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Melioidosis: Treatment and prevention

Melioidosis: Treatment and prevention
Literature review current through: Jan 2024.
This topic last updated: Nov 17, 2023.

INTRODUCTION — Melioidosis is a clinically diverse disease caused by the facultative intracellular gram-negative bacterium, Burkholderia pseudomallei [1-3]. This organism is a widely distributed environmental saprophyte in soil and fresh surface water in endemic regions [4]; the risk of acquiring the infection occurs in these same areas.

The treatment and prognosis of melioidosis will be presented here. The epidemiology, pathogenesis, clinical manifestations, and diagnosis of melioidosis are discussed separately. (See "Melioidosis: Epidemiology, clinical manifestations, and diagnosis".)

ANTIBIOTIC RESISTANCE — B. pseudomallei are intrinsically resistant to penicillin, ampicillin, first- and second-generation cephalosporins, gentamicin, tobramycin, and streptomycin [5-7]. In vitro susceptibility testing of B. pseudomallei for quinolones generally show resistance or intermediate results, and disc diffusion techniques can give "false-sensitive results" [7,8].

The main therapeutic options for melioidosis include beta-lactams (eg, ceftazidime, certain beta-lactam-beta-lactamase inhibitor combinations), carbapenems, trimethoprim-sulfamethoxazole (TMP-SMX), and doxycycline, depending on the phase of treatment. (See 'Initial intensive therapy' below and 'Subsequent eradication therapy' below.)

Naturally occurring resistance is uncommon with ceftazidime and has not been reported with carbapenems, which retain activity against B. pseudomallei isolates with decreased susceptibility to ceftazidime and amoxicillin-clavulanate [9]. However, emergence of resistance in B. pseudomallei during therapy has been documented with all the therapeutic options [10-18]. As an example, decreasing meropenem susceptibility during antibiotic treatment has been reported in association with overexpression of efflux pumps [18].

Earlier studies from Thailand and elsewhere had reported high levels of TMP-SMX resistance; however, subsequent studies from multiple locations have confirmed that resistance of B. pseudomallei to TMP-SMX is extremely uncommon and that the earlier reports were due to methodological issues with susceptibility testing [19-21].

INITIAL INTENSIVE THERAPY — The objective of the initial intensive phase of treatment is to prevent mortality from severe illness associated with melioidosis. We treat all cases of melioidosis with at least two weeks of intravenous antibiotic therapy followed by oral antibiotic eradication therapy. We do this even for apparently mild cases, which are relatively uncommon, because of the high rate of concomitant bacteremia (in approximately half of cases), the potential for deterioration, and the lack of data indicating that oral regimens are comparable with the preferred parenteral regimens in the acute settings.

For selected patients with septic shock, we also use granulocyte-colony stimulating factor (G-CSF) during the initial intensive phase of therapy in addition to supportive care.

Antibiotic therapy

Primary parenteral agent

Non-critically ill patients without CNS infection — For patients with suspected or confirmed melioidosis who do not require intensive care unit (ICU)-level care and do not have central nervous system (CNS) infection, we suggest ceftazidime (50 mg/kg up to 2 g intravenously [IV] every six to eight hours) for initial intensive therapy. We typically use 2 g every six hours to allow more frequent dosing and because this generally results in the 120 mg/kg daily dose evaluated in one of the original trials of ceftazidime. Ceftazidime can also be dosed 1 g IV every three hours or even as a continuous infusion. Continuous infusion administration can facilitate early discharge for home IV therapy and also has theoretical pharmacokinetic advantages of optimizing the time that drug levels exceed the minimum inhibitory concentration (MIC) [22]. (See "Prolonged infusions of beta-lactam antibiotics", section on 'Pharmacologic advantage'.)

Ceftazidime became the preferred agent for intensive therapy based upon the results of a 1989 open-label, randomized trial in Thailand in which ceftazidime (120 mg/kg per day) resulted in a 50 percent reduction in overall mortality among patients with severe melioidosis compared with a three-drug regimen of chloramphenicol, trimethoprim-sulfamethoxazole (TMP-SMX), and doxycycline (37 versus 74 percent, relative risk [RR] 0.5, 95% CI 0.19-0.81) [23]. A mortality benefit was seen in another randomized trial of initial intensive therapy with ceftazidime in combination with TMP-SMX compared with the same non-ceftazidime-based three-drug regimen in the preceding trial [24]. However, patients in the non-ceftazidime group in that trial were sicker at presentation, which reduces confidence in the results. Subsequent trials in patients with severe melioidosis did not identify a difference in mortality with ceftazidime compared with ceftazidime in combination with TMP-SMX (25 versus 27 percent) [25].

Although subsequent data have supported the use of meropenem or imipenem for patients with critical illness, we continue to favor ceftazidime for patients without critical illness because of its established efficacy as well as its narrower spectrum and lower cost compared with the carbapenems. Meropenem or imipenem are potential alternatives for patients without critical illness who cannot use ceftazidime. We also switch to meropenem for patients who are worsening or have persistently positive blood cultures at seven days despite ceftazidime therapy. (See 'Critically ill patients' below.)

High-dose IV amoxicillin-clavulanate (160 mg/kg per day) is generally not recommended for intensive therapy, as it was shown to result in a higher overall therapeutic failure rate (combined mortality and treatment failure) than ceftazidime [26].

Ceftriaxone and cefotaxime are also not appropriate alternatives to ceftazidime for therapy of confirmed melioidosis. In a retrospective study, initial use of these agents was associated with a higher risk of mortality, even if they were later switched to ceftazidime [27].

Critically ill patients — For patients with disease severe enough to require ICU admission, we use meropenem (25 mg/kg up to 1 g IV every eight hours) as initial therapy. Imipenem (25 mg/kg up to 1 g IV every six hours) is an alternative, although it is associated with more neurologic side effects. Care of patients with severe sepsis and septic shock also involves additional non-antibiotic measures (see 'Patients with severe sepsis and septic shock' below). Once patients who do not have CNS infection have improved enough to no longer require ICU-level care, we switch the carbapenem to ceftazidime to complete the course of initial intensive therapy. (See 'Non-critically ill patients without CNS infection' above.)

Clinical data suggest that carbapenems are at least as effective as ceftazidime (the agent of choice for patients without critical illness) and may be superior for severe infection. In a randomized trial in Thailand of almost 300 patients with severe suspected melioidosis (214 of whom were ultimately culture confirmed), the in-hospital mortality rate was not statistically different with imipenem at 50 mg/kg per day versus ceftazidime at 120 mg/kg per day (36 versus 38 percent), although the rate of treatment failure was lower with imipenem (38 versus 50 percent) [28].

Observational data suggest that meropenem may confer a mortality benefit. In a retrospective study of all ICU-managed cases of severe melioidosis in the tropical Top End of the Northern Territory in Australia from 1989 to 2013, mortality decreased from 92 percent during the first eight years of the study to 26 percent during the last eight years [29]. There was a precipitous drop in mortality between 1996 and 1998, coincident with the introduction of meropenem as a first-line agent for severe melioidosis, in addition to implementation of intensivist-led care and adjunctive G-CSF. In an earlier study from the same institution, treatment with meropenem (n = 63) was associated with similar mortality rates as ceftazidime (n = 154; 19 versus 18 percent), even though patients who received meropenem were more likely to have severe sepsis and bacteremia [30]. Among the 49 patients with severe sepsis, meropenem was associated with a lower mortality rate than ceftazidime (26 versus 76 percent).

In vitro data also support the preferential use of carbapenems for severe infection. Meropenem and imipenem have the lowest MICs against B. pseudomallei [9-11,31-33]. Furthermore, in vitro time-kill studies to measure the rate of bacterial killing have shown that the carbapenems perform better against B. pseudomallei than ceftazidime [11], including for various resistant isolates [9].

The rationale for switching from meropenem to ceftazidime following clinical improvement to complete the initial intensive antibiotic course is mainly for antibiotic stewardship. There are also emerging data describing the development of meropenem resistance during treatment, which also supports the approach. (See 'Antibiotic resistance' above.)

Patients with CNS involvement — For patients with neurological melioidosis, we use meropenem and administer it at a higher dose (40 mg/kg up to 2 g IV every eight hours) than for patients without central nervous system (CNS) involvement. Our rationale for using meropenem in this situation is the same as for those who are critically ill; most patients with CNS involvement are critically ill. (See 'Critically ill patients' above.)

Adjunctive antibiotic for non-pulmonary focal infection — For patients with non-pulmonary focal sites of infection, such as neurologic, prostatic, bone, joint, cutaneous, and soft tissue melioidosis, we suggest the addition of TMP-SMX to ceftazidime or a carbapenem during initial intensive therapy. We do not routinely add TMP-SMX for patients with melioidosis who have pneumonia without another focus of infection or have bacteremia without an evident focus.

The dose of TMP-SMX used in intensive therapy varies by age and weight [2,34]. Folic acid (0.1 mg/kg up to 5 mg orally [PO] daily) is also given to prevent or reduce the potential toxicity of the antifolate activity.

For children – TMP-SMX 6 mg/kg of the trimethoprim component [max 240 mg] IV or PO twice daily

For adults weighing 40 to 60 kg – TMP-SMX 240 mg of the trimethoprim component IV or PO twice daily

For adults weighing >60 kg – TMP-SMX 320 mg of the trimethoprim component IV or PO twice daily

Our rationale for adding TMP-SMX for non-pulmonary focal infection is the excellent tissue penetration and intracellular activity of TMP-SMX; there is also the possibility of decreasing the emergence of antimicrobial resistance with combination therapy. (See 'Antibiotic resistance' above.)

However, the available clinical data have not demonstrated a clear benefit with the addition of TMP-SMX during the initial intensive phase of antibiotic treatment [25,35]. Two randomized controlled trials of 449 patients with suspected severe melioidosis in Thailand compared ceftazidime alone with ceftazidime plus TMP-SMX [25]. Although begun independently, the two trials were analyzed together as a prospective, individual-patient data meta-analysis; there was no difference in in-hospital mortality rate between the two groups (25 compared with 27 percent with combination therapy, odds ratio (OR) 0.88, 95% CI 0.46-1.6). A subsequent follow-up of the 190 patients from these trials who had culture-confirmed melioidosis and survived to hospital discharge also demonstrated no long-term benefit of the addition of TMP-SMX [35]. At a median of 71 weeks, there was no difference in mortality or culture-confirmed recurrent melioidosis between combination therapy versus ceftazidime alone (17.8 versus 18.3 percent).

Nevertheless, we continue to favor the addition of TMP-SMX in select patients with melioidosis for the reasons above and because the clinical trial was limited to patients with sepsis and did not include the full range of patients with melioidosis who could potentially benefit. Despite the lack of proven benefit, TMP-SMX is still routinely added to ceftazidime or a carbapenem in other centers.

The potential disadvantages of adding TMP-SMX are antagonism between the antimicrobials and increased toxicity [36]. Antagonism between many of the agents used for melioidosis has been demonstrated in vitro [6,37], but the clinical significance of this remains uncertain. In vitro time-kill studies have shown that adding TMP-SMX had no effect on the action of ceftazidime [11].

Duration of intensive antibiotic therapy — Initial intensive IV antibiotic therapy is given for at least 14 days [7,38,39], which is largely consistent with the duration administered in the clinical trials of intensive antibiotic therapy of melioidosis. However, longer durations of at least four to eight weeks are warranted in certain cases, such as patients who have prolonged critical illness, extensive pulmonary disease, deep-seated collections or organ abscesses, osteomyelitis, septic arthritis, or neurologic melioidosis (table 1) [39].

In resource-limited settings, prolonged IV therapy may not be feasible, and some experts in those settings favor a minimum IV antibiotic duration of 10 days before transitioning to an oral regimen [40]. However, we favor a minimum of 14 days whenever possible because of extensive clinical experience and observational data suggesting that this approach is associated with low relapse rates [41,42].

Specifically, in a retrospective study of over 200 patients with melioidosis who were treated with IV antibiotics for at least 14 days and with longer courses for the above situations, the rate of recrudescence while on therapy was 5 percent and the rate of relapse after therapy completion was 0.5 percent [41]. This was in contrast to the historical 5 percent relapse rate in that region when shorter IV therapy durations were used [43].

Additional management components

Abscess drainage — Prostatic abscesses usually require drainage since treatment failures have developed when this was not performed [44-46]. Drainage can be done under computed tomography (CT) or portable transrectal ultrasound guidance, which can be performed in ventilated patients. Mycotic aneurysms are increasingly recognized as occurring in melioidosis and require urgent surgery, often with insertion of prosthetic vascular grafts [47-49]. By contrast, other internal collections frequently resolve with medical therapy and rarely need to be drained [44].

Patients with severe sepsis and septic shock

Supportive care — Supportive care for patients with melioidosis and severe sepsis include the same measures as for sepsis from other causes and include IV fluid therapy, hemodynamic and ventilatory support, if needed, and prevention of complications of critical illness. These measures are discussed in detail elsewhere. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Supportive therapies' and "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Intravenous fluids (first three hours)'.)

In critically ill ventilated patients who are deteriorating despite standard supportive care and appropriate antibiotics, extracorporeal membrane oxygenation (ECMO) may be lifesaving, if available. (See "Extracorporeal life support in adults in the intensive care unit: Overview", section on 'Initial patient selection for specific ECLS mode'.)

Recombinant G-CSF for patients with septic shock — For patients with septic shock, we suggest consideration of recombinant human granulocyte-colony stimulating factor (G-CSF). For melioidosis, G-CSF is given as 300 mcg IV daily for 10 days (or longer, depending on clinical response) [39,50]. Because of uncertainty regarding the data, some experts choose not to use G-CSF. In resource-limited settings, the cost of G-CSF may be prohibitive.

In a trial in Thailand, 60 patients with suspected melioidosis and severe sepsis were treated with ceftazidime and randomly assigned to receive G-CSF or placebo [51]. Melioidosis was confirmed by culture in 18 patients given G-CSF and in 23 given placebo. G-CSF therapy resulted in a nonsignificant reduction in mortality overall (70 versus 87 percent, hazard ratio 0.81, 95% CI 0.61-1.06) and in the patients with culture-proven melioidosis (83 versus 96 percent, hazard ratio 0.87, 95% CI 0.7-1.1). The duration of survival was longer with G-CSF (34 versus 15 hours). The overall high mortality rate in this trial likely reflects the lack of other supportive measures in a resource-limited setting (eg, no invasive monitoring, limited ventilatory and inotropic support, no dialysis).

The trend in reduced mortality with G-CSF was also suggested by a retrospective study from the Northern Territory of Australia where G-CSF was adopted for use in patients with septic shock due to melioidosis in 1998 [44,52,53]. In that study, the mortality rate among 42 patients with septic shock and culture-confirmed melioidosis who were treated with G-CSF was dramatically lower than that among historical controls who had not received G-CSF (10 versus 95 percent) [53]. Potential confounders that could have contributed to the lower mortality rate included earlier use of effective antibiotics and adoption of a closed intensive care model in the later G-CSF period.

The theory behind the effect is that melioidosis has been associated with functional neutrophil defects, which may be ameliorated by G-CSF.

Monitoring and expected clinical course — Patients should be closely monitored during the initial intensive phase of therapy, with routine evaluation of complete blood count, renal function, and liver function to identify any complications. Symptom resolution in melioidosis is often slower than that seen with other infections and lack of improvement within 24 hours of antibiotic therapy initiation is common [54]. Average time to fever resolution in older studies was nine days, and intermittent fevers have been observed for up to one month.

Patients who presented with bacteremia should have repeat blood cultures every other day until negative [54]. Failure to clear blood cultures by seven days and clinical deterioration during therapy are suggestive of treatment failure and warrant re-examination of the management approach. This includes a switch from ceftazidime to meropenem, the addition of TMP-SMX to ceftazidime or meropenem, and evaluation for deep abscesses or sites of infection that may benefit from drainage or debridement.

SUBSEQUENT ERADICATION THERAPY

Rationale — Eradication therapy, which begins immediately following the initial intensive antibiotic regimen, is considered necessary to prevent relapse of melioidosis. (See 'Risk of relapse' below.)

The use of eradication therapy is supported by observational studies that suggest a higher rate of relapse with short oral antibiotic courses after initial therapy [55-57]. As an example, in a study from Thailand that included nearly 900 patients with culture-confirmed melioidosis who survived the initial intensive treatment phase to receive oral therapy, the relapse rate was 10 percent [56]. In a multivariate analysis, receipt or an appropriate oral regimen for 12 to 16 weeks was associated with a 90 percent lower relapse rate than treatment with less than eight weeks of oral antibiotics. Among those who relapsed, 79 percent had received less than eight weeks of oral antibiotics, compared with 27 percent among those who had no recurrence.

Regimen selection — We suggest oral (PO) trimethoprim-sulfamethoxazole (TMP-SMX) alone for eradication therapy. The dosing varies by weight and age. Folic acid (0.1 mg/kg up to 5 mg PO daily) is also given to prevent or reduce the potential toxicity of the antifolate activity:

For children – TMP-SMX 6 mg/kg of the trimethoprim component up to 320 mg orally twice daily

For adults weighing 40 to 60 kg – TMP-SMX 240 mg of the trimethoprim component orally twice daily

For adults weighing >60 kg – TMP-SMX 320 mg of the trimethoprim component (two double-strength tablets) orally twice daily

Doxycycline (100 mg twice daily or 200 mg once daily) is an alternative agent when TMP-SMX cannot be used because of intolerance or toxicity; it appears to be less effective than TMP-SMX.

TMP-SMX plus doxycycline has been used for eradication therapy in some parts of the world, but TMP-SMX appears to be the critical component of this combination regimen. This was supported by the results of a randomized, multicenter, double-blind trial in Thailand in which 626 patients with culture-confirmed melioidosis received TMP-SMX plus placebo or doxycycline for at least 20 weeks as eradication therapy [58]. After a median follow-up of 17 to 19 months, there was no difference in the rates of culture-confirmed recurrent melioidosis between the two groups (5 versus 7 percent with TMP-SMX plus placebo and TMP-SMX plus doxycycline, respectively; HR 0.81, 95% CI 0.42-1.55). There was a higher rate of adverse drug reactions with TMP-SMX plus doxycycline. Similarly, the standard use of TMP-SMX alone for melioidosis eradication therapy in the Northern Territory, Australia was associated with good outcomes, with relapses being almost exclusively limited to noncompliant patients [44]. Although dosing of TMP-SMX historically varied across studies, after a pharmacokinetic modeling study suggested that sufficient levels are achieved with the weight-based approach listed above, those doses became standard [34,50].

An earlier trial of eradication therapy in Thailand evaluated combination therapy with chloramphenicol (first four weeks only), TMP-SMX, and doxycycline versus doxycycline alone [59]. Relapses were significantly higher with doxycycline alone. Similar failures of doxycycline alone as eradication therapy have been noted in the Northern Territory [60], with some B. pseudomallei relapse isolates showing acquired doxycycline resistance [12]. Nevertheless, doxycycline is the preferred alternative agent for eradication therapy in those in whom TMP-SMX is contraindicated or TMP-SMX is ceased because of adverse events such as renal impairment, bone marrow suppression, rash, or intractable nausea. A subsequent randomized trial in Thailand found no benefit from adding chloramphenicol to a TMP-SMX plus doxycycline regimen [61].

Amoxicillin-clavulanate is less effective in preventing relapse than eradication therapy with TMP-SMX and doxycycline with or without chloramphenicol [7,62]. Amoxicillin-clavulanate is recommended for eradication therapy in pregnancy in Thailand and in younger children if there is TMP-SMX resistance or intolerance, but attention must be paid to correct recommended dosing (20/5 mg/kg orally three times daily), which is more than the standard amoxicillin-clavulanate dosing used for common conditions [63].

Oral quinolones are not recommended for melioidosis. They are associated with high treatment failure and relapse rates when given alone or in combination with azithromycin [64-66]. There are also concerns about inaccurate in vitro susceptibility testing. (See 'Antibiotic resistance' above.)

Duration and monitoring — The optimal duration of eradication therapy is unknown. We suggest a minimum of three months (table 1) (see 'Rationale' above). For patients with osteomyelitis or neurologic melioidosis, we extend the duration to six months. Even longer durations, and potentially lifelong therapy, may be necessary following vascular surgery with grafts for mycotic aneurysms. As above, shorter durations of eradication therapy have been associated with higher rates of relapse. (See 'Rationale' above.)

Close follow-up is important for monitoring the clinical response and for adverse drug effects. We check complete blood count and kidney and liver function tests twice weekly initially, and then extend to weekly, then monthly checks, depending on patient circumstances [36].

The importance of monitoring was highlighted by a study of 203 Australian patients who received TMP-SMX as eradication therapy [36]. Sixty-one patients (30 percent) experienced adverse effects that warranted cessation of therapy, antibiotic switch, or dose reduction. The adverse effects included acute kidney injury (36 percent), bone marrow suppression (21 percent), rash (23 percent), and drug reaction with eosinophilia syndrome (DRESS; 3 percent).

PROGNOSIS

Risk of relapse — Earlier studies using molecular typing of isolates from recurrent melioidosis showed that the majority were true relapses from failed eradication rather than new infection [55,56,60,67-69]. This was illustrated in a retrospective study of 889 Thai patients with culture-confirmed melioidosis who survived and underwent follow-up: 86 patients (9.7 percent) relapsed and 30 (3.4 percent) became reinfected [56].

However, a subsequent analysis of the Darwin prospective melioidosis study from Australia documented that since the late 1990s, recurrent melioidosis has become very uncommon [42]. In this analysis, molecular typing of isolates from recurrent melioidosis cases suggested a shift from predominantly relapsed infection to predominantly reinfection. The decreased rate of relapse cases was attributed to improved antibiotic therapy and, in particular, prolongation of the intensive intravenous (IV) phase [41,70].

Although oral eradication therapy is associated with a lower rate of relapse, there are some reasons that oral eradication therapy is not always sufficient to eliminate relapse:

Relapses are more common in patients with severe disease compared with those with localized melioidosis (relative risk 4.7 for severe infection in one series) [55], emphasizing the importance of a sufficiently long duration of preceding IV intensive therapy to facilitate clearance of high bacterial burdens. Multifocal distribution of disease and positive blood cultures have also been associated with relapse [56].

Another important factor is poor compliance [12,55,60,62]. In the Northern Territory, attempts have been made to maximize compliance cases by regular follow-up during the eradication phase, with free antibiotics and action plans for defaulters, analogous to tuberculosis programs [44].

Treatment of relapses usually requires reinitiation of IV intensive therapy, followed by eradication therapy. Surgical drainage of any persisting collections may be required, and antimicrobial susceptibility testing of relapse isolates is critical to exclude acquired resistance to standard therapies.

Mortality — With early diagnosis and institution of therapy with ceftazidime or meropenem and access to state-of-the-art intensive care therapy, the overall mortality from melioidosis can now be under 10 percent. Nevertheless, the mortality risk depends on the clinical syndrome.

For patients with non-bacteremic melioidosis who receive adequate initial intensive and eradication therapy, the prognosis is excellent. In a series of cases from the Northern Territory between 1989 and 1999, the mortality rate was only 4 percent in such patients [44,60]. There were also no fatalities in those with chronic melioidosis (symptoms of >2 months duration before diagnosis). However, among patients with bacteremia, the mortality rate was 37 percent.

In a randomized controlled treatment trial in Thailand, the following were identified as being independent risk factors for death and treatment failure [25]:

Bacteremia (odds ratio [OR] 2.9)

Respiratory failure (OR 6.7)

Renal failure (OR 3.1)

Similarly, the prognosis of neurologic melioidosis is guarded. In a series of 12 cases from the Northern Territory, five required prolonged intubation, three died, and only three made a complete recovery [71].

Although fulminant melioidosis can occur in healthy individuals, severe disease and fatalities are uncommon in those without defined risk factors (eg, diabetes mellitus, excessive alcohol use, chronic renal disease, chronic lung disease, and immunocompromising conditions, most commonly corticosteroid therapy) when there is access to adequate medical care [72]. In the Northern Territory prospective melioidosis study, only 2 of the 77 fatalities amongst 540 melioidosis patients did not have an identifiable risk factor for melioidosis, and both these patients were older adults (75 and 82 years old) [43]. In that study, both presence of one or more defined risk factors for melioidosis (OR 9.4) and age ≥50 years (OR 2.0) were independent risk factors for death. (See "Melioidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Risk factors'.)

PREVENTION

Avoiding exposure — In endemic areas, individuals with risk factors for melioidosis should avoid skin exposure to soils and surface water during the wet season and should stay indoors during severe weather events when there may be potential aerosolization of B. pseudomallei. Those with cystic fibrosis should avoid travel to melioidosis-endemic regions during the wet season. (See "Melioidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Geographic distribution'.)

Post-exposure prophylaxis — Potential indications for post-exposure prophylaxis against B. pseudomallei include inadvertent laboratory exposure and exposure following a bioterrorism event. In the United States, the Centers for Disease Control and Prevention also recommended post-exposure prophylaxis for selected individuals who were exposed within the prior seven days to an aromatherapy room spray that was implicated as a common source of four non-travel-related cases (two fatal) in 2021 [73,74].

Trimethoprim-sulfamethoxazole (2 double-strength tablets every 12 hours in adults weighing >60 kg) is the recommended regimen for post-exposure prophylaxis; amoxicillin-clavulanate (1500 mg/375 mg every 8 hours in adults weighing >60 kg) is the alternative [54,75]. Each is given for 21 days and should be started as soon as possible following the exposure.

Support for post-exposure prophylaxis comes mainly from animal studies; there are no clinical studies informing the efficacy of prophylaxis [75].

SUMMARY AND RECOMMENDATIONS

Overview of therapy – Treatment of melioidosis consists of an intensive phase with parenteral antibiotics to prevent mortality from severe illness followed by an eradication phase with oral antibiotics to prevent relapse. (See 'Initial intensive therapy' above and 'Subsequent eradication therapy' above.)

Initial primary parenteral antibiotic – For initial antibiotic therapy of patients with melioidosis, we recommend ceftazidime or a carbapenem (meropenem or imipenem) rather than other antibiotic options (Grade 1B):

For initial antibiotic therapy of patients who are critically ill, we suggest meropenem rather than ceftazidime (Grade 2C). We also use meropenem for patients with CNS involvement, most of whom are critically ill. Our preference is based on observational evidence suggesting that meropenem is associated with a mortality benefit compared with ceftazidime for such patients. The dose of meropenem is 25 mg/kg up to 1 g intravenously (IV) every eight hours for patients without CNS involvement and 40 mg/kg up to 2 g every eight hours for those with CNS involvement. Imipenem is a reasonable carbapenem alternative to meropenem. (See 'Critically ill patients' above.)

We use ceftazidime in patients who are not critically ill and do not have CNS involvement. For such patients, ceftazidime is as effective as carbapenems. The dose of ceftazidime is 50 mg/kg up to 2 g IV every six to eight hours; we typically use 2 g every six hours. (See 'Non-critically ill patients without CNS infection' above.)

Adjunctive G-CSF for septic shock – For patients with septic shock, we also suggest recombinant human granulocyte-colony stimulating factor (G-CSF) (Grade 2C). G-CSF is given as 300 mcg IV daily for at least 10 days. Because of uncertainty regarding the data, some experts choose not to use G-CSF. Cost may also be prohibitive in resource-limited settings. (See 'Recombinant G-CSF for patients with septic shock' above.)

Adjunctive antibiotics for select patients – For patients with non-pulmonary organ focal sites of infection (eg, neurologic, prostatic, bone, joint, cutaneous, and soft tissue melioidosis), we suggest the addition of TMP-SMX to ceftazidime or a carbapenem during initial intensive therapy (Grade 2C); TMP-SMX has excellent tissue penetration and thus may be of benefit in such infections. We do not routinely add TMP-SMX for patients who have pneumonia without another focus or have bacteremia without an evident focus. (See 'Adjunctive antibiotic for non-pulmonary focal infection' above.)

Duration of initial therapy – The optimal duration of initial intensive antibiotic therapy is uncertain; IV antibiotics are typically given for at least 14 days, but longer durations are warranted in certain complicated or deep-seated cases (table 1). Symptom resolution in melioidosis is often slower than that seen with other infections; average time to fever resolution is nine days. Failure to clear blood cultures (if initially positive) by seven days or clinical deterioration during therapy suggest potential treatment failure. (See 'Duration of intensive antibiotic therapy' above and 'Monitoring and expected clinical course' above.)

Eradication phase of treatment – For all patients with melioidosis, we suggest following the initial parenteral antibiotic course with an oral antibiotic regimen for at least three months to prevent relapse (table 1) (Grade 2C). We recommend oral TMP-SMX alone rather than doxycycline or the combination of the two (Grade 1A). The dose of TMP-SMX varies by weight and age; for most adults, it is 320 mg of the trimethoprim component (two double-strength tablets) orally twice daily. (See 'Subsequent eradication therapy' above.)

Prognosis – With antibiotic therapy and intensive care, the estimated overall mortality can be less than 10 percent; however, mortality is higher in patients with bacteremia. Most deaths occur in patients with underlying risk factors (eg, diabetes mellitus, excessive alcohol use, chronic renal disease, chronic lung disease, and advanced age). (See 'Prognosis' above.)

Prevention – The main preventive strategy is avoiding exposure in endemic areas. This involves avoiding skin exposure to soils and surface water during the wet season and staying indoors during severe weather events. (See 'Prevention' above.)

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Topic 3136 Version 24.0

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