-4 times a day:

– At least as effective as imipenem/cilastatin for the treatment

of nosocomial pneumonia1,2

– As well tolerated as imipenem/cilastatin therapy1,2

– Showed no unusual or unexpected treatment-emergent AEs1

– Levofloxacin patients received 1 less day of

IV therapy2

1 West M et al Clin Ther 2003;25:485-506;

2 Shorr AF et al Clin Infect Dis 2005;40(suppl 2):S123-S129.

Rational for Combination Antibiotics

for Late Onset HAP

• To provide broader coverage

• Hoping for synergistic or additive action

• May be more effective for mixed infections

Combination Antibiotics in Gram

Negative Infections

• A meta analysis of 17 studies

– Outcome measured : mortality

– Overall odd ratio 0.96

Management Strategies

HAP Suspected (All Disease Severity)

Late Onset (> 5 days) or Risk Factors for Multidrug Resistant (MDR) Pathogens

Empiric Antibiotic Therapy for HAP

ATS/IDSA Guidelines Am J Respir Crit Care Med 2005;171:388-416.

General Principles When

Considering How to De-Escalate

• Identify the organism and know its

susceptibilities

• Assess and potentially modify initial selection

of antibiotics

• Make the decision in the context of patient

progress on the initial regimen

• Individualize the duration of therapy

ATS/IDSA Guidelines Am J Respir Crit Care Med 2005;171:388-416.

• Nosocomial pneumonia:

– Leading causes of death due to infection

– Increase morbidity, mortality, and cost

• Most frequent infecting pathogens:

– Gram-negative bacteria (mostly MDR)

Management of CAP and HAP

• Antibiotic alone is not enough

• Respiratory Care (Most important)

– Controlled oxygen therapy

– Bronchial hygiene

– Ventilatory support

• NIPPV

• Invasive Ventilation

ATS/IDSA Guidelines Am J Respir Crit Care Med 2005;171:388-416

How to slow the development of

bacterial resistance?

• Bacteria resistant to multiple antibiotics are increasing rapidly

• New antibiotics are few and do not keep up

available antibiotics more wisely

CnnD

CDC Features Preventing Antibiotic Resistance Nov 2012

Pharmacodynamic Parameters and Outcome

T > MIC

AUC/MIC

C max /MIC

Beta-lactams Tetracycline Oxazolidinones

Aminoglycosides

Fluoroquinolones Macrolides

Ketolides Glycopeptides

Rebuck JA, Fish DN, Abraham E Pharmacotherapy 2002 Oct; 22(10):1216-25

AUC = area under the curve; C max = maximal plasma concentration after drug dose;

MIC = minimum inhibitory concentration; PAE = post antibiotic effect.

For fluoroquinolones, AUC:MIC predicts microbiologic eradication and clinical efficacy

≥100-125 for Gram-negative rods,

≥ 30 for Gram-positive cocci

Levofloxacin 750 mg Provides Higher Peak Concentrations

*In healthy volunteers who received a single dose.

• Levofloxacin is a concentration- dependent killer

• Increasing dosage

by 50% results in 90% higher peak concentration and 115% higher AUC

• This make it more effective against partially resistant organisms

Peak plasma levels

Mean Levofloxacin Plasma Concentration:

How to use FQ more wisely

• Higher doses of fluoroquinolones

» ? More side effects

Rebuck JA, Fish DN, Abraham E Pharmacotherapy 2002 22(1 0):1 21 6- 25

0 1 2 3 4 5 6 7 8 9 10

750-mg, Short-Course Levofloxacin for CAP: Clinical Success by PSI Class*

Class I/II Class III Class IV

Higher dose, shorter course of

Levofloxacin

– 750 mg/day of levofloxacin for 5 days is at least

as effective as 500 mg/day for 10 days

– There are no more side effects despite the higher doses

– Higher dose, shorter course of levofloxacin

• should improve compliance

• delayed the development of bacterial resistance

• and reduced cost

Dunbar LM, et al Clin Infect Dis 2003;37:752-760

The Management of LRTI

•1 Stratify patients in to subgroups based on risks

and severity instead of etiologies

•2 Pursuing etiologic diagnosis is not always cost

•5 Continuous reevaluation and adjustment of

treatment for each individual patients

ATS/IDSA Guidelines Am J Respir Crit Care Med 2005;171:388-416.