Post on 29-Jan-2023
Treating Patients with Melioidosis
Bart Currie
Infectious Diseases Department, Royal Darwin Hospital
Tropical and Emerging Infectious Diseases Division, MSHR
Northern Territory Medical Program, Flinders University
Melioidosis
• Infection with Burkholderia pseudomallei
• Environmental bacterium – in soil and surface water in endemic areas
• Disease in infected humans and animals
• Strong association with rainfall and environmental damage
Burkholderia pseudomallei
Tier 1 Biothreat Select Agent USA CDC – high mortality – antibiotic resistant – no vaccine – aerosol transmission – potential for bioweoponisation
“The unknown infection in Rangoon”
..an infective disease somewhat resembling glanders..
..prevalent among the ill-nourished
neglected wastrels of the town.
Endemic region of SEA & northern Australia
Melioidosis in Australia
1950 First Australian human case 32yo diabetic in Townsville Fatal septicemic melioidosis
Rimington Med J Aust 1962
1960 First case in the Northern Territory
Crotty Med J Aust 1962
1949 Outbreak in sheep
Winton Queensland (22.5oS) Cottew Aust J Exp Biol Med Sci 1950
Melioidosis Clinical Presentations
• 85% acute illness, recent infection
– Incubation Period 1-21 days (median 9 days)
• 11% chronic illness, recent infection – Sick for > 2 months
• 4% reactivation from latent focus: up to 62 yrs
Melioidosis Clinical Presentations
• 55% blood culture +ve
• 22% present with septic shock
– 75% of these pneumonia is primary site – mortality 50-90% if septic shock
Skin 13%
What determines clinical nature and severity?
• Infecting dose
• Host risk factors
• B. pseudomallei strain virulence factors
• Mode of infection percutaneous vs inhalation vs ingestion
What determines clinical nature and severity?
• Infecting dose
• Host risk factors
• B. pseudomallei strain virulence factors
• Mode of infection percutaneous vs inhalation vs ingestion
What determines clinical nature and severity?
107/109 fatal cases in the Darwin study had at least one risk factor
esp. diabetes, hazardous alcohol use, chronic lung disease
the other two were elderly (aged 75yo and 82yo)
Independent predictors of mortality by multivariable analysis
Presence of ≥ 1 risk factor OR 9.4 (2.3-39.0) Age ≥ 50 y OR 2.0 (1.2-3.3)
PLoS NTD 2010;4:e900
What determines clinical nature and severity?
• Infecting dose
• Host risk factors
• B. pseudomallei strain virulence factors
• Mode of infection percutaneous vs inhalation vs ingestion
B. pseudomallei: a dynamic pathogen
• 2 chromosomes and an “open” genome – 86% “core” and 14% “accessory” genome
• >15Mbp of accessory genome characterised to date
• Genomic heterogeneity from extensive horizontal gene
transfer of multiple genomic islands (GIs) occurring in the environment
• Also core genome recombination >> mutation
In-silico pan-genome from 11 Bps genomes Illumina reads aligned to K96243 type strain
B. pseudomallei: a dynamic pathogen
• Complex intrinsic antimicrobial resistance
BUT • Little diversity in susceptibility patterns of primary isolates
AND
• Acquired resistance is rare although well characterised
AND • No evidence of plasmid or transposon mediated acquired
resistance: acquired resistance is conferred by mutations and/or gene loss
Intrinsic antimicrobial resistance in Bps
• Efflux pumps – aminoglycoside & macrolide resistance (AmrAB-OprB) – trimethoprim resistance (BpeEF-OprC)
• Outer membrane permeability
– polymyxins
• Enzymatic break-down – various β-lactamases: resistance to many β–lactams
eg; penicillin, amoxicillin, cephalexin; reversed by clavulanate
Summary of Current Melioidosis Treatment
ceftazidime or meropenem or imipenem +/- cotrimoxazole (TMP-SMX) (oral or IV)
– for at least 10 (Thailand) or 14 (Australia) days
cotrimoxazole (TMP-SMX) OR co-amoxyclav (Augmentin)
– for 12-20 weeks (Thai) or at least 3 months (Aust)
Initial IV Intensive Therapy
Subsequent Oral Eradication Therapy
Lipsitz et al. EID 2012;18 (12):e2 Wiersinga et al. NEJM 2012;367:1035
Acquired antimicrobial resistance in Bps 1. Ceftazidime
Mostly conferred by Ambler class A β-lactamase (penA) • Mutations lead to amino acid changes near active sites
resulting in increased ceftazidime hydrolysis – C69Y Sam et al., 2009 – P167S Tribuddharat et al., 2003 – S72F (also AMX-CLAV resistance)
• Upregulation of penA via SNP in promoter region Sarovich et al., 2012
Other mechanisms
• Target deletion – large scale genomic loss - (PBP3) Chantratita et al., 2011
Acquired antimicrobial resistance in Bps 2. Other antimicrobials
• No carbapenem resistance described to date
• Efflux pump over-expression?
– may account for doxycycline resistance
• TMP-SMX mechanism unclear but can be high level R
200kb duplication in a high level TMP-SMX resistant Bps Illumina reads aligned to K96243 type strain
Susceptibility profiles in 233 consecutive primary infection Bps: 2009-2012
Ceftazidime
Nicole McMahon, Amy Crowe, Rob Baird RDH
Susceptibility profiles in 233 consecutive primary infection Bps: 2009-2012
Meropenem
Nicole McMahon, Amy Crowe, Rob Baird RDH
Susceptibility profiles in 233 consecutive primary infection Bps: 2009-2012
Trimethoprim/sulfamethoxazole
Nicole McMahon, Amy Crowe, Rob Baird RDH
Susceptibility profiles in 233 consecutive primary infection Bps: 2009-2012
Doxycycline
Nicole McMahon, Amy Crowe, Rob Baird RDH
Susceptibility profiles in 11 relapsed Bps
Doxycycline
Nicole McMahon, Amy Crowe, Rob Baird RDH See also Jenney et al. IJAA 2001;17:109
Doxycycline MIC's: Initial and recurrent B.pseudomallei isolates
0
5
10
15
20
25
30
35
40
0.5 0.75 1 1.5 2 3 4 6 8 12 16 >16
MIC μg/ml
Perc
enta
ge o
f iso
late
s
Initial isolates
Recurrent isolates
Susceptible Intermediate Resistant
Summary of Current Melioidosis Treatment
ceftazidime or meropenem or imipenem +/- cotrimoxazole (TMP-SMX) (oral or IV)
– for at least 10 (Thailand) or 14 (Australia) days
cotrimoxazole (TMP-SMX) OR co-amoxyclav (Augmentin)
– for 12-20 weeks (Thai) or at least 3 months (Aust)
Initial IV Intensive Therapy
Subsequent Oral Eradication Therapy
Lipsitz et al. EID 2012;18 (12):e2 Wiersinga et al. NEJM 2012;367:1035
RCT ceftaz vs chloro/doxy/cotrimoxazole 161 patients
Mortality 37% vs 74% (p = 0.009)
Some Unanswered Therapeutic Questions
• Is IV intensive Tx with ceftazidime or meropenem really required in localised disease such as skin ulcers?
• Is eradication therapy always necessary – eg after 2 weeks IV intensive Tx for mild pneumonia or for bacteremia with no focus?
• Will longer IV intensive Tx alone be adequate for uncomplicated pneumonia – eg 4 weeks ceftazidime via PICC in HITH?
• Will TMP-SMX alone for eradication phase hold up?
• Role of co-amoxyclav vs TMP-SMX in eradication phase: children and pregnancy?
Initial "Intensive" Therapy
Ceftazidime dosing issues
Ceftazidime has no post-antibiotic effect
Walsh et al. AAC 1995;39:2356
• Area under drug level curve important
• Maintain drug level above MIC
• Aim for higher tissue levels - ? more frequent dosing - ? bigger total daily dose - ? longer duration of “intensive” therapy
Continuous infusion elastomeric infusers
via PICC line (Baxter, Sydney)
Hospital in the Home program 6g adult dose over 24 hours
Cost Aus$160/day Huffam et al.
Trop Med Int Health 2004;9:715
Initial "Intensive" Therapy
Carbapenems versus Ceftazidime ??
Carbapenems (imipenem, meropenem)
• RCT Thailand – imipenem at least as effective as ceftazidime - same mortality - fewer treatment failures Simpson et al. CID 1999;29:381
• Meropenem safer at high dose; seizures with imipenem
• Meropenem outcomes at least as good as ceftazidime
- 63 patients with severe melioidosis; mortality 19% Cheng et al. AAC 2004;48:1763
Initial "Intensive" Therapy
Duration
Minimum 10d (Thailand) – 14d (Australia)
Australian Guidelines - 4 weeks or longer if: - septic shock - extensive lung disease - deep seated collections or organ abscesses - osteomyelitis and septic arthritis - neurological melioidosis Therapeutic Guidelines: Antibiotic 14th Ed 2010
Recurrent Melioidosis: Darwin, Australia
1989-2009: 30/465 (6.5%) survivors had recurrent melioidosis after completion of Tx
– 25 (5.4%) relapse & 5 (1.1%) new infection PLoS NTD 2010;4(11):e900
Oct 2009 - Aug 2013: 286 cases, 32 (11%) fatal Only 1/254 (0.4%) survivors has had relapsed
melioidosis after completion of Tx Despite often poor adherence to oral eradication Tx Is it the prolongation of IV therapy now occurring?
Conclusions
• Lowering the bar for prolonging IV “intensive” therapy may account for the decreasing relapse rates in the Darwin Prospective Melioidosis Study
• Over half of patients now get at least 4 weeks of IV therapy (meropenem in ICU, ceftazidime in wards and then via elastomeric infuser in HITH)
• What about the role of the 3m+ oral “eradication” therapy? When is it not needed?
• Needs formal study: the next melioidosis RCT?