Although, thus far, resistance to clinically significant antibiotics in B. pseudomallei
is relatively rare, there is mounting evidence that resistance is more prevalent than previously thought. Not surprisingly, resistance is emerging in response to antimicrobial treatment, both during the intensive and eradication phase, and may become a more prevalent issue with more widespread use of antibiotics throughout regions with endemic melioidosis. Given the paucity of antimicrobial agents useful for melioidosis therapy, resistance to any of the currently used key antibiotics severely undermines the ability to successfully treat the disease. Resistance to carbapenems has not yet been observed and, apart from clinical manifestations that warrant their use, carbapenems should therefore remain drugs of last resort. As mentioned previously, mobile genetic elements, such as plasmids, seem notably absent from B. pseudomallei
. However, many strains are naturally transformable [81
], and conjugative plasmids can be introduced and, with selective pressure, stably maintained in B. pseudomallei
]. Some conjugative multiresistance determinants, especially those containing carbapenemases, including NDM-1 [83
] are disseminating rapidly worldwide [84
] and challenge the treatment of Gram-negative infections. Since many of the regions where carbapenemases and other resistance determinants are emerging overlap with those that are endemic for B. pseudomallei,
it will be wise to monitor drug-resistant B. pseudomallei
for resistance determinants known to be associated with mobile elements.
Understanding resistance mechanisms provides tangible benefits, such as the development of PCR-based assays for rapid detection of known resistance alleles. For example, a SYBR®
Green-based mismatch amplification mutation assay was developed for the detection of single nucleotide polymorphisms in B. pseudomallei penA
that result in ceftazidime resistance [34
]. Ceftazidime-resistant isolates carrying the PBP3 deletion do not grow on common laboratory media unless they are supplemented with glycerol [35
]. The ceftazidime-resistant Thai patient isolates were detected because they were fortuitously plated on Ashdown’s agar, which contains glycerol [59
]. However, this is not common practice and one of the lessons learned from this study is that, following ceftazidime therapy, patient isolates should be routinely plated onto Ashdown’s agar so that the growth-deficient resistant variants can be detected early.
Owing to B. pseudomallei
’s biothreat potential and with no viable vaccine in the pipeline [85
], there is continued interest in developing alternative therapeutic agents that are not (yet) subject to existing resistance mechanisms. Potential novel therapeutic approaches, such as immunoantimicrobial therapy [87
] and use of anti-inflammatories, such as glyburide [88
], have been described, but the perceived patient benefits are, to date, largely observational and will need to be clinically proven. Other, mostly experimental, strategies (e.g., isocitrate lyase inhibitors and silver carbine compounds, among others) have been reviewed [89
]. Most promising are novel compounds in various stages of preclinical or clinical development with activity against B. pseudomallei.
Basilea Pharmaceutica’s (Basel, Switzerland) sulfactam BAL30072 exhibits stellar in vitro
efficacy against B. pseudomallei
]; however, the compound’s in vivo
efficacy in animal models is yet unknown. Several other pharmaceutical companies presented data at diverse scientific meetings on novel developmental compounds with in vitro
and in vivo
efficacy against B. pseudomallei.
These include novel tetracyclines from Tetraphase Pharmaceuticals (MA, USA) [90
], novel GyrB/ParE inhibitors from Trius Therapeutics (CA, USA) [91
] and EV-035 from Evolva SA (Switzerland) [92
]. Aside from the perceived need for new therapeutics for biodefense purposes, melioidosis is an emerging infectious disease and further development of novel antimicrobial agents with efficacy against a pathogen for which there is a paucity of efficacious anti-infectives is warranted.
With the increased attention that B. pseudomallei
received since its listing as a category B select agent [93
], our knowledge about its antimicrobial resistance mechanisms and their implications for treatment of melioidosis has significantly increased. At the time of writing of this review, several clinically significant chromosomally mediated resistance mechanisms have been described, including that of PenA β-lactamase, deletion of PBP3 and efflux (the roles of PenA and efflux are summarized in ). However, the picture is still rather incomplete and more research is needed to fill the remaining gaps in our knowledge.
Summary of Burkholderia pseudomallei resistance mechanisms compromising therapy with clinically significant antibiotics