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1.  Clinical Features and Risk Factors of Oedematous Mycobacterium ulcerans Lesions in an Australian Population: Beware Cellulitis in an Endemic Area 
Introduction
Oedematous lesions are a less common but more severe form of Mycobacterium ulcerans disease. Misdiagnosis as bacterial cellulitis can lead to delays in treatment. We report the first comprehensive descriptions of the clinical features and risk factors of patients with oedematous disease from the Bellarine Peninsula of south-eastern Victoria, Australia.
Methods
Data on all confirmed Mycobacterium ulcerans cases managed at Barwon Health, Victoria, were collected from 1/1/1998–31/12/2012. A multivariate logistic regression model was used to assess associations with oedematous forms of Mycobacterium ulcerans disease.
Results
Seventeen of 238 (7%) patients had oedematous Mycobacterium ulcerans lesions. Their median age was 70 years (IQR 17–82 years) and 71% were male. Twenty-one percent of lesions were WHO category one, 35% category two and 41% category three. 16 (94%) patients were initially diagnosed with cellulitis and received a median 14 days (IQR 9–17 days) of antibiotics and 65% required hospitalization prior to Mycobacterium ulcerans diagnosis. Fever was present in 50% and pain in 87% of patients. The WCC, neutrophil count and CRP were elevated in 54%, 62% and 75% of cases respectively. The median duration of antibiotic treatment was 84 days (IQR 67–96) and 94% of cases required surgical intervention. On multivariable analysis, there was an increased likelihood of a lesion being oedematous if on the hand (OR 85.62, 95% CI 13.69–535.70; P<0.001), elbow (OR 7.83, 95% CI 1.39–43.96; p<0.001) or ankle (OR 7.92, 95% CI 1.28–49.16; p<0.001), or if the patient had diabetes mellitus (OR 9.42, 95% CI 1.62–54.74; p = 0.02).
Conclusions
In an Australian population, oedematous Mycobacterium ulcerans lesions present with similar symptoms, signs and investigation results to, and are commonly mistakenly diagnosed for, bacterial limb cellulitis. There is an increased likelihood of oedematous lesions affecting the hand, elbow or ankle, and in patients with diabetes.
Author Summary
The oedematous form of Buruli ulcer, caused by Mycobacterium ulcerans, is less common representing 7% of cases over a 15 year period in a patient cohort from the Bellarine Peninsula of south-eastern Victoria, Australia. In this study, for oedematous Buruli ulcer cases, fever and pain were usually present and investigations showed leucocytosis, neutrophilia and a raised serum CRP. This is in contrast to other forms of Buruli ulcer which are classically painless and not associated with systemic symptoms. As a result oedematous cases were usually misdiagnosed and treated as bacterial cellulitis leading to delays in diagnosis, progression of disease, increased morbidity and increased complexity of treatment. Compared with non-oedematous forms of Buruli ulcer, we found that oedematous lesions were strongly associated with being located on the dorsum of the hand, the elbow and the ankle, and with patients who had diabetes mellitus. This study aims to increase the awareness of odematous Buruli ulcer disease, and improve the understanding of its clinical presentation and risk factors, to aid clinicians to diagnose and treat early Mycobacterium ulcerans infection when managing patients with cellulitis who have been exposed to areas endemic for Buruli ulcer.
doi:10.1371/journal.pntd.0002612
PMCID: PMC3879256  PMID: 24392172
2.  Incidence, clinical spectrum, diagnostic features, treatment and predictors of paradoxical reactions during antibiotic treatment of Mycobacterium ulcerans infections 
BMC Infectious Diseases  2013;13:416.
Background
Paradoxical reactions from antibiotic treatment of Mycobacterium ulcerans have recently been recognized. Data is lacking regarding their incidence, clinical and diagnostic features, treatment, outcomes and risk factors in an Australian population.
Methods
Data was collected prospectively on all confirmed cases of M. ulcerans infection managed at Barwon Health Services, Australia, from 1/1/1998-31/12/2011. Paradoxical reactions were defined on clinical and histological criteria and cases were determined by retrospectively reviewing the clinical history and histology of excised lesions. A Poisson regression model was used to examine associations with paradoxical reactions.
Results
Thirty-two of 156 (21%) patients developed paradoxical reactions a median 39 days (IQR 20-73 days) from antibiotic initiation. Forty-two paradoxical episodes occurred with 26 (81%) patients experiencing one and 6 (19%) multiple episodes. Thirty-two (76%) episodes occurred during antibiotic treatment and 10 (24%) episodes occurred a median 37 days after antibiotic treatment. The reaction site involved the original lesion (wound) in 23 (55%), was separate to but within 3 cm of the original lesion (local) in 11 (26%) and was more than 3 cm from the original lesion (distant) in 8 (19%) episodes. Mycobacterial cultures were negative in 33/33 (100%) paradoxical episodes. Post-February 2009 treatment involved more cases with no antibiotic modifications (12/15 compared with 11/27, OR 5.82, 95% CI 1.12-34.07, p = 0.02) and no further surgery (9/15 compared with 2/27, OR 18.75, 95% CI 2.62-172.73, p < 0.001). Six severe cases received prednisone with marked clinical improvement. On multivariable analysis, age ≥ 60 years (RR 2.84, 95% CI 1.12-7.17, p = 0.03), an oedematous lesion (RR 3.44, 95% CI 1.11-10.70, p=0.03) and use of amikacin in the initial antibiotic regimen (RR 6.33, 95% CI 2.09-19.18, p < 0.01) were associated with an increased incidence of paradoxical reactions.
Conclusions
Paradoxical reactions occur frequently during or after antibiotic treatment of M. ulcerans infections in an Australian population and may be increased in older adults, oedematous disease forms, and in those treated with amikacin. Recognition of paradoxical reactions led to changes in management with less surgery, fewer antibiotic modifications and use of prednisolone for severe reactions.
doi:10.1186/1471-2334-13-416
PMCID: PMC3854792  PMID: 24007371
Mycobacterium ulcerans; Paradoxical reactions; Antibiotics; Predictors; Incidence; Clinical; Diagnosis; Treatment
3.  Forgotten but not gone - Scrofuloderma in a migrant student from India 
The Australasian Medical Journal  2013;6(7):371-373.
A 34-year-old Indian student who immigrated to Australia five years ago presented with a four-week history of neck pain. Physical examination revealed two firm fixed cervical lymph nodes in the anterior triangle and midline region which were tender on palpation and erythematous on inspection. Cording phenomenon was found on ZN staining of FNA sample and mycobacterium tuberculosis (M.tb ) PCR confirmed the diagnosis with incomplete resistance to isoniazid. Patient was treated with other three first line antituberculosis medications for nine months with an excellent outcome. Prednisolone was also used as adjunctive therapy and tapered during the course of treatment.
doi:10.4066/AMJ.2013.1759
PMCID: PMC3737763  PMID: 23940498
Scrofuloderma; Tuberculosis; Cording phenomenon
4.  Impact of Hiv-Associated Conditions on Mortality in People Commencing Anti-Retroviral Therapy in Resource Limited Settings 
PLoS ONE  2013;8(7):e68445.
Objectives
To identify associations between specific WHO stage 3 and 4 conditions diagnosed after ART initiation and all cause mortality for patients in resource-limited settings (RLS).
Design, Setting
Analysis of routine program data collected prospectively from 25 programs in eight countries between 2002 and 2010.
Subjects, Participants
36,664 study participants with median ART follow-up of 1.26 years (IQR 0.55–2.27).
Outcome Measures
Using a proportional hazards model we identified factors associated with mortality, including the occurrence of specific WHO clinical stage 3 and 4 conditions during the 6-months following ART initiation.
Results
There were 2922 deaths during follow-up (8.0%). The crude mortality rate was 5.41 deaths per 100 person-years (95% CI: 5.21–5.61). The diagnosis of any WHO stage 3 or 4 condition during the first 6 months of ART was associated with increased mortality (HR: 2.21; 95% CI: 1.97–2.47). After adjustment for age, sex, region and pre-ART CD4 count, a diagnosis of extrapulmonary cryptococcosis (aHR: 3.54; 95% CI: 2.74–4.56), HIV wasting syndrome (aHR: 2.92; 95%CI: 2.21 -3.85), non-tuberculous mycobacterial infection (aHR: 2.43; 95% CI: 1.80–3.28) and Pneumocystis pneumonia (aHR: 2.17; 95% CI 1.80–3.28) were associated with the greatest increased mortality. Cerebral toxoplasmosis, pulmonary and extra-pulmonary tuberculosis, Kaposi’s sarcoma and oral and oesophageal candidiasis were associated with increased mortality, though at lower rates.
Conclusions
A diagnosis of certain WHO stage 3 and 4 conditions is associated with an increased risk of mortality in those initiating ART in RLS. This information will assist initiatives to reduce excess mortality, including prioritization of resources for diagnostics, therapeutic interventions and research.
doi:10.1371/journal.pone.0068445
PMCID: PMC3720807  PMID: 23935870
5.  Mycobacterium ulcerans Disease: Experience with Primary Oral Medical Therapy in an Australian Cohort 
Background
Mycobacterium ulcerans (MU) is responsible for disfiguring skin lesions and is endemic on the Bellarine peninsula of southeastern Australia. Antibiotics have been shown to be highly effective in sterilizing lesions and preventing disease recurrences when used alone or in combination with surgery. Our practice has evolved to using primarily oral medical therapy.
Methods
From a prospective cohort of MU patients managed at Barwon Health, we describe those treated with primary medical therapy defined as treatment of a M. ulcerans lesion with antimicrobials either alone or in conjunction with limited surgical debridement.
Results
From 1/10/2010 through 31/12/11, 43 patients were treated with exclusive medical therapy, of which 5 (12%) also underwent limited surgical debridement. The median patient age was 50.2 years, and 86% had WHO category 1 and 91% ulcerative lesions. Rifampicin was combined with ciprofloxacin in 30 (70%) and clarithromycin in 12 (28%) patients. The median duration of antibiotic therapy was 56 days, with 7 (16%) receiving less than 56 days. Medication side effects requiring cessation of one or more antibiotics occurred in 7 (16%) patients. Forty-two (98%) patients healed without recurrence within 12 months, and 1 patient (2%) experienced a relapse 4 months after completion of 8 weeks of antimicrobial therapy.
Conclusion
Our experience demonstrates the efficacy and safety of primary oral medical management of MU infection with oral rifampicin-based regimens. Further research is required to determine the optimal and minimum durations of antibiotic therapy, and the most effective antibiotic dosages and formulations for young children.
Author Summary
Mycobacterium ulcerans (MU) is responsible for disfiguring skin infections which are challenging to treat. The recommended treatment for MU has continued to evolve from surgery to remove all involved tissue, to the use of effective combination oral antibiotics with surgery as required. Our study describes the oral medical treatment utilised for consecutive cases of MU infection over a 15 month period at our institution, in Victoria, Australia. Managing patients primarily with oral antibiotics results in high cure rates and excellent cosmetic outcomes. The success with medical treatment reported in this study will aid those treating cases of MU infection, and will add to the growing body of knowledge about the relative roles of antibiotics and surgery for treating this infection.
doi:10.1371/journal.pntd.0002315
PMCID: PMC3715400  PMID: 23875050
6.  A case of Kingella kingae endocarditis complicated by native mitral valve rupture 
The Australasian Medical Journal  2013;6(4):172-174.
We report a case of Kingella kingae endocarditis in a patient with a history of recent respiratory tract infection and dental extraction. This case is remarkable for embolic and vasculitic phenomena in association with a large valve vegetation and valve perforation. Kingella kingae is an organism known to cause endocarditis, however early major complications are uncommon. Our case of Kingella endocarditis behaved in a virulent fashion necessitating a combined approach of intravenous antibiotic therapy and a valve replacement. It highlights the importance of expedited investigation for endocarditis in patients with Kingella bacteraemia.
doi:10.4066/AMJ.2013.1577
PMCID: PMC3650306  PMID: 23671460
Kingella kingae; Endocarditis; Mitral Valve Rupture
7.  Successful Outcomes with Oral Fluoroquinolones Combined with Rifampicin in the Treatment of Mycobacterium ulcerans: An Observational Cohort Study 
Background
The World Health Organization currently recommends combined streptomycin and rifampicin antibiotic treatment as first-line therapy for Mycobacterium ulcerans infections. Alternatives are needed when these are not tolerated or accepted by patients, contraindicated, or neither accessible nor affordable. Despite in vitro effectiveness, clinical evidence for fluoroquinolone antibiotic use against Mycobacterium ulcerans is lacking. We describe outcomes and tolerability of fluoroquinolone-containing antibiotic regimens for Mycobacterium ulcerans in south-eastern Australia.
Methodology/Principal Findings
Analysis was performed of prospectively collected data including all primary Mycobacterium ulcerans infections treated at Barwon Health between 1998 and 2010. Medical treatment involved antibiotic use for more than 7 days; surgical treatment involved surgical excision of a lesion. Treatment success was defined as complete lesion healing without recurrence at 12 months follow-up. A complication was defined as an adverse event attributed to an antibiotic that required its cessation. A total of 133 patients with 137 lesions were studied. Median age was 62 years (range 3–94 years). 47 (34%) had surgical treatment alone, and 90 (66%) had combined surgical and medical treatment. Rifampicin and ciprofloxacin comprised 61% and rifampicin and clarithromycin 23% of first-line antibiotic regimens. 13/47 (30%) treated with surgery alone failed treatment compared to 0/90 (0%) of those treated with combination medical and surgical treatment (p<0.0001). There was no difference in treatment success rate for antibiotic combinations containing a fluoroquinolone (61/61 cases; 100%) compared with those not containing a fluoroquinolone (29/29 cases; 100%). Complication rates were similar between ciprofloxacin and rifampicin (31%) and rifampicin and clarithromycin (33%) regimens (OR 0.89, 95% CI 0.27–2.99). Paradoxical reactions during treatment were observed in 8 (9%) of antibiotic treated cases.
Conclusions
Antibiotics combined with surgery may significantly increase treatment success for Mycobacterium ulcerans infections, and fluoroquinolone combined with rifampicin-containing antibiotic regimens can provide an effective and safe oral treatment option.
Author Summary
Buruli ulcer is a necrotizing infection of skin and subcutaneous tissue caused by Mycobacterium ulcerans and is the third most common mycobacterial disease worldwide (after tuberculosis and leprosy). In recent years its treatment has radically changed, evolving from a predominantly surgically to a predominantly medically treated disease. The World Health Organization now recommends combined streptomycin and rifampicin antibiotic treatment as first-line therapy for Mycobacterium ulcerans infections. However, alternatives are needed where recommended antibiotics are not tolerated or accepted by patients, contraindicated, or not accessible nor affordable. This study describes the use of antibiotics, including oral fluoroquinolones, in the treatment of Mycobacterium ulcerans in south-eastern Australia. It demonstrates that antibiotics combined with surgery are highly effective in the treatment of Mycobacterium ulcerans. In addition, oral fluoroquinolone-containing antibiotic combinations are shown to be as effective and well tolerated as other recommended antibiotic combinations. Fluoroquinolone antibiotics therefore offer the potential to provide an alternative oral antibiotic to be combined with rifampicin for Mycobacterium ulcerans treatment, allowing more accessible and acceptable, less toxic, and less expensive treatment regimens to be available, especially in resource-limited settings where the disease burden is greatest.
doi:10.1371/journal.pntd.0001473
PMCID: PMC3260310  PMID: 22272368
8.  Candida Infective Endocarditis 
Purpose
Candida infective endocarditis (IE) is uncommon but often fatal. Most epidemiologic data are derived from small case series or case reports. This study was conducted to explore epidemiology, treatment patterns, and outcomes of patients with Candida IE.
Methods
We compared 33 Candida IE cases to 2716 patients with non-fungal IE in the International Collaboration on Endocarditis - Prospective Cohort Study. Patients were enrolled and data collected from June 2000 until August 2005.
Results
Patients with Candida IE were more likely to have prosthetic valves (p<0.001), short term indwelling catheters (p<0.0001), and have healthcare-associated infection (p<0.001). Reasons for surgery differed between the two groups: myocardial abscess (46.7% vs. 22.2% p=0.026) and persistent positive blood cultures (33.3% vs. 9.9%, p=0.003) were more common among those with Candida IE. Mortality at discharge was higher in patients with Candida IE (30.3%) when compared to non-fungal cases (17%, p=0.046). Among Candida patients, mortality was similar in patients who received combination surgical and antifungal therapy versus antifungal therapy alone (33.3% vs. 27.8%, p=0.26). New antifungal drugs, particularly echinocandins, were used frequently.
Conclusions
These multi-center data suggest distinct epidemiologic features of Candida IE when compared to non-fungal cases. Indications for surgical intervention are different and mortality is increased. Newer antifungal treatment options are increasingly used. Large, multi-center studies are needed to help better define Candida IE.
doi:10.1007/s10096-008-0466-x
PMCID: PMC2757733  PMID: 18283504
9.  Genotypic Diversity of Coagulase-Negative Staphylococci Causing Endocarditis: a Global Perspective▿  
Journal of Clinical Microbiology  2008;46(5):1780-1784.
Coagulase-negative staphylococci (CNS) are important causes of infective endocarditis (IE), but their microbiological profiles are poorly described. We performed DNA target sequencing and susceptibility testing for 91 patients with definite CNS IE who were identified from the International Collaboration on Endocarditis—Microbiology, a large, multicenter, multinational consortium. A hierarchy of gene sequences demonstrated great genetic diversity within CNS from patients with definite endocarditis that represented diverse geographic regions. In particular, rpoB sequence data demonstrated unique genetic signatures with the potential to serve as an important tool for global surveillance.
doi:10.1128/JCM.02405-07
PMCID: PMC2395089  PMID: 18367572
10.  Successful treatment of Mycobacterium ulcerans osteomyelitis with minor surgical debridement and prolonged rifampicin and ciprofloxacin therapy: a case report 
Introduction
Treatment for osteomyelitis-complicating Mycobacterium ulcerans infection typically requires extensive surgery and even amputation, with no reported benefit from adjunctive antibiotics.
Case presentation
We report a case of an 87-year-old woman with M. ulcerans osteomyelitis that resolved following limited surgical debridement and 6 months of therapy with rifampicin and ciprofloxacin.
Conclusion
M. ulcerans osteomyelitis can be successfully treated with limited surgical debridement and adjunctive oral antibiotics.
doi:10.1186/1752-1947-2-123
PMCID: PMC2396654  PMID: 18439310
11.  Case Cluster of Necrotizing Fasciitis and Cellulitis Associated with Vein Sclerotherapy 
Emerging Infectious Diseases  2008;14(1):180-181.
doi:10.3201/eid1401.070250
PMCID: PMC2600178  PMID: 18258105
Group A Streptococcus; necrotizing fasciitis; sclerotherapy; polidocanol; varicose vein; letter
12.  Risk Factors for Mycobacterium ulcerans Infection, Southeastern Australia 
Emerging Infectious Diseases  2007;13(11):1661-1666.
Epidemiologic evidence shows that mosquitoes play a role in transmission to humans.
Buruli/Bairnsdale ulcer (BU) is a severe skin and soft tissue disease caused by Mycobacterium ulcerans. To better understand how BU is acquired, we conducted a case–control study during a sustained outbreak in temperate southeastern Australia. We recruited 49 adult patients with BU and 609 control participants from a newly recognized BU-endemic area in southeastern Australia. Participants were asked about their lifestyle and insect exposure. Odds ratios were calculated by using logistic regression and were adjusted for age and location of residence. Odds of having BU were at least halved for those who frequently used insect repellent, wore long trousers outdoors, and immediately washed minor skin wounds; odds were at least doubled for those who received mosquito bites on the lower legs or lower arms. This study provides new circumstantial evidence that implicates mosquitoes in the transmission of M. ulcerans in southeastern Australia.
doi:10.3201/eid1311.061206
PMCID: PMC3375781  PMID: 18217548
Mycobacterium ulcerans; Mycobacterium infections; atypical; communicable diseases; lifestyle; insect vectors; case-control studies; Australia; epidemiology; research
13.  Personal Protective Equipment and Antiviral Drug Use during Hospitalization for Suspected Avian or Pandemic Influenza1 
Emerging Infectious Diseases  2007;13(10):1541-1547.
In a pandemic, many current national stockpiles of PPE and antiviral medications are likely inadequate.
For pandemic influenza planning, realistic estimates of personal protective equipment (PPE) and antiviral medication required for hospital healthcare workers (HCWs) are vital. In this simulation study, a patient with suspected avian or pandemic influenza (API) sought treatment at 9 Australian hospital emergency departments where patient–staff interactions during the first 6 hours of hospitalization were observed. Based on World Health Organization definitions and guidelines, the mean number of “close contacts” of the API patient was 12.3 (range 6–17; 85% HCWs); mean “exposures” were 19.3 (range 15–26). Overall, 20–25 PPE sets were required per patient, with variable HCW compliance for wearing these items (93% N95 masks, 77% gowns, 83% gloves, and 73% eye protection). Up to 41% of HCW close contacts would have qualified for postexposure antiviral prophylaxis. These data indicate that many current national stockpiles of PPE and antiviral medication are likely inadequate for a pandemic.
doi:10.3201/eid1310.070033
PMCID: PMC2851524  PMID: 18258004
Influenza; avian; pandemic; antivirals; health resources; infection control; healthcare workers; disease transmission; research
14.  Peritonitis Due to Curvularia inaequalis in an Elderly Patient Undergoing Peritoneal Dialysis and a Review of Six Cases of Peritonitis Associated with Other Curvularia spp. 
Journal of Clinical Microbiology  2005;43(8):4288-4292.
Fungal peritonitis due to Curvularia species in patients undergoing peritoneal dialysis is a very rare problem. We report a case of peritonitis caused by Curvularia inaequalis. This is the first report in the English literature of this species causing human infection. We also review the six previously reported cases of continuous ambulatory peritoneal dialysis peritonitis caused by other Curvularia species.
doi:10.1128/JCM.43.8.4288-4292.2005
PMCID: PMC1233934  PMID: 16082004
15.  Melioidosis in Tsunami Survivors 
Emerging Infectious Diseases  2005;11(10):1638-1639.
doi:10.3201/eid1110.050740
PMCID: PMC3366758  PMID: 16355505
tsunami; pneumonia; melioidosis; letter

Results 1-15 (15)