Many of the pediatric patients admitted to intensive care have multisystemic complex disorders that affect their ability to combat opportunistic infections. Such patients are frequently transferred to the pediatric intensive care unit (PICU) after a lengthy hospitalization during which they had been treated with a prolonged courses of broad-spectrum antibiotics. Their treatment in the PICU is routinely extended to include even broader antibacterial coverage with such agents as carbapenems. Under such circumstances, highly resistant opportunistic infections can emerge, leading to significant morbidity and mortality.
Stenotrophomonas maltophilia is a Gram-negative, aerobic, nonfermenting, motile bacillus. It is ubiquitous in the environment and carries limited virulence factors.1,2 It has emerged as an opportunistic pathogen to which considerable mortality rates (37.5%) can be attributed.3 The major risk factors associated with acquiring an infection of S. maltophilia are hematologic malignancies, organ transplantation, immunosuppressive syndromes and therapy, cystic fibrosis, prolonged hospitalization, intensive care unit admission, mechanical ventilation, presence of indwelling catheters (vascular, urinary), corticosteroid therapy and broad-spectrum antibiotic treatment.4–8 The clinical presentation of infection is varied and may consist of bacteremia,5,9–12 respiratory tract infections,13–17 urinary tract infections,18,19 endocarditis,20–22 meningitis,23,24 soft-tissue and wound infections, bone and joint infections and peritonitis.5,8S. maltophilia holds noteworthy antimicrobial resistance characteristics and has recently been classified by the World Health Organization as one of the leading multidrug-resistant organisms in hospital settings.25 Thus, S. maltophilia infections have become a significant therapeutic challenge. Given the absence of clinical trials, treatment remains controversial and is chiefly based on in vitro susceptibility tests and expert opinion.26–30 Trimethoprim–sulfamethoxazole (TMP/SMX) is the conventional drug of choice, with ciprofloxacin, minocycline, tigecycline, ceftazidime and ticarcillin/clavulanate, alone or in combination, being considered as alternative options.29,31,32
There is limited information on S. maltophilia infections in the pediatric population33–39 and even less on management strategies in this group. The objective of this study was to investigate the demographics, clinical characteristics, risk factors for associated morbidity and mortality and the treatment strategies for S. maltophilia infections among children hospitalized in pediatric ICUs.
MATERIALS AND METHODS
Settings and Population
This single-center retrospective observational study was based on the review of medical records of patients hospitalized in the 2 PICUs (general and cardiac, 38 beds in total) of the “Edmond and Lily Safra Children’s Hospital,”, a 360-bedded tertiary pediatric hospital in Israel. The study was approved by the institutional review board of the “Chaim Sheba Medical Center.” Included in the study were children between the 0 to 18 years of age who were admitted to the PICUs between January 2012 and June 2017, from whom a blood, respiratory or soft tissue culture positive for S. maltophilia was acquired. Patients were excluded from the study if the isolation of S. maltophilia was registered as a contaminant. Admission swabs that were routinely taken from the patients included in the study were negative. The retrieved information included patient demographics, current and past medical history, length of stay, clinical events, data on laboratory test results, days from hospitalization to positive culture, presence of indwelling catheters, site of culture acquisition, antibiotic susceptibility, treatment (type and duration) and outcome. Further details on the definitions of the terms above can be found online as Supplemental Digital Content 1 (http://links.lww.com/INF/D134).
The BACTEC FX system (Becton Dickinson Microbiology Systems, Baltimore, MD) was used for culture analysis. Identification of bacteria was by the MALDI-TOF system (Bruker, Billerica, MA). Antibiotic susceptibility testing was done by an automated system (BD Phoenix; Becton Dickinson Microbiology Systems). Clinical cutoff points for drug susceptibility were set according to the Clinical and Laboratory Standards Institute (M100-S22).
Data were analyzed using SPSS Statistics 23.0 (SPSS, Chicago, IL). Descriptive statistics were expressed as the median (interquartile range) for continuous variables and the frequency and percentage for categorical variables. The characteristics of survivors and nonsurvivors were compared using the χ2 test for categorical variables and the Mann–Whitney test for continuous variables. The risk factors for estimating prognosis were analyzed by stepwise logistic regression. Survival was estimated using the Kaplan–Meier method, and survival results were compared using the log-rank test. All P values ≤0.05 were considered statistically significant. Multiple logistic regression was used to assess which variables in combination predicted mortality. Goodness-of-fit of the models was estimated by a Hosmer–Lemeshow test. All individual variables that were found to be significantly associated with mortality (P ≤ 0.05) were considered as candidates for the multiple logistic regression. The “backward elimination” method was used to fit the model. Odds ratios (ORs) and 95% confidence intervals (CIs) are given as a measure of effect, where applicable.
Isolation Rates, Patient Demographics and Clinical Characteristics
During the study period, there were 3555 patient stays in the general PICU and 2201 stays in the cardiac PICU. A total of 99 cultures were identified as being positive among 31 patients. Eight positive cultures were excluded from analysis for being regarded as a contamination, leaving a total of 91 cultures eligible for review.
The total incidence of S. maltophilia isolation during the 5.5-year study period was 0.53% (n = 31/5756). The overall annual increase in isolate number for the entire study group (r = 0.94; P = 0.003), for the general PICU (r = 0.92; P = 0.08) and for the cardiac PICU are illustrated in (r = 0.60; P = 0.20) in Figure (Supplemental Digital Content 2, http://links.lww.com/INF/D135).
There were 13 (42%) females and 18 (58%) males whose median age at the time of S. maltophilia isolation was 13 months (range: 3 months to 5 years and 9 months). Congenital cardiac diseases were the most common underlying conditions (8 cases), followed by oncologic diseases (7 cases), immunodeficiency (4 cases), respiratory abnormalities (4 cases), cerebral palsy (2 cases) and other disorders (6 cases). The demographics and underlying diseases of the patients are presented in Table 1.
Bloodstream infections occurred in 21 patients, from whom the primary focus was a central venous catheter (CVC), respiratory system and the skin and soft tissues. Ten patients had isolates acquired from the respiratory system (an endotracheal tube, sputum or bronchoalveolar lavage). The median length of stay before the time of S. maltophilia isolation was 40 days (range: 23.5–59 days). The source of infection was nosocomial in 24 patients, 4 were healthcare associated and 3 were community acquired. At the time of isolation, 27 patients had a CVC, 23 were septic, 14 had fever, 10 were neutropenic, 12 were anemic, 25 had received prior steroid treatment, 9 were treated with chemotherapy, 22 had received prior treatment with carbapenem antibiotics and 26 were mechanically ventilated.
Polymicrobial isolation was present in at least 1 culture in 15 of the 31 patients, 2 of which included more than 3 microorganisms. Additional isolates were coagulase-negative Staphylococcus, Pseudomonas aeruginosa, Acinetobacter species, Enterobacter species, Klebsiella pneumonia, Corynebacterium Striatum, Candida albicans, Candida crusei and Candida parapsilosis. The clinical characteristics of the patients at the time of S. maltophilia isolation are summarized in (Table, Supplemental Digital Content 3, http://links.lww.com/INF/D136).
During the study period, the crude mortality was 61% (19/31 cases). Seven patients died within 7 days of S. maltophilia isolation, 4 between 7 and 30 days, 5 between 30 and 60 days and 3 between 60 and 120 days. The source of isolation was the bloodstream in 13 nonsurvivors. Mortality was lower in CVC-associated bacteremia than in those from other sources (26% vs. 42%, respectively). Respiratory sources of infection led to 6 fatalities. Mortality was lower in bronchoalveolar lavage–associated infections than in those from other sources (5% vs. 26%, respectively).
Comparison of Risk Factors Among Survivors and Nonsurvivors
Risk factors associated with mortality in patients with an isolation of S. maltophilia in the univariate and multivariate analysis are represented in Tables 2 and 3. According to the univariate analysis, patients who did not survive were those who at the time of culture acquisition had a prior longer length of stay (50 days in nonsurvivors vs.18.5 in those who survived; P = 0.002), presented with septic shock (P = 0.003), were mechanically ventilated (P = 0.004), had a CVC (P = 0.03), or had history of steroid or carbapenem treatment before culture retrieval (P = 0.04 and P = 0.004, respectively). Demographic and clinical characteristics that did not seem to have an effect on mortality were gender, age, underlying medical condition, site of isolation, neutropenia, anemia, prior chemotherapy and polymicrobial infections.
On multivariate analysis, being mechanically ventilated was associated with mortality (OR: 5.19; 95% CI: 1.57–413.95; P = 0.02) after adjustment for length of stay, septic shock and prior treatment with a carbapenem. For each additional day of hospitalization, the mortality risk increased by 5.55 (95% CI: 1.01–1.12; P = 0.01). The Hosmer–Lemeshow goodness-of-fit test confirmed a good fit of this model (P = 0.656).
The antibiotic treatment regimen used was based on the standard institutional pharmacy protocol. Antibiotics route of administration and dosages were the following: iv TMP/SMX, 20 mg/kg/24 h; iv minocycline 4 mg/kg/dose; iv ciprofloxacin 30 mg/kg/24 h; iv ceftazidime 150 mg/kg/24 h. The above antibiotic regimen was continued until 2 negative cultures were obtained or mortality had occurred. In cases of persistent or recurrent positive cultures, an alternative treatment regimen was occasionally implemented. The characteristics of antibiotic susceptibility, management and outcomes are presented in Table (Supplemental Digital Content 4, http://links.lww.com/INF/D137). Susceptibility of S. maltophilia to antibiotics shared a common pattern with 94% of all isolates being sensitive to TMP/SMX, levofloxacin and minocycline but only 6% being sensitive to ceftazidime. It is worth noting that the antimicrobial susceptibility pattern observed is specific for our institution and that sensitivities may differ according to local susceptibility patterns. Once the culture result was available, the initial choice of antibiotic regimen had been appropriate in 27 cases (no specific treatment had been initiated in the remaining 4 cases). The specific results of antibiotic treatment were known for all 27 patients and included 20/21 episodes of bacteremia and 7/10 episodes of other sites. After the initiation of appropriate antibiotic therapy, the median time to a negative culture was 11 days (range: 4.75–23.75 days). The median time from a positive culture until demise among the nonsurvivors was 36 days (range: 7.50–104 days; Fig., Supplemental Digital Content 5, http://links.lww.com/INF/D138). Treatment regimens consisting of ciprofloxacin, TMP/SMX or their combination did not produce a significant difference in the interval between the time of a positive culture to a negative one (log-rank P = 0.200), but not implementing any treatment extended the time before a negative culture was obtained. However, there was a significant difference between regimens in the interval between a positive culture to demise (log-rank P < 0.001): the combination of ciprofloxacin and TMP/SMX showed the longest survival time, followed by ciprofloxacin with minocycline, ciprofloxacin alone, no treatment and TMP/SMX alone.
S. maltophilia infections, although rare events, are emerging as a significant cause of morbidity and mortality in critically ill patients and specifically in pediatric patients treated in intensive care settings. The results of the current study demonstrate a significant attributable mortality associated with S. maltophilia infections in critically ill pediatric patients. Furthermore, our results indicate that synergistic treatment consisting of TMP/SMX, ciprofloxacin and minocycline is the most efficient strategy to extend the survival time of pediatric critically ill patients from whom S. maltophilia had been isolated.
The incidence of S. maltophilia infections in the pediatric population has been increasing over recent years.1 Data from the SENTRY Antimicrobial Surveillance Program conducted between 1998 and 2003 indicated that the occurrence of S. maltophilia infections from all sites of isolation ranges from 1.2% among children 7 years of age or younger to 1.4% among children 18 years of age or younger.40,41 More recent studies report isolation rates ranging from 0.8% to 20.3%.33,42 Similarly, the frequency of isolations in our study increased significantly during the 5.5-year study period (Fig., Supplemental Digital Content 2, http://links.lww.com/INF/D135; r = 0.94; P = 0.003). This trend could be partly attributed to an observed increase in the use of carbapenems in patients with long stays in our institution (data not shown).
The understanding that these infections are clinically significant has also been growing, predominantly because of their high attributable mortality. According to studies in adults, mortality is estimated at 37.5%.3 However, only sparse information is available regarding mortality rates in the pediatric population. The reports that are available mostly describe crude mortality rates, which range from 12.5% to 62.5%.5,33,38,39 Attributed mortality was approximately 6% in 2 reports.37,38 In our study, the overall crude mortality rate was 61%, and we estimated the attributed mortality to be approximately 16% by eliminating the polymicrobial episodes from the 7-day mortality rate, which was 23%. This corresponds to the mortality rate directly related to a septic event caused solely by S. maltophilia. However, we were precluded from estimating the precise attributed mortality rate because we had not included matched controls in the study.
Noteworthy, the risk factors for mortality in our study group support the data previously reported in similar studies in children and in adults.4,7,8,11,26,33–35,37–39,43 Our univariate analysis (Tables 2 and 3) revealed that the risk factors that are associated with mortality include longer stays, a higher incidence of septic shock, mechanical ventilation, an indwelling CVC and prior use of steroids or carbapenems. Our multivariate analysis (Table, Supplemental Digital Content 4, http://links.lww.com/INF/D137) demonstrated that mechanical ventilation (OR: 5.19; 95% CI: 1.57–413.95; P = 0.02) and a longer length of stay (OR: 5.55; 95% CI: 1.01–1.12; P = 0.01) were associated with mortality after adjustment for septic shock and prior use of carbapenems. Interestingly, gender, age, underlying disorders, site of isolation, neutropenia, anemia, prior chemotherapy and polymicrobial isolation did not emerge as significant predictors of mortality. It is worth mentioning here that the 3 patients who were regarded as having community-acquired infections were not recently discharged from a hospital nor had they been previously colonized with S. maltophilia. This could perhaps be explained by the ubiquitous presence and opportunistic nature of S. maltophilia and by these individuals being immunocompromised.
The factors underlying the virulence of S. maltophilia are not well understood,44 but several of its characteristics have been implicated as the cause of its pathogenicity. First, it can adhere to surfaces and form biofilms, key elements in the colonization of indwelling devices and human tissue.45,46 Second, it can produce extracellular enzymes (eg, DNase, RNase, proteases, and elastases),47,48 which can degrade materials, such as biosurfactants.49 Third, it possesses highly immunostimulatory but weakly invasive traits, which could contribute to inflammation.50 Last, its intrinsic resistance to frontline antibiotics is probably the principal reason for the increase in its incidence and attributed mortality.51,52
In addition to being resistant to β-lactams (including carbapenems),53 aminoglycosides (except gentamicin),54 older quinolones, tetracycline and macrolides,51S. maltophilia has the capability to quickly develop resistance to newer antibiotics by means of mutations that result in the overproduction of intrinsic multidrug efflux pumps.55 Considering that many of these antibiotics are used as first-line options for nosocomial sepsis events, the treatment of S. maltophilia infections clearly poses a significant challenge.29 Studies in adults have shown that TMP/SMX is the most effective antibiotic against S. maltophilia.31 Other common options of monotherapy include ticarcillin-clavulanate, fluoroquinolones, minocycline and possibly tigecycline.31,56 Several combinations of antimicrobial agents have also been evaluated in an attempt to overcome its potent capacity of resistance and/or to attain synergism.1 Options that have demonstrated synergistic effects include TMP/SMX or b-lactam/b-lactam inhibitors with other antibiotics, such as tigecycline, fluoroquinolones, televancin,57 rifampin58 and aerosolized colistin. TMP/SMX plus ceftazidime plus levofloxacin has been shown to be effective in the treatment of S. maltophilia meningitis.23
There are no controlled trials of treatment of S. maltophilia infections in pediatric populations. Treatment guidelines are mainly based on the results of in vitro susceptibility studies, several case series or case reports and expert opinion. In the current study, 94% of all isolates were susceptible to TMP/SMX, levofloxacin and minocycline (Table, Supplemental Digital Content 4, http://links.lww.com/INF/D137). The interval between the days of S. maltophilia isolation to resolution of infection was not significantly affected by the choice of treatment (Fig., Supplemental Digital Content 5, http://links.lww.com/INF/D138). Interestingly, a combination of ciprofloxacin and TMP/SMX significantly extended the survival time (Fig., Supplemental Digital Content 5, http://links.lww.com/INF/D138). In addition, ciprofloxacin extended survival time significantly more than TMP/SMX when either was given as a monotherapy (Fig., Supplemental Digital Content 5, http://links.lww.com/INF/D138). Because a significant number of patients had succumbed to their baseline illnesses several months after they have been infected with S. maltophilia regardless of the treatment they have received, we chose to study survival time and not crude mortality in relation to antibiotic treatment.
While our findings corroborate the results of previous studies in adults, this is the first report that focused on critically ill pediatric patients.
The retrospective nature of this study and the limited sample size and the variability of therapeutic approaches chosen by the clinical teams restricted our ability to decisively conclude that a specific treatment strategy is superior. We do, however, advocate adopting an active approach, which includes a combination of TMP/SMX, ciprofloxacin or minocycline when encountering S. maltophilia infections in a critically ill child, in spite of the adverse effects associated with these agents.
The authors are appreciative of Esther Eshkol’s linguistic editing. In addition, they are grateful for the dedication and hard work of the nurses and physicians working in the pediatric intensive care unit of The Edmond and Lily Safra Children’s Hospital.
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