updates on the role of broad spectrum penicillinsin the management of community acquired pneumonias

Updates on the role of Broad Spectrum Penicillins in the Management of Community Acquired Pneumonias Victor Lim International Medical University in Kuala Lumpur, Malaysia Global mortality from selected infectious and parasitic diseases and syndromes (2004) 1. World Health Organization: The top 10 causes of death. Fact sheet N°310. November 2008. 2. World Health Organization: Malaria. Fact sheet N°94. April 2010. 3. World Health Organization: Measles. Fact sheet N°286. December 2009. Deaths Deaths (%) Lower respiratory infections 1 4.18 million 7.1% Diarrhoeal diseases 1 2.16 million 3.7% HIV/AIDS 1 2.04 million 3.5% Tuberculosis 1 1.46 million 2.5% Malaria 2 Nearly 1 million (2008) Measles 3 164 000 (2008) Mortality rates of pneumonia in Asia Song JH et al. Int J Antimicrob Agents 2011; 38:108 Pneumonia is also a leading cause of mortality in Vietnam Burden of lower respiratory tract infections  LRTIs accounted for 94.5 million DALYs (Diability- adjusted life years) in 2004 1  Economic burden of CAP in Asia 2  New Zealand ~ Direct medical cost : USD 16.8 million/year ~ Loss of productivity : USD 19.2 million/year  Taiwan ~ Treatment cost : USD 52 million/year 1. WHO (2008) The global burden of disease 2004 update. 2. Song JH et al. Int J Antimicrob Agents 2011; 38:108 Antimicrobial treatment for CAP  Factors to consider  Etiological agents  Resistance patterns  Severity of pneumonia ~ PSI ~ CURB65 (Recommended by both BTS and IDSA)  Cost ~ Outpatient vs Inpatient ~ Parenteral vs Oral Garau J et al, Lancet 2008;371:455−58. Pathogens associated with CAP Pathogen Relative frequency (%) Streptococcus pneumoniae 35−80 Haemophilus influenzae 5−6 Legionella spp 2−15 Mycoplasma pneumoniae 2−14 Chlamydia spp 4−15 Staphylococcus aureus 3−14 Enteric gram-negative bacilli 6−12 Pseudomonas aeruginosa 4−9 Mycobacterium tuberculosis <1−5 Coxiella burnetii 2−4 Moraxella catarrhalis <1 Influenza A virus 10−15 Other viruses 5−10 Unknown 15−40 Streptococcus pneumoniae is the primary bacterial cause of respiratory infections Bacterial Pathogens of CAP in Asia  Regional and national differences  Streptococcus pneumoniae  Accounts for nearly 30% of CAP 1  Klebsiella pneumoniae  In Malaysia and Singapore, commonly seen in patients who require hospitalisation 2,3  Mycoplasma pneumoniae  Most common cause of CAP in 1 Chinese study 4  Asian study found that 11% of CAP due to M. pneumoniae 5 1. Song JH et al. Int J Antimicrob Agents 2011; 38:108 2. Liam CK et al. Respirology 2001; 6:259 3. Lim TK. Ann Acad Med Singapore 1997;26:651 4. Liu Y. et al BMC Infect Dis 2009; 9:31 5. Ngeow YF. Et al. Int J Infect Dis 2005; 9:144 Bacterial Pathogens of CAP in Asia  Burkholderia pseudomallei  Not uncommon as a cause of severe pneumonia especially among diabetics 1  Cause of 15% of CAP in 1 study in NE Thailand 2  Isolated from 24% of CAP patients requiring admission to ICU in Singapore 3 1. Liam CK. Respirology 2007; 12: 162 2. Reechaipichitku; W. et al Southest Asian J Trop Med Publich Health 2002; 33:355 3. Tan YK et al. Eur Respir J 1998; 12:113 Streptococcus pneumoniae Penicillin Resistance Rate Country %R Very high (>50%) Taiwan 2 ~75.0 Vietnam 1 71.4 Japan 2 ~61.0 Korea 1 54.8 Moderately high (20–50%) Hong Kong 1 43.2 Malaysia 1 29.5 Low (< 20%) Singapore 1 17.1 Sri Lanka 1 14.3 China 2 ~12.0 Philippines 1 0.0 1. Song et al. Antimicrob Agents and Chemo 2004;2101–2107. 2. Bell and Turnidge. Commun Dis Intell. 2003;27 Suppl:S61–S66. The Asia Pacific region has among the highest pneumococcal resistance rates in the world based on the old CLSI breakpoints [...]... a result of beta-lactamase production Klebsiella pneumoniae has been shown to be a common cause of CAP For severe CAP in ICU, consider melioidosis Use of amoxicillin or macrolides as monotherapy may not be appropriate CAP guidelines  Hong Kong (Hong Kong University & HK Hospital Authority)1   Japan (Japan Respiratory Society)1   Beta-lactam/inhibitor (mild to moderate bacterial pneumonia) Philippines... http://www.psmid.org.ph/clinical/cap_guidelines_2010.pdf PK/PD and Time-dependent Killing   Dosing regimen should maximise the duration of time above MIC The unbound serum concentration of the antibiotic should be above the MIC for at least 40% to 50% of the dosing interval 8 6 4 Drug A Drug B MIC=2 mg/L 2 B 0 A Time above MIC Time T>MIC for various Augmentin formulations Formulation Reg Mean T > MIC for different MIC values 1 2 4 250/125 tid 40 500/125... to clindamycin Mechanisms of erythromycin resistance in Asia Streptococcus pneumoniae Fluoroquinolone resistance ANSORP Study Data 2004 2009 Ciprofloxacin 6.0% 13.4% Levofloxacin 1.6% 1.7% Gatifloxacin 1.6% 1.5% Moxifloxacin 0.3% 0.4% Hong Kong Fluoroquinolone resistance prevalence2 9–17% Levofloxacin Non-susceptibility rates3 14.1% Gatifloxacin 10.8% Moxifloxacin 11.2% 1 Song JH et al AAC 2004;2101−2107... Chemother 2004; 53(S1):i3-i20 Equivalent time above MIC 12 10 500/125 mg t.i.d mg/l 8 6 9.9h / 24h 4 T>MIC=41% 2 3.3h 3.3h 3.3h 0 0 24 12 Time 12 10 875/125 mg b.i.d mg/l 8 6 9h / 24h 4 4.5h 2 4.5h T>MIC~40% 0 0 12 24 Time Drusano & Craig J Chemother 1997; 9 Suppl 3:38-44 Conclusions  Community acquired pneumonia continues to be a leading cause of morbidity and mortality globally  There are regional... Sun et al Zhonghua Yi Xue Za Zhi 2009 Nov 17;89(42):2983-7 Jean SS et al Eur J Clin Microbiol Infect Dis 2009;28(8):1013–7 MOH Malaysia 2009 Available at: http://www.imr.gov Inoue et al., Int J Infect Dis 2005 Jan;9(1):27–36 Van PH et al Poster Presentation ICID 2008 Choice of empirical therapy  Selection of antibiotics would depend on    Most likely pathogens The resistance patterns of these pathogens... antibiotic Rx, DRSP risk)    Respiratory quinolone Betalactam and macrolide/doxycycline Inpatient (non-ICU)    Respiratory quinolone Beta-lactam and macrolide In-patient (ICU)  Respiratory quinolone  Beta-lactam and azithromycin Adapting International Guidelines to the Local Situation  In Asia      Macrolide resistance in Streptococcus pneumoniae is common Ampicillin/amoxicillin resistance in Haemophilus... ≥2 Effect of new penicillin breakpoints for Strep pneumoniae Invasive non-meningitis pneumococcal disease in US, 2006-7 Old breakpoints New breakpoints Susceptible 74.7% 93.2% Intermediate 15.0% 5.6% Resistant 10.3% 1.2% MMRW 2008/57(50); 1353-1355 In Asia Based on an ANSORP surveillance study performed from 2008–2009, only 0.7% of S pneumoniae isolates obtained from non-meningeal infections from 11... 80.7 (SH Kim et al, AAC 2012) Resistance mechanisms of S pneumoniae to macrolides • • Target modification (erm) – production of an enzyme that modifies the target ribosome through methylation of an adenine residue – results in high-level resistance to macrolides and clindamycin Active efflux (mef) – ATP-dependent efflux pump that removes macrolide from the cell – results in moderate-level resistance to... patterns of these pathogens based on local data Other factors to consider  Cost of treatment ~ Oral vs Parenteral  Prudent use to limit emergence of resistance Treatment guidelines for CAP  Generally international guidelines are followed   Infectious Disease Society of America (IDSA) and British Thoracic Society (BTS) Guidelines In Asia Pacific there is a need to modify the guidelines  Different resistance... clarithromycin   Parenteral antibiotics Alternative : iv cephalosporin and clarithromycin In the current guidelines, cephalosporins and fluoroquinolones are included as alternatives but not preferred choices, largely on the basis that their use has been consistently associated with hospital acquired infections, notably C difficile associated disease IDSA Guidelines for CAP (2011)  Outpatient treatment . Updates on the role of Broad Spectrum Penicillins in the Management of Community Acquired Pneumonias Victor Lim International Medical University in Kuala Lumpur,. Presentation ICID. 2008. Choice of empirical therapy  Selection of antibiotics would depend on  Most likely pathogens  The resistance patterns of these pathogens based on local data  Other factors. Pathogens of CAP in Asia  Burkholderia pseudomallei  Not uncommon as a cause of severe pneumonia especially among diabetics 1  Cause of 15% of CAP in 1 study in NE Thailand 2  Isolated from 24% of