MANAGEMENT OF COMMUNITY ACQUIRED PNEUMONIA IN THE ASIA PACIFIC REGION

MANAGEMENT OF COMMUNITY ACQUIRED PNEUMONIA IN THE ASIA PACIFIC REGION Chong-Kin LIAM Department of Medicine Faculty of Medicine University of Malaya Kuala Lumpur liamck@ummc.edu.my

COMMUNITY ACQUIRED PNEUMONIA A common disorder Annual incidence in USA - 12 per 1000 adults - 25-44 per 1000 in those aged >65 years Marfarlane J. Semin Respir Infect 1994; 9:153-65

COMMUNITY ACQUIRED PNEUMONIA In Japan Annual incidence: 15 per 1000 adults and children Annual incidence requiring hospitalisation: 3.4 per 1000 adults and children 6 th leading cause of death worldwide JRS guidelines (2005). Respirology 2006; 11:S79-S133

CAP: Key Bacterial Pathogens In most studies, Streptococcus pneumoniae is the most commonly identified pathogen followed by Haemophilus influenzae 40% S. pneumoniae H. influenzae 20% Bartlett JG, et al. Clin Infect Dis. 1998;26:811-838; Marrie TJ. Infect Dis Clin North Am. 1998;12:723-740; Reimer LG, Carroll KC. Clin Infect Dis.1998;26:742-748.

CAP: Key Bacterial Pathogens.. and atypical pathogens: Mycoplasma pneumoniae Chlamydophila pneumoniae and Legionella spp. S. pneumoniae H. influenzae 6% 40% Legionella spp. M. pneumoniae Atypical pathogens: 23% 10% 7% 20% C. pneumoniae Bartlett JG, et al. Clin Infect Dis. 1998;26:811-838; Marrie TJ. Infect Dis Clin North Am. 1998;12:723-740; Reimer LG, Carroll KC. Clin Infect Dis.1998;26:742-748.

CAP: Key Bacterial Pathogens Other bacteria include Moraxella catarrhalis, Staphylococcus aureus, Klebsiella spp., and other gram-negative bacilli 1% 16% S. pneumoniae H. influenzae 6% 40% Legionella spp. M. pneumoniae Atypical pathogens: 23% 10% 7% 20% C. pneumoniae M. catarrhalis Others Bartlett JG, et al. Clin Infect Dis. 1998;26:811-838; Marrie TJ. Infect Dis Clin North Am. 1998;12:723-740; Reimer LG, Carroll KC. Clin Infect Dis.1998;26:742-748.

Clinical Practice Guidelines Ambulatory patients Hospitalised patients (non-icu) Severe (ICU) CAP patients are generally categorised into 3 groups outpatients inpatients intensive care patients

IDSA / ATS Consensus Guidelines on the management of CAP in adults. Clin Infect Dis 2007; 44:S27-72 Most common microbial aetiologies of CAP (in the West) Outpatient S. pneumoniae M. pneumoniae H. influenzae C. pneumoniae Respiratory viruses* Influenza A and B, adenovirus, RSV & parainfluenza Inpatient (non-icu) S. pneumoniae M. pneumoniae C. pneumoniae H. influenzae Legionella species Aspiration Respiratory viruses* For all 3 categories of patients, the number one pathogen is pneumococcus Inpatient (ICU) S. pneumoniae Staph. aureus Legionella spp. Enterobacteriaceae spp. Pseudomonas spp. H. Influenzae Ref: File TM. Community-acquired pneumonia. Lancet 2003; 362:1991-2001 [Based on collective data from recent studies]

IDSA / ATS Consensus Guidelines on the management of CAP in adults. Clin Infect Dis 2007; 44:S27-72 Most common microbial aetiologies of CAP (in the West) Outpatient S. pneumoniae M. pneumoniae H. influenzae C. pneumoniae Respiratory viruses* Influenza A and B, adenovirus, RSV & parainfluenza Inpatient (non-icu) S. pneumoniae M. pneumoniae C. pneumoniae H. influenzae Legionella species Aspiration Respiratory viruses* For all 3 categories of patients, the number one pathogen is pneumococcus Atypical pathogens are also prominently represented Inpatient (ICU) S. pneumoniae Staph. aureus Legionella spp. Gram-negative bacilli H. Influenzae Legionella - an important pathogen in patients with severe CAP

Aetiologies of CAP Requiring Hospitalization in Asia 1 Location No. of patients Rank order / Frequency of microbial cause (%) 1 2 3 4 5 Unknown Okayama 1 Ishida T, et al. Chest 1998;114:1588-93 93 326 S pneumoniae 23 H influenzae 7 M pneumoniae 5 K pneumoniae 4 S milleri 4 39 Okayama 2 3 hospitals Miyashita N, et al. Chest 2000;119:1295-6 200 S pneumoniae 21 H influenzae 11 M pneumoniae 10 C pneumoniae 8 S aureus 5 42 Korea 3 Woo JH, et al. Korean J Infect Dis 2001, 33:1-7 562 (588 cases) S pneumoniae 22 K pneumoniae 15 Ps aeruginosa 10 S aureus 10 S viridans 6 62 Hong Kong 4 CHS Chan, et al. Chest 1992;101:442-6 90 M tuberculosis 12 S pneumoniae 12 Chlamydia spp 6 Viral 6 H influenzae 4 59 The aetiology of CAP in Japan is quite similar to that of Western countries High incidence of infection by Gram ve bacilli Infection due to M tuberculosis may commonly present as CAP in countries with a high prevalence of TB

Aetiologies of CAP Requiring Hospitalization in Asia 2 Location Khon Kaen 5 Reechaipichitkul W, et al. Southeast Asian J Trop Med Public Health 2005; 36:156-61 61 Bangkok 5a 3 hospitals Wattanathum, et al. Chest 2003;123:1512-9 Singapore 6 Hui KP, et al. Singapore Med J 1992;101:442-6 No. of patients 254 147 96 Rank order / Frequency of microbial cause (%) 1 2 3 4 5 Unknown S pneumoniae 11 S pneumoniae 22 M tuberculosis 21 B pseudomallei 11 1.4% in Bangkok 5a Gram -ve bacilli 18 (K. pneum 10) S pneumoniae 12 K pneumoniae 10 C. pneumoniae 16 Gram -ve bacilli 10 M pneumoniae 9 M pneumoniae 7 H influenzae 5 C pneumoniae 4 L pneumophila 5 29 M pneumoniae 5 43 42 K. Lumpur 7 Liam CK, et al. Respirology 2001;6:259-64 64 127 K pneumoniae 10 S pneumoniae 6 H influenzae 6 M pneumoniae 4 Ps aeruginosa 4 58 Penang 8 Hooi LN, et al. Med J Malaysia 2001;56:275-83 98 M tuberculosis 15 K pneumoniae 7 Ps aeruginosa 6 S aureus 5 S pneumoniae Studies in Singapore and Malaysia (countries with a high prevalence of TB) also show pulmonary TB commonly presents as CAP 3 57

Aetiologies of CAP Requiring Hospitalization in Asia 3 Location Khon Kaen 5 Reechaipichitkul W, et al. Southeast Asian J Trop Med Public Health 2005; 36:156-61 61 Bangkok 5a 3 hospitals Wattanathum, et al. Chest 2003;123:1512-9 Singapore 6 Hui KP, et al. Singapore Med J 1992;101:442-6 No. of patients 254 147 96 Rank order / Frequency of microbial cause (%) 1 2 3 4 5 Unknown S pneumoniae 11 S pneumoniae 22 M tuberculosis 21 B pseudomallei 11 1.4% in Bangkok 5a Gram -ve bacilli 18 (K. pneum 10) S pneumoniae 12 K pneumoniae 10 C. pneumoniae 16 Gram -ve bacilli 10 M pneumoniae 9 M pneumoniae 7 H influenzae 5 C pneumoniae 4 L pneumophila 5 29 M pneumoniae 5 43 42 K. Lumpur 7 Liam CK, et al. Respirology 2001;6:259-64 64 127 K pneumoniae 10 S pneumoniae 6 H influenzae 6 M pneumoniae 4 Ps aeruginosa 4 58 K. Lumpur 9 Liam CK, et al. Respirology 2006;11:786-92 346 K pneumoniae 11 M pneumoniae 9 L pneumophila 6 M tuberculosis 5 S pneumoniae Studies in Singapore and Malaysia (countries with a high prevalence of TB) also show pulmonary TB commonly presents as CAP 4 53

Location Aetiologies of Severe CAP Requiring ICU Admission United Kingdom (4 studies) Other parts of Europe (10 studies) Singapore NUH Lee KH, Lee KH, et al. Singapore Med J 1996;37:374-77 77 Singapore SGH Tan YK, Tan YK, et al. Eur Respir J 1998;12:113-15 15 Khon Kaen Reechaipichitkul W, et al.southeast Asian J Trop Med Public Health 2004;35:430-3 No. of patients 185 1148 59 57 105 Rank order / Frequency of microbial cause (%) 1 2 3 4 5 Unknown S pneumoniae 22 S pneumoniae 22 K pneumoniae 15 B pseudomallei 18 B pseudomallei 29 Legionella spp 18 Gram ve enteric bacilli 9 H influenzae 8 M tuberculosis 16 S pneumoniae 21 Patients who met ATS criteria for severe CAP Viruses 10 S aureus 7 S aureus 7 Klebsiella spp 9 K pneumoniae 19 S aureus 9 C pneumoniae 7 B pseudomallei 7 S aureus 9 H influenzae 12 Influenza A & B 5 32 Legionella spp 6 43 S pneumoniae 5 32 M pneumoniae 7 28 S aureus 6 41 91.4% of patients had co-morbidity, most common was diabetes mellitus; Mortality: 21%

Location Aetiologies of Severe CAP Requiring ICU Admission No. of patients Rank order / Frequency of microbial cause (%) 1 2 3 4 5 Unknown S pneumoniae Legionella spp Viruses S aureus Influenza A Burkholderia pseudomallei should be considered a & B United Kingdom 185 (4 studies) causative 22 organism 18 in patients 10 with 9severe CAP 5 32 Other parts of Europe (10 studies) Singapore NUH Lee KH, Lee KH, et al. Singapore Med J 1996;37:374-77 77 Singapore SGH Tan YK, Tan YK, et al. Eur Respir J 1998;12:113-15 15 Khon Kaen Reechaipichitkul W, et al.southeast Asian J Trop Med Public Health 2004;35:430-3 1148 59 57 S pneumoniae 22 K pneumoniae 15 B pseudomallei 18 in Gram Southeast ve S aureus Asia C pneumoniae enteric bacilli 9 H influenzae 8 M tuberculosis 16 7 S aureus 7 Klebsiella spp 9 7 B pseudomallei 7 S aureus 9 Legionella spp particularly if the patient has diabetes mellitus 105 B pseudomallei 29 S pneumoniae 21 K pneumoniae 19 H influenzae 12 6 43 S pneumoniae 5 32 M pneumoniae 7 28 S aureus 6 41

Location Nova Scotia 1 Marrie TJ, et al. Am J Med 1996;101:508-15 15 Argentina Erard PH, et al. Am Soc Microbiol 1991;108:56A Lausanne Bochud PY, et al. Medicine 2001;80:752-87 87 Aetiologies of CAP treated on an ambulatory basis No. of patients 149 54 170 Rank order / Frequency of microbial cause (%) 1 2 3 4 5 Unknown M pneumoniae 23 S pneumoniae 13 S pneumoniae 23 C pneumoniae 11 M pneumoniae 7 M pneumoniae 14 M pneumoniae & C pneumoniae 3 C pneumoniae 4 Influenza virus 12 Influenza A 3 Influenza A 4 C pneumoniae 5 C burnetii 3 48 Cryptococcus spp 4 65 C burnetii 2 46 Finland Jokinen C, et al. Clin Infect Dis 2001;15:1141-54 54 169 S pneumoniae 37 M pneumoniae 14 Chlamydiae 9 Viruses 8 H influenzae 4 45 Bangkok 3 hospitals Wattanathum, et al. Chest 2003;123:1512-9 Japan 3 hospitals (Okayama) Miyashita N, et al. J Med Microbiol 2005; 54:395-400 400 98 106 C pneumoniae 37 M pneumoniae 27 M pneumoniae 30 S pneumoniae 12 S pneumoniae 13 C pneumoniae 11 L pneumophila 8 H influenzae 5 Mixed infection 13 Viruses 2 M catarrhalis 2 25 47

AsiA-CAP Study Ngeow YF, et al. Int J Infect Dis 2005 May;9:144-53 Results from 1374 patients with paired sera showed infection rates for Mycoplasma pneumoniae 12.2% Chlamydophila pneumoniae 4.7% Legionella pneumophila 6.6% Overall infection rate by atypical respiratory pathogens = 23.5%

Severity Assessment The key to deciding initial site of care Outpatient Medical ward Critical care ward / ICU Severity assessment is made on the basis of prognostic criteria: patients age comorbidities physical, laboratory and radiographic findings

Severity assessment & Prognostication Severity of illness score (e.g., CURB-65) Prognostic models (e.g., PSI) can be used to identify patients who may be treated as outpatients (Strong recommendation; level I evidence) IDSA / ATS Consensus Guidelines on the management of CAP in adults. Clin Infect Dis 2007; 44:S27-72

Severity Assessment Pneumonia Severity Index (PSI) Requires computation of a score based on 20 variables Fine MJ, et al. A prediction rule to identify low-risk patients with CAP. N Engl J Med 1997;336:243-50

Severity Assessment Pneumonia Severity Index (PSI) stratifies patients into 5 mortality risk classes: Risk Risk class Score 30-day mortality Low I No predictors 0.1% Low II < 70 0.6% Low III 71 90 0.9% Moderate IV 91 130 9.3% High V > 130 27.0% Fine MJ, et al. A prediction rule to identify low-risk patients with CAP. N Engl J Med 1997;336:243-50

Severity Assessment Pneumonia Severity Index (PSI) On the basis of associated mortality rates, patients in Risk class 30-day mortality I 0.1% II 0.6% III 0.9% IV 9.3% V 27.0% Treat as outpatients Treat in an observation unit or short hospitalisation Treat as inpatients Fine MJ, et al. A prediction rule to identify low-risk patients with CAP. N Engl J Med 1997;336:243-50

Severity Assessment CURB-65 score (6-point) adopted by BTS Score 1 point for each feature present Confusion Urea > 7 mmol/l Respiratory rate > 30/min Blood pressure (SBP < 90 mmhg or DBP < 60 mmhg) Age > 65 yrs Lim WS, et al. Thorax 2003;58:377-382

CURB-65 score Risk of mortality Score 0 0.7% Score 1 3.2% Recommendations Patients who have a CURB-65 score of 0 or 1 are at low risk of death - can be treated as having non-severe pneumonia and may be suitable for home treatment Score 2 13% Score 3 17% Score 4 41.5% Score 5 57% At increased risk of death - should be considered for short stay inpatient treatment or hospital supervised outpatient treatment (use clinical judgement) Patients who have a CURB-65 score of 3 or more are at high risk of death and should be managed as severe pneumonia Lim WS, et al. Thorax 2003;58:377-382

There is growing evidence that CURB, CURB-65 and CRB-65 all allow for similar predictions of death from CAP as compared to the PSI

A prospective observational study of 1016 consecutive inpatients with CAP in an Emergency Department mean (SD) age: 72 (+ 17) yrs The ability of the three rules to predict 30 day mortality was compared Yan Man S, et al. Prospective comparison of 3 predictive rules (PSI, CURB-65, CRB-65) for assessing severity of CAP (and to predict 30-day mortality) in Hong Kong. Thorax 2007; 62: 348-53

PSI class 30-day mortality (%) I 0 II 0.8 III 5 IV 9.3 V 22.1 CURB-65 0 0.9 1 3.6 2 7.3 3 16.4 4 26.6 5 37.5 CRB-65 0 2.3 1 5.1 2 11.2 3 23.2 All 3 predictive rules showed the same trend of increasing mortality with worsening risk groups (p <0.001) 4 40 Yan Man S, et al. Prospective comparison of 3 predictive rules for assessing severity of CAP in Hong Kong. Thorax 2007; 62: 348-53

Sensitivity, specificity, positive and negative predictive values of 30 day mortality of the different predictive rules All 3 clinical decision rules had high negative predictive values but low positive predictive values at all cut-off points and are therefore more useful in ruling out serious illness Yan Man S, et al. Prospective comparison of 3 predictive rules for assessing severity of CAP in Hong Kong. Thorax 2007; 62: 348-53

Sensitivity, specificity, positive and negative predictive values of 30 day mortality of the different predictive rules PSI : complicated computation of a score may not be practical for routine application in busy hospital emergency departments or primary care settings CURB-65 : simpler to apply CRB-65 : is also easily applicable in primary care settings All 3 clinical decision rules had high negative predictive values but low positive predictive values at all cut-off points and are therefore more useful in ruling out serious illness Yan Man S, et al. Prospective comparison of 3 predictive rules for assessing severity of CAP in Hong Kong. Thorax 2007; 62: 348-53

ICU admission rates also increased with the risk levels of each rule, but were only statistically significant in CURB-65 and CRB-65 Yan Man S, et al. Prospective comparison of 3 predictive rules for assessing severity of CAP in Hong Kong. Thorax 2007; 62: 348-53

Sensitivity and specificity for high-risk group of the 3 predictive rules in identifying ICU admission Sensitivity (%) Specificity (%) PSI 29.3 82.7 CURB-65 41.5 75.0 CRB-65 24.4 90.3 Because of their low sensitivities, none of the 3 rules appears to be useful for identifying patients requiring ICU care Modified ATS 90.2 59.1 rule Ewig S, et al. Severe CAP: assessment of severity criteria. Am J Respir Crit Care Med 1998;158:1102 8. Yan Man S, et al. Prospective comparison of 3 predictive rules for assessing severity of CAP in Hong Kong. Thorax 2007; 62: 348-53

Sensitivity and specificity for high-risk group of the 3 predictive rules in identifying ICU admission Sensitivity (%) Specificity (%) PSI 29.3 82.7 CURB-65 41.5 75.0 CRB-65 24.4 90.3 Although far from being perfect, the modified American Thoracic Society score is currently the best tool in identifying Because of their low sensitivities, none of the 3 rules appears to be useful for identifying patients requiring patients ICU for care ICU admission Modified ATS 90.2 59.1 rule Ewig S, et al. Severe CAP: assessment of severity criteria. Am J Respir Crit Care Med 1998;158:1102 8. Yan Man S, et al. Prospective comparison of 3 predictive rules for assessing severity of CAP in Hong Kong. Thorax 2007; 62: 348-53

Site-of-care decisions 1 Prediction rules give an indication of disease severity Prediction rules have not been found to be useful in predicting ICU admission Generally, patients of higher risk classes have higher rates of ICU admission Unlike 30 day mortality, the association is not strong enough to allow for individual predictions and decisions Criteria for ICU admission vary from country to country and from hospital to hospital Criteria for ICU admission: disease severity is not the only factor to consider; other factors to consider: disease prognosis, pre-morbid status, age of patient, and the availability of ICU resources

Site-of-care decisions 2 All predictive rules serve only as a guide to clinical management Severity of illness is not the only factor to be considered when deciding on admission Social and home circumstances must be considered as well Physicians should always exercise clinical judgment and common sense in making these decisions

Criteria for severe CAP Major criteria Need for mechanical ventilation Septic shock requiring vasopressors 2007 IDSA / ATS Consensus Guidelines

Criteria for severe CAP Major criteria Need for mechanical ventilation Septic shock requiring vasopressors Minor criteria Respiratory rate >30 breaths/min PaO 2 /FiO 2 ratio <250 Multilobar infiltrates Confusion/disorientation Uraemia (BUN level, >20 mg/dl) Leukopenia (WBC count, <4 x 10 9 /L) Thrombocytopenia (platelet count, <100 x 10 9 /L) Hypothermia (core temperature, <36ºC) Hypotension requiring aggressive fluid resuscitation 2007 IDSA / ATS Consensus Guidelines

ICU admission decision Direct admission to an ICU is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring intubation and mechanical ventilation (Strong recommendation; level II evidence) Direct admission to an ICU or high-level monitoring unit is recommended for patients with 3 of the minor criteria for severe CAP (Moderate recommendation; level II evidence) Mandell LA, et al. IDSA / ATS Consensus Guidelines on the management of CAP in adults. Clin Infect Dis 2007; 44:S27-72

ICU admission decision Direct admission to an ICU is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring intubation and mechanical ventilation (Strong recommendation; level II evidence) Direct admission to an ICU or high-level monitoring unit is recommended for patients with 3 of the minor criteria for severe CAP (Moderate recommendation; level II evidence) This recommendation requires prospective validation Mandell LA, et al. IDSA / ATS Consensus Guidelines on the management of CAP in adults. Clin Infect Dis 2007; 44:S27-72

Effects of antibiotic administration within 4 hrs of arrival at the hospital on in-hospital & 30-day mortality * 18 16 14 12 10 8 6 4 2 0 OR:0.86 OR:0.62 Hosp Fine II-III Hospital IV-V 30 days Fine II- III OR:0.87 30 days Fine IV-V < 4h > 4 h *In Medicare patients older than 65 yrs who had not received pre-hospital antibiotic therapy (n = 13,771) Houck PM, et al. A retrospective study on Medicare patients. Arch Intern Med 2004;164:637 44

Effects of antibiotic administration within 4 hrs of arrival at the hospital on in-hospital & 30-day mortality * OR:0.87 15% 18 reduction in both in-hospital and 30-day mortality 16 14 12 10 8 6 4 2 0 OR:0.86 OR:0.62 Hosp Fine II-III Hospital IV-V 30 days Fine II- III 30 days Fine IV-V < 4h > 4 h *In Medicare patients older than 65 yrs who had not received pre-hospital antibiotic therapy (n = 13,771) Houck PM, et al. A retrospective study on Medicare patients. Arch Intern Med 2004;164:637 44

Treat early Initiation of antimicrobial therapy within 4 hrs of arrival at the hospital was associated with a 0.4 day shorter mean LOS Houck PM, et al. A retrospective study on Medicare patients. Arch Intern Med 2004; 164:637-44

Guidelines for managing CAP Principles of empirical therapy Treat early Initiation of antimicrobial therapy within 4 hrs of arrival at the hospital was associated with a 0.4 day shorter mean LOS Houck PM, et al. A retrospective study on Medicare patients. Arch Intern Med 2004; 164:637-44 In the 2003 IDSA guidelines (also JRS guidelines 2005), initiating antibiotic therapy within 4 hrs after registration for hospitalised patients was a performance indicator 2007 IDSA / ATS Consensus Guidelines: Rather than designating a specific window in which to initiate treatment, hospitalized patients with CAP should receive the first antibiotic dose in the ED

Guidelines for managing CAP Principles of empirical therapy Treat early Cannot reliably differentiate aetiology based on clinical and radiological findings

Guidelines for managing CAP Principles of empirical therapy Treat early Cannot reliably differentiate aetiology based on clinical and radiological findings Treat the most likely pathogens S. pneumoniae (?DRSP*); H. influenzae Atypicals Others (co-morbidity and local epidemiology)

Antibiotic Resistance Issues Resistance to commonly used antibiotics for CAP is major consideration in choosing empirical therapy Resistance patterns vary by geography Therefore, antibiotic recommendations must be modified based on local susceptibility patterns

Mandell Mandell LA, LA, et et al. al. IDSA IDSA // ATS ATS Consensus Consensus Guidelines. Guidelines. Clin ClinInfect Dis Dis2007; 44:S27-72 44:S27-72 American American Thoracic Thoracic Society Society Guidelines Guidelines Am Am J J Respir RespirCrit CritCare Care Med Med2001; 163:1730-54 163:1730-54 Risk factors for infection with -resistant Streptococcus pneumoniae Age <2 yrs or >65 yrs therapy within the previous 3 months Alcoholism Medical comorbidities Immunosuppressive illness or therapy Exposure to a child in a day care centre Probably related to greater exposure to antibiotics among these categories of individuals and increased selection of antibiotic-resistant strains Mandell LA, et al. IDSA / ATS Consensus Guidelines on the management of CAP in adults. Clin Infect Dis 2007; 44:S27-72

Risk factors for infection with -resistant Streptococcus pneumoniae Age <2 yrs or >65 yrs therapy within the previous 3 months Alcoholism Medical Recent treatment comorbidities with antimicrobials - the most significant: Immunosuppressive illness or therapy Exposure Recent therapy to a or child repeated in a courses day care of therapy centrewith s, macrolides,, or fluoroquinolones are risk factors for pneumococcal resistance to the same class of antibiotic Mandell LA, et al. IDSA / ATS Consensus Guidelines on the management of CAP in adults. Clin Infect Dis 2007; 44:S27-72

Prevalence of penicillin-resistant S. pneumoniae* in 12 Asian countries (1996-1997 1997 and 2000-2001) 2001) Asian Network for Surveillance of Resistant Pathogens (ANSORP) China (Beijing, Shanghai) 9.8% 19.8% 0% 23.4% Vietnam 28.2% 20.6% Saudi Arabia 32.6% 71.4% NA 20.5% NA 10.3% India 3.8% 7.8% 0% 0% Thailand 35.7% 26.9% 22.2% 26.9% Penicillin-intermediate intermediate (MIC 0.12 1 1 mg/l) Penicillin-resistant (MIC 2 mg/l) Malaysia 6.0% 9.1% 3.0% 29.5% Hong Kong NA 24.1% NA 43.8% South Korea 24.3% 9.7% 55.4% 54.8% * Clinical isolates Taiwan 9.3% 24.6% 29.4% 38.6% Philippines NA 27.3% NA 0% Singapore 4.9% 28.6 % 18.2 % 17.1% Song JH, et al. ANSORP. Antimicrob Agents Chemother June 2004; 48:2101-7

Prevalence of penicillin-resistant S. pneumoniae* in 12 Asian countries (1996-1997 1997 and 2000-2001) 2001) Asian Network for Surveillance of Resistant Pathogens (ANSORP) China (Beijing, Shanghai) South Korea 9.8% 19.8% 24.3% 9.7% 0% 23.4% 55.4% 54.8% Vietnam 28.2% 20.6% Taiwan Saudi Arabia 32.6% 71.4% 9.3% 24.6% NA 20.5% Hong Kong 29.4% 38.6% NA 10.3% India NA 24.1% 3.8% 7.8% Philippines NA 43.8% 0% 0% NA 27.3% and 29.4% were penicillin-resistant NA 0% Thailand 35.7% 26.9% Singapore 22.2% 26.9% IDSA / ATS Consensus Guidelines on the management of CAP in adults. CID 4.9% 2007; 28.6 44:S27-72 % 18.2 % 17.1% The available data suggest that the clinically relevant level of Malaysia penicillin resistance 6.0% is 9.1% a MIC of at least 4 mg/l 3.0% 29.5% Penicillin-intermediate intermediate (MIC 0.12 1 1 mg/l) Penicillin-resistant (MIC 2 mg/l) * Clinical isolates Overall, 23% of S pneumoniae isolates were penicillin-intermediate Feikin DR,, et al. Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995 1997. Am J Public Health 2000; 90:223 9. Song JH, et al. ANSORP. Antimicrob Agents Chemother June 2004; 48:2101-7

Prevalence of resistance of S. pneumoniae to other s and erythromycin in Asia Jan 2000 Jun 2001 China (Beijing, Shanghai) Co-amoxiclav 2.7%, 7.3% Cefuroxime 4.5%, 19.8% Ceftriaxone 0.0%, 1.1% Erythromycin 0.9%, 73.9% South Korea Co-amoxiclav 6.5%, 9.7% Cefuroxime 3.2%, 61.3% Ceftriaxone 3.2%, 3.2% Erythromycin 0.0%, 80.6% Jun 2001 ANSORP Taiwan Co-amoxiclav 3.5%, 1.8% Cefuroxime 8.8%, 40.4% Ceftriaxone 1.8%, 0.0% Erythromycin 1.8%, 86.0% Vietnam Co-amoxiclav 14.3%, 22.2% Cefuroxime 4.8%, 74.2% Ceftriaxone 9.5%, 3.2% Erythromycin 1.6%, 92.1% Hong Kong Co-amoxiclav 0.9%, 3.6% Cefuroxime 10.0%, 50.0% Ceftriaxone 3.7%, 0.0% Erythromycin 0.0%, 76.8% Intermediate Resistant Song JH, et al. ANSORP. Antimicrob Agents Chemother June 2004; 48:2101-7

Prevalence of resistance of S. pneumoniae to other s and erythromycin in Asia Jan 2000 Jun 2001 Jun 2001 ANSORP Saudi Arabia Co-amoxiclav 0.0%, 0.0% Cefuroxime 2.6%, 12.8% Ceftriaxone 0.0%, 0.0% Erythromycin 0.0%, 10.3% India Co-amoxiclav 0.0%, 0.0% Cefuroxime 0.0%, 1.3% Ceftriaxone 0.0%, 0.0% Erythromycin 0.0%, 1.3% Thailand Co-amoxiclav 0.0%, 0.0% Cefuroxime 1.9%, 36.5% Ceftriaxone 1.9%, 0.0% Erythromycin 5.8%, 36.5% Intermediate Resistant Malaysia Co-amoxiclav 2.3%, 0.0% Cefuroxime 2.3%, 29.5% Ceftriaxone 0.0%, 2.3% Erythromycin 6.8%, 34.1% Singapore Co-amoxiclav 0.0%, 0.0% Cefuroxime 5.7%, 28.6% Ceftriaxone 0.0%, 0.0% Erythromycin 2.9%, 40.0% Philippines Co-amoxiclav 0.0%, 0.0% Cefuroxime 0.0%, 0.0% Ceftriaxone 0.0%, 0.0% Erythromycin 4.5%, 18.2% Song JH, et al. ANSORP. Antimicrob Agents Chemother June 2004; 48:2101-7

Susceptibilities of S. pneumoniae isolates to fluoroquinolones in 11 Asian countries Jan 2000 Jan 2000 Jun 2001 China (Beijing, Shanghai) South Korea Taiwan Levofloxacin 0.0%, 0.0% Levofloxacin 0.0%, 0.0% Levofloxacin 0.0%, 1.8% Gatifloxacin 0.0%, 0.0% Gatifloxacin 0.0%, 0.0% Gatifloxacin 1.8%, 1.8% Moxifloxacin 0.0%, 0.0% Moxifloxacin 0.0%, 0.0% Moxifloxacin 1.8%, 0.0% Ciprofloxacin 3.6% Ciprofloxacin 6.5% Ciprofloxacin 7.0% Saudi Arabia India Hong Kong Levofloxacin 0.0%, 0.0% Levofloxacin 0.0%, 1.3% Levofloxacin 0.0%, 8.0% Gatifloxacin 0.0%, 0.0% Gatifloxacin 0.0%, 1.4% Gatifloxacin 0.9%, 8.3% Moxifloxacin 0.0%, 0.0% Moxifloxacin 1.3%, 0.0% Ciprofloxacin Moxifloxacin 6.3%, 1.8% 2.6% Ciprofloxacin 4.0% Ciprofloxacin 11.8% Thailand Vietnam Philippines Levofloxacin 0.0%, 0.0% Levofloxacin 0.0%, 0.0% Levofloxacin 0.0%, 0.0% Gatifloxacin 0.0%, 0.0% Gatifloxacin 0.0%, 0.0% Gatifloxacin 0.0%, 0.0% Moxifloxacin 0.0%, 0.0% Moxifloxacin 0.0%, 0.0% Moxifloxacin 0.0%, 0.0% Ciprofloxacin 3.8% Ciprofloxacin 4.8% Ciprofloxacin 9.1% Malaysia Singapore Levofloxacin 0.0%, 0.0% Levofloxacin 2.9%, 0.0% Gatifloxacin 0.0%, 0.0% Gatifloxacin 0.0%, 0.0% Moxifloxacin 0.0%, 0.0% Moxifloxacin 0.0%, 0.0% Intermediate Ciprofloxacin 4.6% Ciprofloxacin 5.9% Resistant Song JH, et al. ANSORP. Antimicrob Agents Chemother June 2004; 48:2101-7

Multi-drug resistant S pneumoniae classes of antibiotics) in 12 Asian countries Jan 2000 pneumoniae (i.e., resistance to at least 3 Jan 2000 Jun 2001 Overall rate of multi-drug resistant S pneumoniae was 26.8% MDR S pneumoniae : 71.4% of isolates from Vietnam 44.9% of isolates from Hong Kong 42.5% of isolates from Korea 30.9% of isolates from Taiwan Song JH, et al. ANSORP. Antimicrob Agents Chemother 2004; 48:2101-7

e of ce to e ed ished ses tive am.e., oses a e is a sted ccal vitro, es. Drug-resistant resistant S. pneumoniae (DRSP) The clinical relevance of DRSP for pneumonia is uncertain Current levels of resistance do not generally result in CAP treatment failures when appropriate agents (amoxicillin, ceftriaxone, or cefotaxime) and doses are used (even in bacteremia) There are data to suggest that resistance to macrolides and older FQs (ciprofloxacin and levofloxacin) results in clinical failure To date, no failures have been reported for the newer fluoroquinolones (moxifloxacin and gemifloxacin) Mandell LA, et al. IDSA / ATS Consensus Guidelines on the management of CAP in adults. Clin Infect Dis 2007; 44:S27-72

ERS, ATS 2001, IDSA 2003, IDSA/ATS 2007 algorithm for CAP CAP Outpatient treatment Inpatient treatment No cardiopulmonary disease History of cardiopulmonary disease Mild to moderate illness Severe CAP No modifiers +/- modifiers Risks for Ps aeruginosa No C/P disease No Modifier + C/P disease +/or Modifier Yes No

CAP: empirical antibiotic therapy IDSA/ATS 2007 Empirical antibiotic recommendations have not changed significantly from those of previous guidelines IDSA / ATS Consensus Guidelines on the management of CAP in adults. Clin Infect Dis 2007; 44:S27-72

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Inpatient, non-icu Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [strong recommendation, level 1 evidence] or Doxycycline III [weak recommendation,, level 3 evidence] ICU Mandell LA, et al. Clin Infect Dis 2007; 44:S27-72

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [level 1 evidence] or Doxycycline III [level 3 evidence] Presence of comorbidities or antimicrobial use within previous 3 mths or other risks for DRSP infection Respiratory FQ I or + macrolide I Inpatient, non-icu Comorbidities: chronic heart, lung, liver or renal disease; diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressing conditions or use of immunosuppressive drugs Use of antimicrobials within the previous 3 months: an alternative from a different class should be selected ICU Increase the likelihood of infection with DRSP and enteric gramnegative bacteria Mandell LA, et al. Clin Infect Dis 2007; 44:S27-72

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [level 1 evidence] or Doxycycline III [level 3 evidence] Presence of comorbidities or antimicrobial use within previous 3 mths or other risks for DRSP infection Respiratory FQ I or + macrolide I In regions with high rate (>25%) of infection with high-level (MIC >16 µg/ml) macrolide-resistant S. pneumoniae Respiratory FQ III or + macrolide III Inpatient, non-icu Respiratory FQ alone I or + macrolide I ICU The major discriminating factor between the 2 regimens is the patient s prior antibiotic exposure (within the past 3 months). Preferred s include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients Mandell LA, et al. Clin Infect Dis 2007; 44:S27-72

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [level 1 evidence] or Doxycycline III [level 3 evidence] Presence of comorbidities or antimicrobial use within previous 3 mths or other risks for DRSP infection Respiratory FQ I or + macrolide I In regions with high rate (>25%) of infection with high-level (MIC >16 µg/ml) macrolide-resistant S. pneumoniae Respiratory FQ III or + macrolide III Inpatient, non-icu Respiratory FQ alone I or + macrolide I ICU Preferred s include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients Mandell LA, et al. Clin Infect Dis 2007; 44:S27-72

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [level 1 evidence] or Doxycycline III [level 3 evidence] Presence of comorbidities or antimicrobial use within previous 3 mths or other risks for DRSP infection Respiratory FQ I or + macrolide I In regions with high rate (>25%) of infection with high-level (MIC >16 µg/ml) macrolide-resistant S. pneumoniae Respiratory FQ III or + macrolide III Inpatient, non-icu Respiratory FQ alone I or + macrolide I ICU Preferred s include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients Doxycycline is an alternative to the macrolide [level III evidence] Mandell LA, et al. Clin Infect Dis 2007; 44:S27-72

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [level 1 evidence] or Doxycycline III [level 3 evidence] Presence of comorbidities or antimicrobial use within previous 3 mths or other risks for DRSP infection Respiratory FQ I or + macrolide I In regions with high rate (>25%) of infection with high-level (MIC >16 µg/ml) macrolide-resistant S. pneumoniae Respiratory FQ III or + macrolide III Inpatient, non-icu Respiratory FQ alone I or + macrolide I For penicillin-allergic patients Respiratory FQ I ICU Mandell LA, et al. Clin Infect Dis 2007; 44:S27-72

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [level 1 evidence] or Doxycycline III [level 3 evidence] Presence of comorbidities or antimicrobial use within previous 3 mths or other risks for DRSP infection Respiratory FQ I or + macrolide I In regions with high rate (>25%) of infection with high-level (MIC >16 µg/ml) macrolide-resistant S. pneumoniae Respiratory FQ III or + macrolide III Inpatient, non-icu Respiratory FQ I or + macrolide I For penicillin-allergic patients Respiratory FQ I ICU For all patients admitted to the ICU, coverage for S. pneumoniae and Legionella species should be ensured by using a potent antipneumococcal and either a macrolide or a FQ Mandell LA, et al. Clin Infect Dis 2007; 44:S27-72

IDSA / ATS Consensus Guidelines on the management of CAP in adults. Clin Infect Dis 2007; 44:S27-72 Most common microbial aetiologies of CAP Outpatient S. pneumoniae M. pneumoniae H. influenzae C. pneumoniae Respiratory viruses Inpatient (non-icu) S. pneumoniae M. pneumoniae C. pneumoniae H. influenzae Legionella species Aspiration Respiratory viruses Inpatient (ICU) S. pneumoniae Legionella spp. H. Influenzae Enterobacteriaceae spp. Staph. aureus Pseudomonas spp. A review of 9 recent studies (that included 890 patients with CAP admitted to the ICU): the most common pathogens in the ICU population were (in descending order of frequency) S. pneumoniae, Legionella species, H. influenzae, Enterobacteriaceae species, S. aureus, and Pseudomonas species. The atypical pathogens collectively account for 20% of severe CAP episodes. The dominant atypical pathogen in severe CAP is Legionella. File TM. Community-acquired pneumonia. Lancet 2003; 362:1991-2001

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [level 1 evidence] or Doxycycline III [level 3 evidence] Presence of comorbidities or antimicrobial use within previous 3 mths or other risks for DRSP infection Respiratory FQ I or + macrolide I In regions with high rate (>25%) of infection with high-level (MIC >16 µg/ml) macrolide-resistant S. pneumoniae Respiratory FQ III or + macrolide III Inpatient, non-icu Respiratory FQ I or + macrolide I For penicillin-allergic patients Respiratory FQ I ICU The recommended standard empirical regimen should routinely cover the 3 most common pathogens that cause severe CAP, all of the atypical pathogens, and most of the relevant Enterobacteriaceae species. Mandell LA, et al. Clin Infect Dis 2007; 44:S27-72

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [level 1 evidence] or Doxycycline III [level 3 evidence] Presence of comorbidities or antimicrobial use within previous 3 mths or other risks for DRSP infection Respiratory FQ I or + macrolide I In regions with high rate (>25%) of infection with high-level (MIC >16 µg/ml) macrolide-resistant S. pneumoniae Respiratory FQ III or + macrolide III Inpatient, non-icu Respiratory FQ I or + macrolide I For penicillin-allergic patients Respiratory FQ I * cefotaxime, ceftraxone, ampicillin/sulbactam, ICU * + azithromycin II or * + respiratory FQ I Mandell LA, et al. Clin Infect Dis 2007; 44:S27-72

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [level 1 evidence] or Doxycycline III [level 3 evidence] Presence of comorbidities or antimicrobial use within previous 3 mths or other risks for DRSP infection Respiratory FQ I or + macrolide I In regions with high rate (>25%) of infection with high-level (MIC >16 µg/ml) macrolide-resistant S. pneumoniae Respiratory FQ III or + macrolide III Inpatient, non-icu Respiratory FQ I or + macrolide I For penicillin-allergic patients Respiratory FQ I ICU * + azithromycin II or * + respiratory FQ I For penicillin-allergic patients Respiratory FQ + aztreonam Mandell LA, et al. Clin Infect Dis 2007; 44:S27-72

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [level 1 evidence] or Doxycycline III [level 3 evidence] Presence of comorbidities or antimicrobial use within previous 3 mths or other risks for DRSP infection Respiratory FQ I or + macrolide I In regions with high rate (>25%) of infection with high-level (MIC >16 µg/ml) macrolide-resistant S. pneumoniae Respiratory FQ III or + macrolide III Inpatient, non-icu Respiratory FQ I or + macrolide I For penicillin-allergic patients Respiratory FQ I ICU * + azithromycin II or * + respiratory FQ I For penicillin-allergic patients Respiratory FQ + aztreonam If Pseudomonas is a consideration III Anti-pneumococcal pneumococcal,, anti- pseudomonal (piperacillin-tazobactam, cefepime, imipenem,, or meropenem) + either ciprofloxacin or levofloxacin (750 mg) or Mandell LA, et al. Clin Infect Dis 2007; 44:S27-72

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [level 1 evidence] or Doxycycline III [level 3 evidence] Presence of comorbidities or antimicrobial use within previous 3 mths or other risks for DRSP infection Respiratory FQ I or + macrolide I In regions with high rate (>25%) of infection with high-level (MIC >16 µg/ml) macrolide-resistant S. pneumoniae Respiratory FQ III or + macrolide III Inpatient, non-icu Respiratory FQ I or + macrolide I For penicillin-allergic patients Respiratory FQ I ICU * + azithromycin II or * + respiratory FQ I For penicillin-allergic patients Respiratory FQ + aztreonam If Pseudomonas is a consideration III Anti-pneumococcal pneumococcal,, anti- pseudomonal + aminoglycoside + azithromycin or Mandell LA, et al. Clin Infect Dis 2007; 44:S27-72

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [level 1 evidence] or Doxycycline III [level 3 evidence] Presence of comorbidities or antimicrobial use within previous 3 mths or other risks for DRSP infection Respiratory FQ I or + macrolide I In regions with high rate (>25%) of infection with high-level (MIC >16 µg/ml) macrolide-resistant S. pneumoniae Respiratory FQ III or + macrolide III Inpatient, non-icu Respiratory FQ I or + macrolide I For penicillin-allergic patients Respiratory FQ I ICU * + azithromycin II or * + respiratory FQ I For penicillin-allergic patients Respiratory FQ + aztreonam If Pseudomonas is a consideration III Anti-pneumococcal pneumococcal,, anti- pseudomonal + aminoglycoside + anti- pneumococcal FQ (for penicillin-allergic patients, substitute the with aztreonam) Mandell LA, et al. Clin Infect Dis 2007; 44:S27-72

IDSA/ATS Consensus Guidelines on the management of CAP in adults Site of treatment IDSA / ATS Guidelines 2007 Recommended empirical antibiotics for CAP Outpatient Previously healthy and no antimicrobial use within previous 3 mths Macrolide I [level 1 evidence] or Doxycycline III [level 3 evidence] Presence of comorbidities or antimicrobial use within previous 3 mths or other risks for DRSP infection Respiratory FQ I or + macrolide I In regions with high rate (>25%) of infection with high-level (MIC >16 µg/ml) macrolide-resistant S. pneumoniae Respiratory FQ III or + macrolide III Inpatient, non-icu Respiratory FQ I or + macrolide I For penicillin-allergic patients Respiratory FQ I ICU * + azithromycin II or * + respiratory FQ I For penicillin-allergic patients Respiratory FQ + aztreonam If Pseudomonas is a consideration III Anti-pneumococcal pneumococcal,, anti- pseudomonal + aminoglycoside + anti- pneumococcal FQ (for penicillin-allergic patients, substitute the with aztreonam) If CA-MRSA is a consideration Add vancomycin or linezolid III

2007 IDSA / ATS Consensus Guidelines Duration of antibiotic therapy Patients with CAP should be treated for a minimum of 5 days (level I evidence) Before discontinuation of therapy - should be afebrile for 48 72 h - should have no more than 1 CAP-associated sign of clinical instability (level II evidence) Criteria for clinical stability Temperature <37.8C Heart rate < 100 /min Respiratory rate < 24 /min Systolic blood pressure >90 mm Hg Arterial oxygen saturation > 90% or po 2 > 60 mm Hg on room air Ability to maintain oral intake* Normal mental status*

Adjusted OR for 30-day all-cause mortality plotted against compliance with guideline-recommended antibiotics at Intermountain Healthcare hospitals Adjusted OR for 30-day all-cause mortality Circle area reflects the number of admissions per hospital The odds of mortality are 0.92 (p = 0.007) for each 10% increase in compliance Dean, N. C. et al. Chest 2006;130:794-799

Any advantages in following guidelines? Reduction in hospital admission rate Shortens length of hospital stay (LOS) Reduction in in-hospital and 30-day mortality? Help control bacterial resistance in the community (minimise use of excessive antibiotics and improves accuracy of therapy) However, the impact of guidelines on resistance remains to be shown

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