International melioidosis treatment guidelines recommend a minimum 10 to 14 days’ intravenous antibiotic therapy (intensive phase), followed by 3 to 6 months’ oral therapy (eradication phase). This approach is associated with rates of relapse, defined as recurrence following the eradication phase, that can exceed 5%. Rates of recrudescence, defined as recurrence during the eradication phase, have not previously been reported. In response to low eradication phase completion rates in Australia, a local guideline has evolved over the last ten years recommending a longer minimum intensive phase duration for many cases of melioidosis. This retrospective cohort study reviews antibiotic duration for the first episode of care for all patients diagnosed with melioidosis and surviving the intensive phase during a recent three year period in the tropical north of Australia’s Northern Territory; we also review adherence to the current local guideline and treatment outcomes. Of 215 first episodes of melioidosis surviving the intensive phase, the median (interquartile range) intensive phase duration was 26 (14-34) days. One hundred and eight (50. 2%) patients completed eradication therapy; 58 (27. 0%) patients took no eradication therapy. At 28 months’ follow-up, one (0. 5%) relapse and eleven (5. 1%) recrudescences had occurred. On exact logistic regression analysis, the only independent risk factors for recrudescence were self-discharge during the intensive phase (odds ratio 6. 2 [95% confidence interval 1. 2-30. 0]) and septic shock (odds ratio 5. 3 [95% confidence interval 1. 1-25. 7]). Relapsed melioidosis is rare in patients who receive a minimum intensive phase duration specified by our guideline and extended according to clinical progress. Recrudescence rates may improve with reductions in rates of self-discharge. Given the low relapse rate despite a high rate of eradication therapy non-adherence, the duration and necessity of eradication therapy for different patients after guideline-concordant intensive therapy should be evaluated further.
Burkholderia pseudomallei, the cause of melioidosis, is a soil- and water-borne bacterium endemic to northern Australia and parts of south-east Asia [1]. It most commonly causes pneumonia, bacteremia without evident focus, deep-seated abscesses and skin infection but can affect almost any part of the body [2]. It causes more serious disease in patients with impaired innate immunity such as those with diabetes and has a high mortality rate ranging from 9% to 49% [3–5]. It is intrinsically resistant to most antibiotics and requires prolonged therapy for cure [5–8]. Current international guidelines suggest treatment with a minimum 10 to 14 days’ intravenous antibiotics (intensive phase) followed by 3 to 6 months’ oral antibiotics (eradication phase) [1,9, 10]. Options for the intensive phase include ceftazidime or a carbapenem [10–13]; options for the eradication phase include trimethoprim-sulfamethoxazole (TMP-SMX), doxycycline or amoxicillin-clavulanate [10,14–19]. Whilst there is provision in these international guidelines to extend the intensive phase to four weeks or greater in severe cases of melioidosis, the focus of the international guidelines is on switching to the eradication phase once the patient has been afebrile for 48 hours with negative blood cultures and an ability to take medication orally [9,10,17]. Despite treatment according to such guidelines, patients still have a high rate of relapse. In the Northern Territory (NT) of Australia, from 1989 to 2009,5. 2% of 465 patients surviving the intensive phase have had molecularly confirmed relapse [4,20]. In Thailand, rates of relapse between 1986 and 2004 were at least 9. 3% [5]. More recent data from a Thai randomized controlled trial demonstrated a relapse rate of somewhere between 1. 1% and 6. 4% [17]. Choice and duration of oral eradication therapy have been found to be the strongest risk factors for relapse [5]. A substantial proportion of our patients fail to complete the eradication phase and many live in remote communities making follow up difficult. In response to this, intensive phase therapy in our region has been progressively lengthened over the last 10 years. This is reflected in a local guideline developed at Royal Darwin Hospital (RDH) directing duration of therapy according to site of infection which in many cases extends intensive therapy far beyond defervescence with negative blood cultures and an ability to take oral antibiotics. In this study, we review antibiotic duration received by patients with melioidosis over a recent three year period, clinician and patient adherence to the local guideline and associated outcomes.
This study was a retrospective analysis of data from the ongoing Darwin Prospective Melioidosis Study [4,21], a prospective cohort study. The study size was determined by the number of patients diagnosed with melioidosis during a recent period in and since which the guideline being evaluated has remained substantially unchanged. All patients with culture-confirmed melioidosis in the tropical Top End of the NT diagnosed between 1st October 2009 and 30th September 2012 who survived the intensive phase were eligible for inclusion in the study. Antibiotic therapy was managed by the Infectious Diseases Department at RDH. Exclusion criteria included cases that represented recrudescence or relapse of melioidosis first diagnosed prior to 1st October 2009 and cases with incomplete or inaccessible records. Antibiotic type and duration were reviewed for both the intensive and eradication phases along with demographic, clinical and laboratory data; these data had been recorded prospectively as part of the ongoing Darwin Prospective Melioidosis Study [4,21]. Intensive phase was defined as the period of time during which the patient received intravenous therapy directed against B. pseudomallei irrespective of clinician-intended duration. Eradication phase was defined as the period of time commencing at the end of the intensive phase and finishing at the guideline-recommended end date of eradication therapy irrespective of actual duration received. Intensive and eradication therapy referred to the intravenous and oral antibiotics directed against B. pseudomallei during the intensive and eradication phase respectively. Recrudescence and recurrence were defined as return of clinical illness during and after the eradication phase respectively with concomitant culture of B. pseudomallei from a clinical specimen. Recurrence was further defined as either relapse or reinfection when isolates from the initial and subsequent illness were identical or different respectively by multilocus sequence typing (MLST) [20]. Cure was defined as the absence of death during the eradication phase or recrudescence or relapse at the end of the follow-up period. Risk factors were defined as in the Darwin Prospective Melioidosis Study [4]. Antibiotic duration-determining focus (ADDF) was the focus requiring the longest minimum intensive phase duration according to the local guideline; if there were two or more such foci requiring the same minimum intensive phase duration, the ADDF was whichever of these appeared lowest on Table 1, this being the focus generally considered most difficult to cure. Self-discharge was defined as voluntary cessation of inpatient status prior to completion of the clinician-planned intensive phase irrespective of guideline minimum duration. Non-adherence to eradication therapy was defined as cessation of eradication therapy prior to recrudescence or, if patients did not recrudesce, prior to the end of the eradication phase. The Darwin Melioidosis Guideline is summarized in Table 1. First line intensive therapy was ceftazidime unless the patient was in the intensive care unit (ICU) or allergic or intolerant to ceftazidime in which case meropenem was used. If there were a collection (including skin abscess or septic arthritis), bone or central nervous system (CNS) involvement, TMP-SMX, doxycycline or amoxicillin-clavulanate (in order of preference) was added early during the intensive phase for tissue penetration, usually orally. Subsequent oral eradication therapy used the same choice of these latter three antibiotics. Eradication phase was 90 days for each ADDF except osteomyelitis, CNS infection and arterial infection when 180 days was used. As noted in Table 1, there was a small change to the guideline on 1st October 2010; clinician adherence was assessed against the final version of the guideline. Patients who survived the intensive phase were generally reviewed at monthly infectious diseases outpatient visits until completion of eradication therapy. Where patients failed to attend appointments, eradication therapy was assumed to have ceased at the last infectious diseases appointment attended or the last of any subsequent entries documenting therapy in the RDH medical record or NT-wide shared electronic health record. Follow-up data until 1st December 2014 were included; follow-up between the last clinic appointment and 1st December 2014 was performed retrospectively by reviewing hospital and community shared electronic health records. Melioidosis is a notifiable disease in the NT; data on melioidosis recurrence were based on Australia-wide laboratory notification of positive cultures to the NT public health unit. Data not normally distributed were expressed as median ± interquartile range (IQR). Bivariate analysis of categorical and continuous variables was performed using the two-tailed Fisher exact test (due to low expected cell values) and the Wilcoxon rank-sum test respectively. Significant variables on bivariate analysis at p < 0. 05 were assessed by multivariate analysis using exact logistic regression; exact methods were used due to the infrequency of recrudescence. Stepwise elimination of variables least significant on bivariate analysis was performed until all variables remaining in the model were statistically significant. Analyses were performed using Stata version 12 (StataCorp, College Station, TX). This study was approved by the Human Research Ethics Committee of the NT Department of Health and the Menzies School of Health Research (HREC 02/38). As this was a retrospective observational study of a large dataset of a notifiable disease and data were analyzed anonymously, consent was not required.
Two hundred and fifty patients were diagnosed with melioidosis and managed by the RDH Infectious Diseases Department between 1st October 2009 and 30th September 2012. Twenty-seven (10. 8%) of these died during the intensive phase, one was a relapse of a case diagnosed prior to 1st October 2009 and a further seven had incomplete antibiotic data due to missing files or partially interstate treatment; these patients were excluded leaving 215 patients in the study. All 215 patients were followed up as outlined in the methods and data analysis was performed on all patients except where stated. Baseline characteristics are shown in Table 2. The median (IQR) age was 49. 6 (39. 0–60. 5) years; 119 (55. 3%) patients were male and 15 (7. 0%) were under 18 years of age. The cohort had a high rate of comorbidity with 181 (84. 2%) patients having at least one recognized risk factor for melioidosis. In addition, melioidosis was of characteristic severity with 128 (59. 5%) patients bacteremic, 47 (21. 9%) requiring intensive care and 32 (14. 9%) developing septic shock. Intensive therapy duration is shown in Table 3. The median (IQR) intensive phase duration for the 215 patients overall was 26 (14–34) days. Twenty (9. 3%) patients self-discharged during the intensive phase. Of 133 (61. 9%) patients who completed their intravenous therapy through the RDH Hospital in the Home program, the median (IQR) duration of infusor therapy was 14 (8–22) days. Median intensive phase duration according to ADDF is shown in Fig. 1. When self-dischargers were excluded, patients with bacteremia with no focus or osteomyelitis as an ADDF tended to have a longer intensive phase duration than the guideline minimum duration. For patients with bacteremia with no focus, the most common reasons for prolonged therapy were immunosuppression (1 on cancer chemotherapy, 1 on high dose dexamethasone for cerebral metastases and 1 with systemic lupus erythematosus-related neutropenia) and, in hindsight, incorrectly suspected other foci of infection (3 patients). Patients with osteomyelitis were more likely to have multifocal disease as depicted in Fig. 2 and tended to be slower to improve resulting in an extension of the intensive phase. Eradication phase duration was bimodal with one peak occurring at 90 days (93 [43. 3%] patients) and a second peak at 0 days (58 [27. 0%] patients). Only 108 (50. 2%) patients completed the guideline-specified eradication phase. In total, 70. 7% of eradication therapy days were with TMP-SMX; 29. 3% were with doxycycline. No patients received amoxicillin-clavulanate. Adherence to the guideline-specified minimum intensive phase duration by clinicians according to ADDF is demonstrated in Fig. 3; self-discharging patients are excluded as it was not possible for clinicians to adhere in these cases. Of the remaining 195 patients, 43 (22. 1%) received less than the guideline-directed minimum intensive phase duration. In most cases of clinician non-adherence, the ADDF was skin abscess, pneumonia or deep-seated collection. Of the pneumonia cases, most had minor degrees of hilar/mediastinal lymphadenopathy and did not receive four weeks’ intensive therapy; of the deep-seated collection cases, most occurred in the first year of the study when it was common for patients to receive two rather than four weeks’ intensive therapy from last drainage. Despite this, 42/43 (97. 7%) clinician non-adherent cases had cure of their infection. Of the 215 patients, 197 (91. 6%) patients were cured. The median (range) duration of follow-up from the onset of the eradication phase for these cured patients was 45. 9 (28. 4–61. 1) months. Six (2. 8%) patients died during the eradication phase. All six were palliated with eradication therapy ceased by the attending physicians prior to death. Five patients had incurable malignancy and one had advanced dementia. Two of the six patients had fever before dying but were not investigated due to their palliative status. A third patient, a 64 year old man with bacteremia with no focus, had been treated with four weeks’ ceftazidime followed by two weeks’ cotrimoxazole; this was then ceased due to a rash and was not replaced due to his palliative status in the context of squamous cell carcinoma of the lung with brain metastases, hypercalcemia and delirium requiring dexamethasone. He died 27 days after cessation of cotrimoxazole. Three days prior to dying he had a throat swab collected to investigate pneumonia; this grew B. pseudomallei 2 days after death. He was counted as a death during the eradication phase rather than a recrudescence as he was being actively palliated. The remainder of the six patients had no clinical evidence of infection prior to death. Eleven (5. 1%) patients recrudesced after their initial admission. The median (IQR) time to recrudescence from the end of the intensive phase was 24 (13–43) days; the median (IQR) time from the last day of taking eradication therapy was 10 (0–22) days with four (36%) patients still taking their eradication therapy when they recrudesced. Of these four, three had an appropriate intensive phase duration according to the guideline but two of these recrudesced with infected foreign bodies that had not initially been evident clinically (staghorn calculus and suspected vascular graft infection) and the third had bronchiectasis with persistent sputum positivity. Only one (0. 5%) relapse occurred. This was a 34 year old man with pneumonia, mediastinal lymphadenopathy and an undrained liver abscess who self-discharged after 15 days’ intensive therapy and took no eradication therapy. He relapsed 15 months later with severe sepsis due to worsening pulmonary abscesses and mediastinal lymphadenopathy but had a stable-appearing liver abscess. One (0. 5%) patient had reinfection. He was considered for the purpose of analysis to have had cure of his original infection. There were no patients with clinically-suspected but culture-unproven recrudescence or recurrence. Bivariate analysis was performed to assess for significant predictors of recrudescence. Patients who died during the eradication phase were excluded due to a shorter exposure to the possibility of recrudescence and a likely bias toward not diagnosing recrudescence due to the palliative nature of these patients. This left 209 patients in the analysis. Results of analysis of categorical variables are shown in Table 4. The median (IQR) age for patients who did and did not recrudesce was 46. 3 (41. 2 to 55. 6) and 49. 6 (38. 8–59. 9) years respectively (p = 0. 47). The only variables significantly predicting recrudescence were diabetes, having osteomyelitis as an ADDF, admission to ICU, septic shock and self-discharge. Multivariate analysis showed that only two of these variables were statistically significant independent predictors of recrudescence; these were self-discharge (odds ratio 6. 2 [95% confidence interval 1. 2–30. 0, p < 0. 05]) and septic shock (odds ratio 5. 3 [95% confidence interval 1. 1–25. 7, p < 0. 05]). A subgroup analysis was performed on the 58 patients who took no eradication therapy; 52 (89. 7%) were cured, 2 (3. 4%) died during the eradication phase, 3 (5. 2%) recrudesced and 1 (1. 7%) relapsed.
We have developed a guideline for duration of intensive phase therapy for melioidosis that we think is responsible for the very low rate of relapse now seen in the Top End of the NT. Its immediate applicability in some developing regions is uncertain due to funding and resource issues. However, given the excellent cure rates with our intensive phase guideline despite poor adherence to subsequent eradication therapy, we believe that further research evaluating the duration and necessity of the eradication phase for different ADDFs is now warranted.
Melioidosis is an infection caused by the soil bacterium Burkholderia pseudomallei; patients usually present with pneumonia, blood-stream infection and/or skin or internal organ abscesses. Melioidosis occurs most commonly in northern Australia and parts of Southeast Asia. It has a high mortality rate and, with standard treatment, a relapse rate greater than 5%; patients who relapse often represent severely unwell. Treatment comprises an intensive (intravenous antibiotic) phase, followed by a prolonged eradication (oral antibiotic) phase. Previous studies have found that the intensive phase is important to prevent mortality, and the eradication phase is important to prevent relapse. However, these studies have not been designed to detect an effect of intensive therapy on relapse rate. We know that adherence to eradication therapy is poor, and many of our patients live remotely making follow-up difficult. In order to address this, we have developed a new treatment guideline which stipulates a longer intensive phase for most patients. We show that adherence to this guideline is associated with very low relapse rates despite poor adherence to eradication therapy. It is possible that for many patients the eradication phase could be shortened or avoided when this intensive phase guideline is followed; this requires further research.
Intravenous Therapy Duration and Outcomes in Melioidosis: A New Treatment Paradigm