Monotherapy with minocycline or trimethoprim/sulfamethoxazole for treatment of Stenotrophomonas maltophilia infections Free

Abstract

Objectives

Stenotrophomonas maltophilia is a Gram-negative bacillus intermittently isolated from hospitalized patients. Trimethoprim/sulfamethoxazole is considered the treatment of choice for S. maltophilia infections, though limited by toxicities. Minocycline is utilized at our institution for S. maltophilia infections due to its improved tolerability and in vitro susceptibility rates. Our objective was to evaluate the effectiveness of minocycline monotherapy compared with trimethoprim/sulfamethoxazole monotherapy for treatment of S. maltophilia infections.

Methods

Patients were identified via microbiology laboratory data and those with at least one positive culture for S. maltophilia were cross-referenced with pharmacy data to detect patients who received trimethoprim/sulfamethoxazole or minocycline. Patients initially receiving combination therapy were excluded. Our primary outcome was treatment failure, defined as receipt of alternative antibiotics with in vitro activity against S. maltophilia, isolation of S. maltophilia on repeat culture or death within 30 days of treatment.

Results

Forty-five patients were evaluated. Overall mortality rate was 9% and equal between groups; 41% of patients (9/22) who received trimethoprim/sulfamethoxazole and 30% (7/23) of patients who received minocycline experienced treatment failure (P = 0.67). Patients who received minocycline were more likely to have had a recent acute kidney injury (AKI) (43.5% versus 9%; P = 0.017) or chronic lung disease (52% versus 9%; P = 0.003). Logistic regression showed consistent results of non-inferiority of the primary outcome when controlling for rates of underlying lung pathology and recent AKI (P = 0.728).

Conclusions

Treatment failure did not differ between patients receiving trimethoprim/sulfamethoxazole or minocycline monotherapy for treatment of S. maltophilia infections.

Introduction

Stenotrophomonas maltophilia, formerly known as Xanthomonas maltophilia or Pseudomonas maltophilia, is an MDR, aerobic, non-fermenting, Gram-negative bacillus.^1–3S. maltophilia is frequently isolated from water, soil, animals, plants and hospital equipment and has the ability to form biofilms in addition to colonizing immunocompromised or mechanically ventilated hosts.^1–7S. maltophilia is recognized with increasing frequency to be an important nosocomial pathogen, which is problematic due to its extensive intrinsic antibiotic resistance to extended-spectrum penicillins, third-generation cephalosporins, carbapenems and aminoglycosides.^1,3,5,7,8

The worldwide incidence of S. maltophilia infections ranges from 7 to 37 cases per 10 000 patients and has increased in frequency over the past decade.^6,9 The majority of these infections occur in patients with multiple comorbidities including cystic fibrosis, neutropenia, immunosuppression, organ transplantation and patients in the ICU.⁸

Long considered the treatment of choice, trimethoprim/sulfamethoxazole is active against >90% of S. maltophilia isolates; however, intravenous drug shortages and adverse effects limit its utility in many cases.^2,10 Other antibiotics with in vitro activity against S. maltophilia include fluoroquinolones (FQs), tetracyclines, ticarcillin/clavulanate, colistin and ceftazidime. Recently, FQs have been shown to be an effective alternative to trimethoprim/sulfamethoxazole for S. maltophilia infections.¹¹ However, FQs may be problematic in some patients due to drug interactions, risk of QTc prolongation and a concern regarding development of resistance while on therapy for isolates with higher MICs.¹²

Minocycline, first introduced in the 1960s, has recently emerged as a potential treatment option for S. maltophilia infections, particularly those of pulmonary nature, due to its rapid and extensive penetration into the lungs.¹³ Additional favourable characteristics include a more benign safety profile than alternative agents and high oral bioavailability, making intravenous to oral step-down therapy very simple. Recent experience in the use of minocycline against MDR Acinetobacter infections further emphasizes the potential utility of a long-forgotten antibiotic.^14,15

In the wake of a long-standing shortage of intravenous trimethoprim/sulfamethoxazole, our institution has utilized FQs and minocycline as the primary treatment alternatives. The in vitro susceptibility of S. maltophilia to moxifloxacin, our preferred FQ for S. maltophilia, and minocycline exceeds 90% at our institution. Unfortunately, while recent literature has evaluated FQ use for S. maltophilia, clinical data for minocycline are lacking. As such, we sought to assess the rates of treatment failure in patients infected with S. maltophilia treated with minocycline or trimethoprim/sulfamethoxazole monotherapy.

Methods

Study design

This was a retrospective chart review from January 2006 to December 2012 performed at University Hospital, University Health System, San Antonio, TX, USA. The institutional review board at the University of Texas Health Science Center at San Antonio, as well as the hospital's research department, approved the study.

Inclusion criteria included all patients with at least one positive culture for S. maltophilia who were treated with either trimethoprim/sulfamethoxazole or minocycline as monotherapy ≥48 h. Though it is not considered standard of care, combination therapy is sometimes utilized for treatment of S. maltophilia and we chose to exclude those patients, as their outcomes would not accurately reflect the activity of the agents in question. Patients were identified for inclusion via a query of the microbiology laboratory database and all patients with at least one positive culture for S. maltophilia from any site were included. The list was then cross-referenced with pharmacy billing data to identify patients with inpatient charges for minocycline or trimethoprim/sulfamethoxazole. Preliminary review of medical records was then performed to validate that patients had received antimicrobial therapy for ≥48 h. Exclusion criteria consisted of any patient who was pregnant, incarcerated or had received concomitant antibiotics that demonstrated in vitro activity (defined as ‘susceptible’ or ‘intermediate’) against S. maltophilia at our institution during the first 48 h of therapy with minocycline or trimethoprim/sulfamethoxazole.

The primary objective was to assess the rates of treatment failure in patients infected with S. maltophilia treated with minocycline or trimethoprim/sulfamethoxazole monotherapy. Treatment failure was defined as isolation of S. maltophilia on follow-up culture from the same site as the initial infection within 30 days of the initial culture, in-hospital death within 30 days of the initial positive culture or receipt of an alternative or additional antibiotic possessing in vitro activity against S. maltophilia during any point of initial therapy, as this may serve as a surrogate marker for treatment failure.

Pertinent patient data including age, gender, site of infection, isolation of additional pathogens from the same site, allergies and comorbidities were collected for all patients. Markers of infection, such as fever (temperature >100.4°F) and leucocytosis (white blood cell count >12 × 10⁹/L) at the time of initial culture, were also collected to help assess colonization versus infection in our cohort.

Susceptibility testing

Antimicrobial susceptibility testing was performed using Kirby–Bauer disc diffusion or broth microdilution and CLSI breakpoints where available. If no CLSI breakpoint existed, the FDA breakpoint in the product labelling was utilized (Table 1). In the case of moxifloxacin, a susceptibility breakpoint of 2 mg/L was utilized based on extrapolation of the levofloxacin breakpoint set by CLSI and literature supporting the enhanced in vitro activity of moxifloxacin against S. maltophilia.¹⁶

Statistical analysis

Descriptive statistics were used to summarize patient demographics and outcomes. Mann–Whitney U-tests were used to analyse continuous data as they did not conform to a normal distribution. Nominal data were analysed using χ² analyses. In order to mitigate the effects of foreseen confounding variables, logistic regression analyses were performed to control for baseline differences. An a priori level ≤0.05 was set to determine statistical significance for all comparisons. All statistical analyses were analysed with SPSS^® Statistical Software (Release 21, SPSS, Chicago, IL, USA).

Results

A query of the microbiology laboratory database produced 736 medical record numbers associated with at least one positive culture for S. maltophilia from blood, urine, respiratory tract or other body fluids. Once cross-referenced with pharmacy billing data, 155 patients were identified as having received ≥48 h of therapy with trimethoprim/sulfamethoxazole or minocycline. Of this cohort, 110 records were excluded due to receipt of combination therapy against S. maltophilia during the first 48 h of treatment. Forty-five patients who received either minocycline (n = 23) or trimethoprim/sulfamethoxazole (n = 22) as monotherapy were included in the final analysis. Patients receiving minocycline were more likely to have underlying chronic lung disease (e.g. asthma, cystic fibrosis, COPD and interstitial lung disease) or have had a recent acute kidney injury (AKI) defined as occurring anytime during the current hospitalization prior to initiation of antibiotics (Table 2). Other baseline characteristics did not differ between groups. Both groups contained a noteworthy number of patients who required mechanical ventilation at the time of culture, consistent with prior studies.

S. maltophilia was isolated most commonly from sputum cultures [minocycline 39% (9/23); trimethoprim/sulfamethoxazole 36% (8/22)]. The remaining sites of infection are included in Table 2. Polymicrobial infection was common, with 73% of patients growing S. maltophilia in combination with at least one other bacterial pathogen. Antimicrobial susceptibility rates to S. maltophilia isolates were similar between groups (Table 3). Approximately half of patients in both groups [minocycline 52% (12/23); trimethoprim/sulfamethoxazole 55% (12/22)] were found to have leucocytosis at the time of culture, while 30% in the minocycline arm (7/23) and 55% in the trimethoprim/sulfamethoxazole arm (12/22) had an accompanying fever (temperature >100.4°F).

Patients treated with minocycline received significantly longer courses of therapy on average (13 versus 7 days; P = 0.009) (Table 4). Median hospital and ICU lengths of stay were similar. More patients in the minocycline arm [35% (8/23)] were treated with intravenous therapy as compared with the trimethoprim/sulfamethoxazole arm [9% (2/22)], with average daily doses of 200 mg/day and 8.5 mg/kg/day trimethoprim, respectively.

Patients experiencing treatment failure did not differ significantly between groups [minocycline 7/23 (30%) patients versus trimethoprim/sulfamethoxazole 9/22 (41%) patients; P = 0.67]. Approximately half of patients [43% (9/23) minocycline versus 50% (11/22) trimethoprim/sulfamethoxazole] had evaluable follow-up cultures in the 30 days following therapy initiation. The majority of patients who met the predefined criteria for treatment failure did so due to isolation of S. maltophilia on repeat culture from the same site. Of the 10 patients in the minocycline arm with evaluable repeat cultures, 5/23 (50%) grew S. maltophilia compared with 7/22 (63%) patients receiving trimethoprim/sulfamethoxazole (P = 0.75). No patient developed resistance while on therapy with either minocycline or trimethoprim/sulfamethoxazole. Thirty day in-hospital mortality was low and similar between groups [minocycline n = 2 (8.7%); trimethoprim/sulfamethoxazole n = 2 (9%)]. We were unable to confirm whether the cause of death was due to the infection being studied. Logistic regression showed consistent results when controlling for rates of underlying lung pathology as well as recent AKI (P = 0.728).

Discussion

S. maltophilia is a durable pathogen with extensive intrinsic antimicrobial resistance that has recently affected hospitalized patients throughout the USA with increasing frequency.⁹ Though trimethoprim/sulfamethoxazole has long been accepted as the standard of care, it may not be an ideal treatment option in some patients due to adverse effects such as nephrotoxicity and hyperkalaemia. Furthermore, frequent drug shortages of intravenous trimethoprim/sulfamethoxazole have led to a need for alternative antimicrobial agents. Therefore, our study chose to compare outcomes in patients treated with minocycline, to which S. maltophilia demonstrates high in vitro susceptibility rates at our institution. To our knowledge, no previous investigation exists that explores the use of minocycline as monotherapy for treatment of S. maltophilia. In the setting of substantial comorbidities, many patients are often colonized with this pathogen or are being treated with multiple antimicrobial agents for various infections. As a result, linking clinical outcomes to one specific antimicrobial agent is often difficult, likely limiting the amount of available literature on the topic. Regardless, as increasing numbers of critically ill patients present S. maltophilia infections, identifying other safe and efficacious treatments outside of trimethoprim/sulfamethoxazole is essential. Though the results are limited due to small sample size and inadequate power, this study represents the largest published clinical dataset on the use of minocycline for infections due to S. maltophilia.

Our study was unable to detect a significant difference in treatment failure between patients receiving minocycline and those receiving trimethoprim/sulfamethoxazole. Although not statistically significant, there were notable numerical differences in recent AKI and chronic lung disease in the minocycline group, which may indicate a greater severity of underlying illness. These patients also received significantly longer courses of therapy. Due to the retrospective nature of the study, the rationale behind treatment duration differences is unclear. Plausible explanations for shorter trimethoprim/sulfamethoxazole treatment durations include decreased severity of illness at initiation compared with patients receiving minocycline or early cessation due to adverse effects, or conversely, adequate clinical response. Patients treated with minocycline may have also received longer courses due to the lack of clinical experience with this agent. We attempted to determine this by comparing the number of patients in whom a follow-up culture was taken. This was used as a surrogate marker for failure to respond to therapy or progression of illness. A similar number of follow-up cultures were collected in each treatment group, and in minocycline and trimethoprim/sulfamethoxazole groups, follow-up cultures were drawn 14 or 15 days, respectively, after the initial culture (P = 0.46). As such, it does not appear that those treated with minocycline required an increased number of early, repeat cultures, which may have indicated suboptimal clinical response. Follow-up cultures were typically collected after treatment completion, indicating the patient may have had new signs or symptoms of infection. This would not be uncommon in a population in which over half of the patients were receiving mechanical ventilation.

The mean weight-based trimethoprim dosage utilized was 8.5 mg/kg/day, indicating that a significant number of patients may have received lower than recommended doses, though these data were not normalized based on renal function. Although the optimal dose of trimethoprim for treatment of S. maltophilia is unknown, a dosing strategy of 15 mg/kg/day is commonly recommended.¹⁷ It is unclear if the primary outcome would have been significantly different if all patients received higher doses of trimethoprim/sulfamethoxazole.

Consistent with other published studies, our study found S. maltophilia to be commonly isolated alongside other bacterial pathogens.¹² Only 27% (12/45) of the entire cohort exhibited a monomicrobial S. maltophilia infection. The role of S. maltophilia in polymicrobial infections is unknown; therefore, evaluating the impact of therapy in these infections is difficult.

The most significant confounding issue in studies evaluating treatment of S. maltophilia is the differentiation of colonization versus infection.^12,18,19S. maltophilia is known to colonize the airways of mechanically ventilated patients and those with underlying lung disease and may continue to be isolated on culture in the absence of true infection. In an attempt to evaluate colonization versus infection, we reviewed certain infectious markers such as total neutrophil count and presence of fever. Our analysis revealed leucocytosis in approximately half of the patient cohort at the time of culture and fever in approximately one-third of patients. Other factors may have played a role in the decision to initiate antimicrobial therapy such as change in ventilator requirements or radiographic imaging of the lungs. Regardless, in all cases the physician chose to initiate antimicrobial therapy and continue for >48 h, thus a clinical diagnosis of infection was made. Whether it was an infecting or colonizing pathogen, S. maltophilia was isolated on repeat culture in a similar number of patients receiving minocycline compared with trimethoprim/sulfamethoxazole. As such, this warrants further investigation into the use of minocycline for treatment of S. maltophilia infections in the future.

Conclusions

With the increasing presence of S. maltophilia infections in hospitalized patients, additional treatment options are necessary due to high intrinsic resistance and suboptimal antimicrobial adverse effect profiles. Minocycline is a viable treatment alternative due to its high bioavailability and excellent tolerability. The results of our study suggest minocycline as a possible treatment option, as treatment failure did not differ between patients receiving trimethoprim/sulfamethoxazole or minocycline monotherapy for treatment of S. maltophilia infections.

Funding

This study was carried out as part of our routine work.

Transparency declarations

None to declare.

References