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

The Darwin Prospective Melioidosis Study

Darwin

819 cases over 23.5 years 109 deaths (13%)

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

Chronic melioidosis Sick > 2 months

11% of cases Mis-diagnosed as TB

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

What % of cases overall are from inhalation?

Is it 10%??

Is it 50%??

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?

Presenter

Presentation Notes

A novel broad range monosulfactam antibiotic It was previously noted that the unique pattern of penicillin binding protein inhibition and bactericidal mode of action of BAL30072 confer potent in vitro activity against Gram-negativebacteria [5]. BAL30072 is a novel sulfactam antibiotic with potent antimicrobial activity against a broad range of Gram-negative bacteria, including clinically increasingly problematic multidrug-resistant pathogens such as Pseudomonas aeruginosa, Acinetobacter spp., Klebsiella spp. and Enterobacter spp. BAL30072 is stable towards many types of beta-lactamases that can deactivate most of the currently marketed beta-lactam antibiotics such as cephalosporins and carbapenems. The compound is taken up very readily into bacteria, exploiting essential nutrient uptake systems and is able to circumvent resistance caused by changes in the outer membrane of Gram-negative bacteria. The compound has shown to be highly compatible with agents used for treating Gram-positive infections and even works synergistically with some agents used for treating Gram-negative infections, such as carbapenems and aminoglycosides. hospital-acquired pneumonia (including ventilator-associated pneumonia), complicated intra-abdominal infections or complicated urinary tract infections.

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?

Acknowledgements RDH ID Registrars & Physicians

RDH Microbiology Lab Scientists

RDH ICU, ED, Ward and HITH Doctors & Nurses

NT CDC Staff

International Collaborators

Menzies Melioidosis Team

Funding: NHMRC, ARC, NIH, Aust PM+C & US DHS & DOD