Summary and interpretation of findings
In our study, we were able to identify the microbiological profiles and patterns of ABR of isolates from weapon-wounded civilians. The most commonly isolated bacteria was
S. aureus (49.1%), followed by Enterobacterales (28.5%),
P. aeruginosa (13.2%), Enterococci species (3.2%) and
A. baumannii (2%). Our findings are similar to those reported by Fily et al. where
S. aureus was also the most frequently isolated bacteria, with similar proportions of
Enterobacteriaceae (31.5%),
P. aeruginosa (13.5%) and
A. baumannii (2.8%) [
32]. However, the proportion of
S. aureus reported by Fily et al. (26.3%) was lower than that in our findings [
32]. One explanation may be the inclusion of only bone samples from patients with osteomyelitis with the exclusion of soft tissue samples, in contrast to our study, which included SST samples (including superficial swabs), regardless of the underlying infection.
When comparing our results to that from military personnel, the microbiological profiles of confirmed extremity wound infections of military personnel were different with proportions of
S. aureus isolates of 3% and
A. baumannii of 17% [
19]. In fact, one study on patients admitted to a military hospital in Iraq showed statistically significant differences between U.S. military patients and non-military non-U.S. patients [
33]. The isolated bacteria of U.S. military patients compared to non-military non-U.S. patients included
S. aureus (26 vs. 5%),
K. pneumoniae (3 vs. 13%), and
P. aeruginosa (3 vs. 10%) [
33]. The differences in profiles among isolates from military personnel as compared to civilians might be due to several factors, including—although not limited to—the timeliness and quality of care they have access to at the moment of injury.
When comparing our results to similar studies conducted among civilian weapon wounded, the proportion of MDR isolates reported in our study is lower than that reported by MSF where the same definitions of MDR are applied. The study by Alga et al. reports that MDR was detected in 73% of patients with positive wound cultures resulting from conflict-related injuries (versus 55.7% from our study) [
34]. Other small studies among civilian patients also report a higher proportion of MDR with 69% MDR isolates from war-associated wound infections [
23] and 66% MDR isolates from post-trauma infections [
35]. In addition, the proportion of MDR is still higher in other studies compared to our study, even when we solely consider specimens from bone cultures (61.8%). Possible explanations for the discrepancy can be that other studies included only patients with clinical signs of an infection [
23,
34], only infections of acute injuries [
34], a small sample [
23,
34,
35] and/or different definitions of MDR [
23,
35]. On the other hand, the isolates from confirmed extremity wound infections of military personnel had lower proportion of MDR ranging between 32 and 44% [
19].
Our results show higher odds and proportion of MDR amongst Enterobacterales. This is similar to the available literature on MDR Enterobacterales, with a proportion of MDR ranging between 63% for Proteus and 100% for
E. coli [
34]. These proportions were higher than that of other isolates reported in the same study (e.g., MRSA and
P. aeruginosa) [
34]. We identified that isolates from patients from Iraq had higher odds of MDR compared to that from other countries. One possible explanation might be the high proportion of Enterobacterales amongst this group of patients. Other possible explanations can be that Iraqi patients had longer delay since injury, a greater number of previous surgeries before presenting to WTTC, more antibiotic treatment courses, presence of polymicrobial infections [
32] and/or high community resistance rates [
36].
Our results on the proportion of MRSA (48.5%) are consistent with the literature as a systematic review by Truppa et al. report a percentage median resistance in conflict-affected countries of 43.37% [
30]. Another study reported 42% MRSA among
S. aureus isolates in Syrian patients with war-associated wound infections [
23]. Likewise, for the proportion of MDR Enterobacterales (83.8%), Fily et al. report a similar proportion of MDR Enterobacteriaceae (86.2%), although the latter only includes isolates from post-traumatic osteomyelitis [
32]. Evidence of MDR Enterobacterales in the Middle East region suggest that it is endemic for carbapenemase-producing Enterobacterales [
39,
40]. In addition, the lowest proportion of isolates was
A. baumannii isolates (n = 7, 2%). This is comparable to another study on chronic osteomyelitis due to war injury where the proportion of
A. baumannii isolates was also the lowest among the different isolates (n = 6, 4%) [
21]. Fily et al. also reported a similar proportion of
A. baumannii isolates (n = 21, 2.8%). Additionally, MDR
A. baumannii isolates have been reported in war injuries [
21,
41‐
43]. In our study, three out of seven
A. baumannii isolates were MDR. Murphy et al. also reported a similar proportion of MDR
A. baumannii isolates (three out of six) in Iraqi civilians with war-related chronic osteomyelitis [
21].
Strengths and limitations of the study
This study has a number of strengths. We have reported the susceptibility of bacteria isolated from war-wounded civilians, adding to the literature on a specific population for which there is limited available literature. We also did not restrict our inclusion to particular bacteria, rather we included all isolated bacteria from the population of interest. In addition, we used data from the WHONET database, a uniform standardized database. This ensured the homogeneity of the data and allowed the comparison of the microbiological susceptibility data of different years and of that reported in different studies in the literature.
On the other hand, there are several limitations to this study. One limitation is the retrospective design of the study based on laboratory data. There was missing and/or limited information on the clinical presentation, medical history and sociodemographic characteristics of the patients. It was not possible to discern between different stages across the continuum of wound infections, namely: contamination, defined as presence or proliferation of bacteria without any sign of local or systemic inflammation; critical colonization (defined as presence of microbiological isolates without signs of inflammation but interfering with the process of wound healing); and infection (i.e., skin and soft tissue infections, bone infections, prosthetic infections, or concomitant infections) [
44,
45]. Another limitation is the small sample size or possible confounding because of which we might not have been able to detect statistically significant associations, as in the case of the association between the specimen type and MDR, which was only marginally significant. An important additional limitation of this study lies with the lack of possibility to discriminate before community
versus hospital-acquired infections, as the date of admission of the patient and collection of the samples could not be used as proxy measure for the timing of the colonization/infection. In fact, the vast majority of patients were affected by chronic complications of war-related wounds. Because of this, they came to the attention of the ICRC after an important clinical journey which implied previous outpatient and/or inpatient care, for which documentation was often not available to the ICRC care providers; on the other hand, the timing of sample collection, particularly for bone biopsies, but also for superficial wound, would often be deferred beyond the first 24–48 h from admission, in order to proceed with the complete clinical workout needed in preparation for the elective surgery. Finally, although the WHONET is a standardized method of reporting microbiological data, due to the poor harmonization and low standardization of surveillance of ABR in the Middle East, it is difficult to compare data from other studies conducted on war-wounded civilians in this setting [
38].
Implications for clinical practice and future research
Based on the findings of our study, we propose strengthening antibiotic stewardship in general, and in orthopedic surgical projects conducted in similar settings, in specific. This is of great importance especially that antimicrobial stewardship programs in health care facilities have shown a positive impact in LMICs [
46]. We also reinforce the recommendation already formulated by MSF that bone biopsies be regularly conducted before reconstructive orthopedic surgical interventions in weapon-wounded civilians in such settings [
32,
34].
The ICRC guidelines for antibiotic prophylaxis and treatment in war wounds were first published in 2010 [
47] and revised in 2019 [
48]. These are based on recommendations by WHO [
49], MSF (personal communication following consultations with the MSF team in their Amman reconstructive surgical project), army guidelines and review papers, and provide the basis of war wounds management for many international organizations offering surgical services in conflict-affected settings.
The specific ICRC guidelines for antibiotic prophylaxis in elective surgery in the context of the WTTC project were adapted from existing American [
50], Scottish [
51] and Swiss guidelines [
52] for reconstructive orthopedic surgery. These guidelines restrict the use of antibiotic prophylaxis in orthopedic surgery to cases with implant insertion. A single dose of cefazolin is recommended, unless there is evidence that the patient harbors bacteria warranting use of a different antibiotic prophylaxis (e.g. MRSA colonization/infection, other MDR bacteria). In cases of acute orthopedic surgery, e.g. in the acute weapon-wounded, cefazolin is also the recommended first-line antibiotic, but with the addition of gentamicin and metronidazole, if the injury is more than 72 h old [
48]. In these cases, antibiotics are given for 48 to 72 h. The addition of gentamicin is suggested in the presence of signs of local inflammation, while that of metronidazole roots in the knowledge that the risk of anaerobic infections increases with time from injury to delayed surgery, and acknowledging the difficulties to culture anaerobic bacteria even under optimal circumstances [
48].
Where empirical treatment of SST and bone infections is warranted, whether pending results of cultures or due to lack of microbiological diagnostics, cefazolin is also first choice. In septic patients, the empirical treatment regimen is a combination of cefazolin, gentamicin and metronidazole. However, if there is no adequate response within few days, then the treatment options adopted in the management of complicated war wounds in WTTC were the switch to meropenem, with the potential addition of vancomycin in case the patient was still not adequately responding. These guidelines were mostly based on the surgeons’ previous experience in treating similar cases in different settings, as well as on the high prevalence of ESBL and MRSA in the specific context of WTTC. The empirical treatment guidelines were used exclusively in cases where no microbiological evidence was available. In other cases, susceptibility profile-guided antibiotic prescription was the norm, under the guidance of the hospital infectious diseases specialist.
Considering the resistance profiles documented in the reconstructive surgical project implemented in the WTTC and reported in this study, an update of the current guidelines might be warranted. Moreover, when planning the implementation of a complex surgical project targeting patients presenting complex war wounds, a rigorous antibiotic stewardship protocol should be put in place, including the update of antibiotic prophylaxis and treatment protocols based on the continuous monitoring of the local resistance profiles, as it has already been stressed in other Middle Eastern settings [
34].
Additionally, on a broader scale, there is a need to establish a robust national surveillance system in order to understand local resistance profiles, that should guide national guidelines for the management of infectious diseases. It would also be essential to adopt novel solutions for ABR testing, such as innovative accessible laboratories as the Mini-Lab designed by MSF [
53], in order to expand the capacity of ABR testing, and ultimately reporting.
Finally, there is a need for large-scale prospective studies that consider the clinical presentation and medical history of patients when identifying resistance profiles and factors associated with resistance in a war-affected populations, as this would provide better insight on both the source of infection (community versus hospital-acquired), and therefore on the prophylactic and empirical antibiotic treatment protocols for civilians and military personnel.