Multi-Drug–Resistant Organisms in Burn Infections

Abstract

Background:

Infection is the most frequent complication after severe burns and remains the predominant cause of death. Burn patients may require multiple courses of antibiotics, lengthy hospitalizations, and invasive procedures that place burn patients at especially high risk for infections with multi-drug–resistant organisms (MDROs).

Methods:

The published literature on MDROs in burn patients was reviewed to develop a strategy for managing these infections.

Results:

Within a burn unit meticulous infection prevention and control measures and effective antimicrobial stewardship can limit MDRO propagation and decrease the antibiotic pressure driving the selection of MDROs from less resistant strains. Several new antimicrobial agents have been developed offering potential therapeutic options, but familiarity with their benefits and limitations is required for safe utilization. Successful management of MDRO burn infections is supported by a multifactorial approach. Novel non-antibiotic therapeutics may help combat MDRO infections and outbreaks.

Conclusions:

Multi-drug–resistant organisms are being identified with increasing frequency in burn patients. Effective sensitivity testing is essential to identify MDROs and to direct appropriate antibiotic choices for patient treatment.

Despite an overall decreasing incidence of burn injuries worldwide [1] and decreasing mortality rates over the past few decades associated with improvements in systems of care for burn-injured patients [2,3], the estimated 11 million burn injuries suffered worldwide each year continue to represent a substantial public health threat [4,5]. Burn wounds represent an ideal milieu for establishment of a primary wound infection, and interventions that have increasingly allowed burn victims to survive the initial physiologic insult contribute to the risk for pneumonias, urinary tract infections (UTIs), and blood stream infections (BSIs) [4,6,7]. Infection remains the most frequent complication of burn injuries and is the predominant cause of death [4,8 –10].

The widespread emergence of antimicrobial resistance represents a global crisis with attributable deaths projected to exceed 10 million annually by 2050 [11]. The U.S. Centers for Disease Control and Prevention reports more than 2.8 million antibiotic-resistant infections occur in the United States each year resulting in more than 35,000 deaths [12]. Multi-drug–resistant organisms (MDROs) are an increasingly frequent cause of burn infections [13 –17]. Burn victims often receive multiple courses of antibiotic agents, undergo invasive procedures, and require multiple and lengthy periods of hospitalization, all of which are associated with increased MDRO risk [4,6,18]. This review discusses the epidemiology and management of bacterial MDRO infections in burn victims with a focus on the mutually reinforcing measures of infection prevention and control, antibiotic stewardship, and appropriately targeted antibiotic agents, as well as technologies that may contribute to care in the future.

Epidemiology of MDROs in Burn Patients

The typical sequential stages that accompany the transition from initially sterile burn wound(s) to wound(s) infected with MDROs are well described [4,6,8]. Endogenous microbial flora initially predominate with gram-positive skin flora colonization of most wounds within the first two days, followed by gram-negative members of the respiratory and gastrointestinal tract flora within the subsequent few days. Although skin and soft tissue infections predominate during the early hospital course, nosocomial infections typically reflective of associated supportive medical intervention including ventilator-associated pneumonias (VAPs), catheter-associated UTIs, and catheter-associated BSIs tend to occur later with a median onset of more than 30 days [7].

Burn patients show a propensity for colonization and infection by pathogens associated with multi-drug resistance. Keen et al. [8] reported the 15 top bacterial organisms recovered in culture samples from patients at a U.S. military burn ICU during the period of 2003–2008. Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Staphylococcus aureus were the four most common micro-organisms, accounting for 76% of all isolates. These four pathogens consistently account for 65%–80% of all positive cultures from burn victims from geographically dispersed regions [15 –17,19]. The two remaining members of the MDRO-prone ESKAPE grouping [20], Enterococcus spp. and Enterobacter spp., are less common, but still clinically relevant in burn patients [8,16,17,19,21].

Infection Prevention and Control

Multi-drug–resistant organisms are strongly associated with burn center outbreaks [22], and addressing the MDRO threat hinges on appreciating the two potential origins of burn infection pathogens: endogenous flora (carried by the burn patient) under antimicrobial pressure during the hospital course and exogenous organisms (acquired within the facility via contact with healthcare workers or fomites) [6,9].

The impact of interventions aimed against fomites within the hospital setting on MDRO acquisition has been emphasized by Lindford et al. [23] where despite a pre-intervention colonization rate of 39%, a nearly eight-year elimination of multi-drug–resistant Acinetobacter spp. was demonstrated. Additionally, patients admitted to rooms occupied previously by a patient harboring an MDRO had a 10%–30% decrease in the likelihood of acquiring the same MDRO with enhanced terminal disinfection (ultraviolet [UV] device plus standard disinfectant, bleach instead of standard disinfectant, or bleach and UV device) [24]. Barbut et al. [25] achieved a nearly 85% reduction in methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii infection rates after implementation of an infection control bundle that included hydrogen peroxide vapor-based decontamination. An Acinetobacter baumannii outbreak in another burn center was similarly halted by use of an aerosolized hydrogen peroxide disinfection system [26].

Baier et al. [27] reported disrupting a MRSA outbreak in a burn intensive care unit that occurred despite a comprehensive set of pre-existing infection control measures by universal patient decolonization. Kim et al. [28] also reported a steep reduction in MRSA health-care–associated infections after the addition of universal nasal mupirocin decolonization of patients, which highlights effectively how endogenous colonizing strains can be a reservoir driving high MDRO infection rates.

Somewhat unexpectedly several reports have shown marginal effectiveness of universal contact precautions in limiting the spread of MDROs [29]. One study, however, found 42% of nursing assistants' hands were contaminated with Clostridium difficile spores after providing care for an infected patient despite wearing disposable gloves [30], and many burn unit outbreaks have been associated with hand carriage of pathogens [22]. The high rate of hand contamination identified after glove removal (but prior to hand disinfection) may explain why patient decolonization has halted some outbreaks, but universal precautions have shown mixed results [31].

Antimicrobial Stewardship and Rapid Diagnostics

Antimicrobial stewardship is defined commonly as coordinated efforts to ensure appropriate utilization of antimicrobial agents, and has been shown to improve patient outcomes, increase patient safety, and decrease the risk of Clostridium difficile [32]. The tight linkage between MDROs and burn infections is an additional justification for the vigilant exercise of antimicrobial stewardship because such activities have consistently been found to reduce the incidence of infection and colonization with MDROs, and are even more effective when coupled with infection control measures [33].

Technologies for rapid identification and antimicrobial susceptibility testing of pathogens play a central role in antimicrobial stewardship efforts [32,34]. As an example, the Accelerate PhenoTest™ BC Kit (Accelerate Diagnostics, Tucson, AZ) typically can provide pathogen identification and phenotypic antimicrobial susceptibility results for positive blood culture samples for the 14 bacterial pathogens and two Candida spp. covered by the system within seven hours versus the 48–72 hours required routinely by the current reference standard methods [35]. Such rapid data availability should support antimicrobial de-escalation and a substantial reduction in time to appropriate antimicrobial therapy in nearly half of all cases [36]. Comparable findings have been reported for multiplex polymerase chain reaction (PCR)-based systems, including Biofire^® Filmarray^® blood culture identification (BCID; bioMérieux, Marcy l'Etoile, France) [37] and Verigene^® systems (Luminex, Austin, TX) [38], both of which provide for the detection of multiple common bacterial pathogens and the presence of antibiotic resistance genes relevant to MDROs.

Ventilator-associated pneumonia is common in burn patients [4,39] and the administration of inadequate empiric antibiotic therapy is associated with worse patient outcomes [40]. New rapid diagnostic methods, several of which allow for MDRO identification, include systems harnessing multiplex PCR, peptide nucleic acid fluorescent in situ hybridization, automated microscopy, and analysis of exhaled breath condensate fluid or volatile organic compounds [40]. Some systems are already U.S. Food and Drug Administration (FDA)-approved for clinical use, and all portend an improved ability to accurately target causative pathogens diminishing the risk for VAP-associated selection of MDROs.

Peptide nucleic acid fluorescent in situ hybridization (PNA-FISH) is a method for rapid, culture-free identification of micro-organisms and FDA-approved kits for use with blood cultures are available, but has only been applied recently for the detection of pathogens within burn wounds in an animal model [41]. An ability to identify rapidly micro-organisms predominating within burn wounds could likewise assist in decreasing the antibiotic pressure selecting for MDROs.

Therapeutic Options for MDROs

Methicillin-resistant Staphylococcus aureus

Vancomycin remains a first-line option for MRSA infections [42], but appropriate dosing in burn patients is challenging because enhanced vancomycin clearance and dynamic renal function accentuate the risk of both underdosing and nephrotoxicity [43 –45]. Vancomycin trough concentrations of 15–20 mg/L are used routinely as a surrogate measure to determine adequate dosing, but area under the concentration time curve-based dosing has been associated with reduced risk of nephrotoxicity and improved outcomes in serious MRSA infections [46,47]. For MRSA isolates with vancomycin mean inhibitory concentration (MIC) >2 mcg/mL an alternative agent should be considered [42,44].

Daptomycin offers an alternative for MRSA wound infections and BSI, and relatively straightforward renal dosing makes it attractive in patients with dynamic renal function. Daptomycin, however, has no clinical utility in lung infections because of its inactivation by pulmonary surfactant. Moreover, increasing daptomycin MIC during therapy because of cell wall changes can be seen in prior vancomycin exposure [45,48]. Some experts favor doses of 8–10 mg/kg intravenous daily in the critically ill [45,48].

Linezolid is widely used to treat MRSA pneumonia, as well as skin and soft tissue infections. In critically ill patients it achieves high concentrations in pulmonary epithelial lining fluid and interstitial tissues [49]. Because of its bacteriostatic nature, it is not generally recommended for treatment of BSI and its prolonged use may be limited by tolerability [24].

A fifth-generation cephalosporin, the unique increased binding affinity of ceftaroline for PBP-2a has resulted in its primary role as an agent for the treatment of refractory MRSA infections [50]. The first report of successful ceftaroline use in a burn-related infection details treatment of MRSA pneumonia complicating an inhalation injury in which ceftaroline was dosed 600 mg every eight hours as a prolonged two-hour infusion (Table 1) to compensate for the altered pharmacokinetics of a burn victim [51]. A recent systematic review noted that 12 of 22 studies utilized every eight-hour dosing [52]. Analyses have suggested a higher rate of adverse drug reactions (17%–21% of patients overall), including severe neutropenia, thrombocytopenia, eosinophilia, and rash, than those found during pre-approval clinical trials, particularly with courses of therapy of more than 21 days [50,53,54]. Methicillin-resistant Staphylococcus aureus resistance to ceftaroline is well documented and may be high in some geographic regions even prior to introduction of the drug [42,55].

Table 1.

Characteristics of Recently Approved Antibiotic Agents for Multi-Drug–Resistant Gram-Positive Organisms

Agent/date approved^a	Dose studied^b	Activity			Optimal PK-PD target	PD kill characteristics	Renal dose adjustment^c	Additional considerations^d
Agent/date approved^a	Dose studied^b	MRSA	VRE faecium	VRE faecalis	Optimal PK-PD target	PD kill characteristics	Renal dose adjustment^c	Additional considerations^d
Ceftaroline 2010	600 mg q12h	++^e	—	—	fT > MIC	Time-dependent	≤50	Consider ceftaroline 600 mg q8h infused over 2 h
Delafloxacin 2017	300 mg q12h	++	—	+/-	AUC_0-24:MIC	Concentration-dependent with time-dependence	≤50^f
Eravacycline 2018	1 mg/kg q12h	++	++	++	AUC_0-24:MIC	Concentration-dependent with time-dependence	Not required	Dose should be reduced for Child-Pugh C
Omadacycline 2018	100 mg q12h × 2 doses then q24h	++	++	++	AUC_0-24:MIC	Concentration-dependent with time-dependence	Not required	No dose adjustments are necessary for hepatic impairment
Lefamulin 2019	150 mg q12h	++	++	—	AUC_0-24:MIC	Concentration-dependent with time-dependence	Not required	Dose should be reduced for Child-Pugh C
Lefamulin 2019	150 mg q12h	++	++	—	AUC_0-24:MIC	Concentration-dependent with time-dependence	Not required	May cause fetal harm

Year of initial approval by U.S. Food and Drug Administration.

Intravenous dosing listed.

Estimated creatinine clearance (mL/min) at which dosing should be altered from routine dosing. In the setting of renal dysfunction requiring renal replacement therapy, or augmented renal clearance, most current literature evidence should be used to guide dose optimization.

Inter- and intra-patient PK/PD variability is appreciated in patients with burn injuries. Therapeutic drug monitoring should be considered to better inform optimal dosing of these agents.

++ coverage provided, +/- variable activity, — no coverage provided

Measured by estimated glomerular filtration rate calculated using the Modification of Diet in Renal Disease (MDRD) formula.

MRSA = methicillin-resistant Staphylococcus aureus; VRE = vancomycin-resistant Enterococcus; PK/PD = pharmacokinetics/pharmacodynamics; PD = pharmacodynamics; fT>MIC = percentage of time above MIC for free drug; AUC_0-24:MIC = 24-h area under the serum concentration-time curve (AUC) divided by the minimum inhibitory concentration (MIC).

Daptomycin combination regimens (especially with ceftaroline), have attracted attention for refractory MRSA bacteremia or deep-seated infections based on in vitro synergy data backed up by case series demonstrating success [48]. A randomized trial comparing vancomycin or daptomycin plus an anti-staphylococcal β-lactam versus standard therapy for initial MRSA BSI was terminated early because of an excess of acute kidney injury in the combination therapy group, and found no substantial improvement in the composite end point of mortality, persistent bacteremia, relapse, or treatment failure [56], suggesting combination therapies will require careful study prior to widespread utilization.

Eravacycline and omadacycline are recently approved tetracycline-derived antibiotics. Both are active in vitro against MRSA, achieve good lung penetration, and have in vivo efficacy for lung and skin and soft tissue infections in an animal model [57 –59]. Eravacycline is approved for complicated intra-abdominal infection (cIAI) and omadacycline for acute bacterial skin and skin structure infections as well as community acquired pneumonia, but limited clinical efficacy data for off-label applications (such as VAP or BSI) have been published to date [60].

Vancomycin-resistant enterococci

Vancomycin resistance is far more common in Enterococcus faecium than Enterococcus faecalis, but resistance to essentially all anti-gram–positive agents has been observed in both species [59,61]. Vancomycin-resistant enterococci (VRE) may retain susceptibility to β-lactams, but this is not typical. Linezolid and high-dose daptomycin (8–10 mg/kg per day) have been used as therapeutic options [62]. Development of daptomycin resistance is inversely related to increased susceptibility to β-lactams, leading to the successful utilization of daptomycin in combination with ampicillin, ceftriaxone and ceftaroline [61,62]. Eravacycline and omadacycline both display activity against VRE, but eravacycline's unpredictable urine concentrations limited its clinical efficacy in UTIs [63], and data for the efficacy of omadacycline in VRE UTIs are still limited.

Enterobacteriaceae

The Klebsiella pneumoniae carbapenemases (KPCs; Table 2) are one of the the most prevalent mechanisms for carbapenem resistance in Enterobacteriaceae worldwide [63], and the recently introduced β-lactam/β-lactamase inhibitor combinations, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and meropenem-vaborbactam (Table 3) have shown in vitro activity and clinical efficacy including in critically ill patients [63 –65].

Table 2.

Characteristics of Cinically Important β-Lactamases

Ambler class	Common name	Mediate resistance to	Examples
A	Narrow spectrum (penicillinase)	Penicillins, early cephalosporins	TEM-1/-2, SHV-1
A	Extended spectrum β-lactamase	Narrow- and extended-spectrum penicillins, cephalosporins	SHV-2, CTX-M
A	Serine carbapenemases	All β-lactams	KPC-2, KPC-3
B	Metallo-β-lactamase (carbapenemase)	All β-lactams except aztreonam	IMP-1, VIM-1, NDM-1
C	Cephalosporinases	Cephalosporins	AmpC, CMY-2
D	Oxacillinases	Oxacillin/cloxacillin	OXA-1, OXA-10
D	Cephalosporinases	Oxacillin/cloxacillin, cephalosporins	OXA-11, OXA-15
D	Carbapenemases	Oxacillin/cloxacillin, carbapenems	OXA-23, OXA-48

Table 3.

Characteristics of Recently Approved Antibiotic Agents Active Against Multi-Drug–Resistant Gram-Negative Organisms

Agent/date approved^a	Dose studied^b	Activity							Optimal PK-PD Target	PD kill characteristics	Renal dose adjustment^d	Additional considerations^e
		ESBL	CRE				CRPA	CRAB
		ESBL	Class A^c	Class B	Class C	Class D	CRPA	CRAB
Ceftolozane-tazobactam 2014	1.5–3 g q8h	+/-^f	—	—	++^g	—	++^g	—	fT>MIC >40%	Time-dependent	≤50	Continuous or prolonged infusion may be considered with CRPA infections or ACR.
Ceftolozane-tazobactam 2014	1.5–3 g q8h	+/-^f	—	—	++^g	—	++^g	—	fT>MIC >40%	Time-dependent	CVVH/CVVHD/CVVHDF: 1.5–3 g q8h
Ceftazidime-avibactam 2015	2.5 g q8h	++	++	—	++	+/-	++	—	fT>MIC >50–70%	Time-dependent	≤50
Ceftazidime-avibactam 2015	2.5 g q8h	++	++	—	++	+/-	++	—	fT>MIC >50–70%	Time-dependent	CVVH 1.5 g q8h
Meropenem-vaborbactam 2017	4 g q8h over 4 h	++	++	—	++	—	—	—	fT>MIC >40%	Time-dependent	≤50^h
Meropenem-vaborbactam 2017	4 g q8h over 4 h	++	++	—	++	—	—	—	fT>MIC >40%	Time-dependent	CVVHD: 2 g q8h over 3 h
Delafloxacin 2017	300 mg q12h	+/-	—	—	—	—	—	—	AUC_0-24:MIC	Concentration-dependent with time-dependence	≤50^h
Plazomicin 2018	15 mg/kg q24h	++	++	+/-	++	++	+/-	+/-	AUC_0-24:MIC	Concentration-dependent with time-dependence	<90	ESRD/RRT dosing: No data available
Plazomicin 2018	15 mg/kg q24h	++	++	+/-	++	++	+/-	+/-	210–315 mg·h/L	Concentration-dependent with time-dependence	<90	ESRD/RRT dosing: No data available
Eravacycline 2018	1 mg/kg q12h	++	++	++	++	++	—	++	AUC_0-24:MIC	Concentration-dependent with time-dependence	Not required	Dose should be reduced for Child-Pugh C
Omadacycline 2018	100 mg q12h × 2 doses then q24h	++	++	++	++	++	—	++	AUC_0-24:MIC	Concentration-dependent with time-dependence	Not required	No dose adjustments are necessary with hepatic impairment
Omadacycline 2018	100 mg q12h × 2 doses then q24h	++	++	++	++	++	—	++	AUC_0-24:MIC	Concentration-dependent with time-dependence	Not required	In vitro ESBL activity limited to Escherichia coli
Imipenem-relebactam 2019	1.25 g q6h	++	++	—	++	—	—	—	T>MIC	Time-dependent	<90
Cefiderocol 2019	2 g q8h over 3 h	++	++	++	++	++	++	++	fT>MIC >75%	Time-dependent	<60	Follow manufacturer-provided guidance for RRT and ACR dosing.

Year of initial approval by U.S. Food and Drug Administration.

Intravenous dosing listed.

Ambler class of β-lactamase expressed.

Estimated Creatinine Clearance (mL/min) at which dosing should be altered from routine dosing. In the setting of renal dysfunction requiring renal replacement therapy, or augmented renal clearance, most current literature evidence should be used to guide dose optimization.

Inter- and intra-patient PK/PD variability is appreciated in patients with burn injuries. Therapeutic drug monitoring should be considered to better inform optimal dosing of these agents.

++ coverage provided, +/- variable activity, — no coverage provided.

Strains that hyperexpress AmpC may be resistant.

Measured by estimated Glomerular Filtration Rate calculated using the Modification of Diet in Renal Disease (MDRD) formula.

ESBL = extended-spectrum β-lactamase; CRE = carbapenem-resistant Enterobacteriaceae; CRPA = carbapenem-resistant Pseudomonas aeruginosa;

CRAB = carbapenem-resistant Acinetobacter baumannii; PK/PD = pharmacokinetics/pharmacodynamics; PD = pharmacodynamics; fT>MIC = percentage of time above MIC for free drug;

AUC_0-24:MIC = 24-h area under the serum concentration-time curve (AUC) divided by the minimum inhibitory concentration (MIC); CVVH = continuous venovenous hemofiltration;

CVVHD = continuous venovenous HD; CVVHDF = continuous venovenous hemodiafiltration; ESRD = end-stage renal disease; HD = hemodialysis;

ACR = augmented renal clearance (CrCl ≥120 mL/min).

Antibiotic susceptibility testing may be necessary to confirm the activity of the newer β-lactam/β-lactamase inhibitors. Klebsiella pneumoniae carbapenemases-producing Klebsiella pneumoniae may develop resistance in the face of treatment with ceftazidime-avibactam [66], and treatment-associated resistance meropenem-vaborbactam has been reported [65]. Furthermore, vaborbactam and relebactam do not inhibit the class D β-lactamases, and specific class D β-lactamases (e.g., OXA-23) are not inhibited by avibactam. Moreover, none of the new β-lactamase inhibitors have activity against the class B metallo-β-lactamases, and reports of Enterobacteriaceae expressing both class B and class D β-lactamases exist [67]. An emerging strategy is combination therapy using aztreonam (not hydrolyzed by the class B metallo-β-lactamases) with a new β-lactam/β-lactamase inhibitor. Optimal dosing strategies to maximize clinical effects have not been determined [67,68], and aztreonam-avibactam is currently undergoing clinical trials [69].

Cefiderocol is a novel siderophore cephalosporin stable against hydrolysis by class A, B, and D β-lactamases [66]. Cefiderocol has been used in patients with strains expressing both class B and class D β-lactamases, but with mixed results [70,71]. Plazomicin and eravacycline display high levels of activity against KPC-producing Enterobacteriaceae, however, there are limited clinical efficacy data available, and plazomicin resistance in NDM carbapenemase-carrying strains is common because of co-carriage of resistance mechanisms [66].

Pseudomonas aeruginosa

Ceftolozane-tazobactam is a β-lactam/β-lactamase inhibitor combination FDA approved for the treatment of complicated intra-abdominal infections (in combination with metronidazole,) complicated UTIs including pyelonephritis, and the treatment of hospital-acquired pneumonia/VAP. Ceftolozane has potent anti-pseudomonal activity and evades multiple resistance mechanisms that may defeat other β-lactams [72]. Although tazobactam has no activity against carbapenemases, the combination had in vitro activity against 67%–89% of carbapenem-non-susceptible Pseudomonas aeruginosa [66]. A review of published reports of its off-label use included an 84.4% clinical success rate for multi-drug–resistant Pseudomonas infections, but only 68.2% rate for extensively drug-resistant infections [73].

Ceftazidime-avibactam susceptibility rates for meropenem-non-susceptible isolates are variable and MICs are often close to the susceptibility/resistance breakpoint [74]. Imipenem-cilastatin-relebactam is active against the majority of carbapenem-non-susceptible Pseudomonas aeruginosa strains [66,75]. Cefiderocol also displayed low MIC₉₀ values, suppressing the growth of more than 99% of meropenem non-susceptible and MDR strains of Pseudomonas aeruginosa; many of these strains were also ceftolozane-tazobactam–resistant. Fewer PER- and NDM-expressing strains of Pseudomonas aeruginosa were inhibited at ≤4 mcg/mL (73% vs 86.5% of non-expressing strains), similar to a decrease seen with such strains of Acinetobacter baumannii [76].

Acinetobacter spp.

A substantial portion of Acinetobacter baumannii isolates worldwide are carbapenem resistant, and the sub-group of carbapenem-hydrolyzing OXAs are prevalent [12,77] leaving all of the recently approved β-lactam/β-lactamase inhibitor combinations (Table 3) without clinical utility in most cases [78]. The polymyxins retain the most frequent reports of susceptibility [79], but their use is complicated by a high risk of serious side effects and difficulty ensuring adequate dosing, particularly in burn victims. Randomized control trial data provide limited support for combination regimens of polymyxins administered with one or more other agents [75,77,78]. Susceptibility to minocycline has remained stable leaving it as a clinically useful agent in some cases [79]. Tigecycline susceptibility is still frequently identified, but its use is limited by side effects, low serum concentrations inadequate for BSIs, and mixed clinical efficacy data in comparative clinical trials [66].

Cefiderocol displayed MIC₉₀ values of 1–4 mcg/mL against Acinetobacter baumannii, and was highly active against carbapenem resistant strains in multiple surveillance studies [76]. Of note, however, for those isolates with cefiderocol MIC >4 mcg/mL, Acinetobacter baumannii was the micro-organism identified most frequently and associated with evidence for PER- and NDM-β-lactamases. Furthermore, activity was restored in the presence of β-lactamase inhibitors [76], suggesting cefiderocol in combination with avibactam, or possibly even aztreonam and avibactam, might have clinical utility in the most difficult cases of carbapenem-resistant Acinebacter baumannii.

Eravacycline has in vitro activity against tetracycline-resistant Acinetobacter baumannii isolates, but with limited activity against isolates expressing the efflux pump AdeABC. Eravacycline MICs were found to be two- to eight-fold lower than tigecycline MICs against carbapenem-resistant Acinetobacter baumannii. It has in vitro activity against colistin-resistant and ceftazidime-avibactam–resistant strains [78], but published clinical efficacy data for carbapenem-resistant Acinetobacter baumannii is still sparse. Furthermore, it failed to meet end points in two separate phase 3 trials for complicated urinary tract infection [63].

Developmental Non-Antibiotic Therapeutics

Harnessing bacteriophage against MDROs has attracted substantial attention based on the ability of bacteriophage to target MDRO specifically while exerting minimal influence on a patient's endogenous flora [80 –82]. A randomized controlled trial of a topically applied bacteriophage cocktail for Pseudomonas aeruginosa-infected burn wounds found the cocktail was associated with fewer adverse events and could reduce the bacterial burden within the wounds, but the standard of care treatment (1% sulfadiazine silver emulsion cream) leads to a sustained reduction in bacterial burden more quickly [83]. Response was limited by patients harboring Pseudomonas aeruginosa less susceptible to phage within the cocktail, and the application of low concentrations of phage.

Antimicrobial light therapy has received research attention [84]. Antimicrobial photodynamic inactivation (aPDI) involves the generation of cytotoxic moieties after irradiation of photosensitizers with the appropriate wavelengths of light and showed efficacy against MRSA in a mouse model of burn wound infection, as well as against Acinetobacter baumannii and Pseudomonas aeruginosa in a mouse abrasion wound model [84]. Antimicrobial blue light (aBL) is an alternative that does not require exogenous photosensitizers and successfully inactivated Acinetobacter baumannii [85] and Candida albicans [86] in mouse burn wound infections. Antimicrobial photodynamic inactivation and aBL did not generate tolerance or resistance within target micro-organisms in studies using sub-lethal exposures to examine this potential risk [84].

Blood stream infections pose a particular risk to burn injury patients and the difficulty in distinguishing the burn inflammatory response from BSIs works against efforts to limit antibiotic exposures. Different groups have converged upon the concept of removing pathogens and/or inflammatory mediators from the blood stream via adsorptive and hemofiltration technologies [87 –90]. Lending credence to this concept, You et al. [91] identified a mortality benefit for early continuous high-volume hemofiltration in burn patients with sepsis, building on work that suggested hemofiltration may offer clinical benefit specifically in severely burned patients with shock and acute lung injury/acute respiratory distress syndrome [92]. The evidence suggesting benefit of high-volume hemofiltration, however, has been mixed [88], and others [93] have questioned whether the mortality benefit noted by You et al. [91] derived from an improved achievement of de-resuscitation rather than an immunomodulatory effect.

Conclusion

The post-antibiotic era is not coming, it has already arrived [12]. MDROs are among the most serious antimicrobial resistance threats faced today in the burn population. Through a comprehensive focus on infection prevention and control measures along with antibiotic stewardship and rapid diagnostics the incidence of MDROs within a burn unit can be mitigated. Given their mutually reinforcing nature, these activities will have their greatest effect if consistently implemented and not just emphasized in response to outbreaks. Additionally, multiple antimicrobials with a role in the management of MDRO infections have been approved in the past few years; preserving their activity until new antibiotic-independent technologies are ready for routine application relies on appropriate utilization of these regimens now.

Footnotes

Acknowledgments

The opinions or assertions contained herein are the private views of the authors and are not be construed as official or reflecting the views of the Department of the Army, the Defense Health Agency, the Department of Defense, or the U.S. Government. This work was prepared as part of their official duties; and, as such, there is no copyright to be transferred.

Funding Information

No funding was received for this work.

Author Disclosure Statement

No competing financial interests exist.

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