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

Garau J et al, Lancet 2008;371:455−58.Pathogens associated with CAP Pathogen Relative frequency % Streptococcus pneumoniae is the primary bacterial cause of respiratory infections... Ba

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.

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

 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

Garau J et al, Lancet 2008;371:455−58.

Pathogens associated with CAP

Pathogen Relative frequency (%)

Streptococcus pneumoniae is the primary bacterial

cause of respiratory infections

Bacterial Pathogens of CAP in Asia

 Regional and national differences

 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

 Not uncommon as a cause of severe pneumonia

especially among diabetics1

 Cause of 15% of CAP in 1 study in NE Thailand2

 Isolated from 24% of CAP patients requiring admission to ICU in Singapore3

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

Old CLSI Interpretative Breakpoints for

 intermediate resistant strains respond well to standard doses

 Increased doses may effectively treat strains with MIC of 2

New respiratory breakpoints for

Streptococcus pneumoniae established in

2008

MIC μg/mL Susceptible Intermediate Resistant

Effect of new penicillin breakpoints for Strep

infections from 11 Asian countries were categorised as

penicillin-resistant ( penicillin MIC ≥ 8 g/mL)

(SH Kim et al, AAC 2012)

1 Song JH et al J Antimicrob Chemother 2004;53(3):457–63.

2 Johnson J et al Poster Presentation ICAAC 2004.

3 Srifuengfung et al South East Asian J Trop Med Public Health 2004; 39(3): 461-6.

Macrolide resistance

Erythromycin resistance continues to be very common in Asia (2008/9 strains)

Country % Resistance to Erythromycin

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 macrolides but remains

susceptible to clindamycin

Mechanisms of erythromycin resistance in Asia

Haemophilus influenzae

Country % Ampicillin Res Korea 58.5% (Bae et al 2010)

Hong Kong ~25% (Bell and Turnidge 2003)

Australia ~26% (Bell and Turnidge 2003)

China 15.3% (Sun et al, 2009)

Taiwan 55% (Jean et al, 2009)

Singapore ~26% (Bell and Turnidge 2003)

Malaysia 18.3% (Malaysia MOH 2009)

Japan 8.5% (Inoue 2000); BLNAR common

Vietnam 49% (Van et al, 2008)

Bae S et al Antimicrob Agents Chemother 2010;54(1):65–71 Bell and Turnidge Commun Dis Intell 2003;27 Suppl:S61–S66 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

 Most likely pathogens

 The resistance patterns of these pathogens based on local data

 Cost of treatment

~ Oral vs Parenteral

 Prudent use to limit emergence of resistance

Treatment guidelines for CAP

 Infectious Disease Society of America (IDSA) and British Thoracic Society (BTS) Guidelines

 Different resistance patterns

 Different spectrum of pathogens causing CAP

British Thoracic Society Guidelines 2009

(Adults)

 Oral antibiotics

 Amoxycillin

 Oral antibiotics for most patients : amoxycillin and

macrolide

 Parenteral : iv penicillin/amoxycillin and clarithromycin

 Alternatives :

~ oral doxycycline or quinolone

~ iv levofloxacin or cephalosporin and clarithromycin

British Thoracic Society Guidelines 2009

(Adults)

 Parenteral antibiotics

 Iv Augmentin and clarithromycin

 Alternative : iv cephalosporin and clarithromycin

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 (no risk factors)

Adapting International Guidelines to the Local Situation

 Macrolide resistance in Streptococcus pneumoniae is

common

 Ampicillin/amoxicillin resistance in Haemophilus

influenzae is high primarily as 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

not be appropriate

CAP guidelines

 Hong Kong (Hong Kong University & HK Hospital Authority)1

 Amoxicillin/clavulanate ± macrolide (OPD and general ward)

 Japan (Japan Respiratory Society)1

 Beta-lactam/inhibitor (mild to moderate bacterial pneumonia)

 Philippines 2010 (Philippines Society for Microbiology & Infectious

Diseases, College of Chest Physicians, Academy of Family Physicians, College of Radiology) 2

 Beta-lactam/inhibitor ± macrolide (comorbid illnesses)

 Singapore (College of Physicians, Academy of Medicine of Singapore)1

 Beta-lactam/inhibitor (OPD elderly/comorbid illnesses)

 Beta-lactam/inhibitor ± macrolides (general ward)

 Malaysia (Malaysian Thoracic Society)1

 Beta-lactam/inhibitor (general ward)

1 Alpuche C et al Int J Antimicrob Agents 2007;30(Suppl 2):S135–8.

2 Philippine Clinical Practice Guidelines Available at: http://www.psmid.org.ph/clinical/cap_guidelines_2010.pdf.

PK/PD and Time-dependent Killing

the dosing interval

Time above MIC Time

2

Drug A

Drug B

A B

4 6 8

0

MIC=2 mg/L

T>MIC for various Augmentin

Equivalent time above MIC

 Community acquired pneumonia continues to

be a leading cause of morbidity and mortality

globally

 There are regional differences in terms of

aetiological agents and resistance patterns

 Need to tailor our guidelines according to the

local situation

 Beta-lactam/inhibitor with or without a macrolide would be generally be an appropriate choice in the treatment of CAP in Asia