ABSTRACT
Complicated Staphylococcus aureus infections, including bacteremia, are often associated with treatment failures, prolonged hospital stays, and the emergence of resistance to primary and even secondary therapies. Daptomycin is commonly used as salvage therapy after vancomycin failure for the treatment of methicillin-resistant S. aureus (MRSA) infections. Unfortunately, the emergence of daptomycin resistance, especially in deep-seated infections, has been reported, prompting the need for alternative or combination therapy. Numerous antibiotic combinations with daptomycin have been investigated clinically and in vitro. Of interest, the combination of daptomycin and trimethoprim-sulfamethoxazole (TMP-SMX) has proved to be rapidly bactericidal in vitro to strains that are both susceptible and nonsusceptible to daptomycin. However, to date, there is limited clinical evidence supporting the use of this combination. This was a multicenter, retrospective case series of patients treated with the combination of daptomycin and TMP-SMX for at least 72 h. The objective of this study was to describe the safety and effectiveness of this regimen in clinical practice. The most commonly stated reason that TMP-SMX was added to daptomycin was persistent bacteremia and/or progressive signs and symptoms of infection. After the initiation of combination therapy, the median time to clearance of bacteremia was 2.5 days. Microbiological eradication was demonstrated in 24 out of 28 patients, and in vitro synergy was demonstrated in 17 of the 17 recovered isolates. Further research with this combination is necessary to describe the optimal role and its impact on patient outcomes.
INTRODUCTION
According to the National Healthcare Safety Network (NHSN) at the Centers for Disease Control and Prevention, Staphylococcus aureus remains the most common pathogen causing hospital-acquired infections, and resistance to methicillin remains at >50% (1). In addition, the first documented isolates with decreased susceptibility to vancomycin (vancomycin-intermediate S. aureus) and full resistance to vancomycin were initially reported in 1997 and 2002, respectively (2, 3). Organisms expressing heterointermediate susceptibility to vancomycin, while remaining phenotypically susceptible to vancomycin, have been associated with high vancomycin treatment failure rates (4–6). Currently, there is no consensus regarding optimal treatment; however, the majority of isolates remain susceptible to nonglycopeptide therapies such as daptomycin. Daptomycin is a concentration-dependent cyclic lipopeptide with bactericidal activity against Gram-positive bacterial pathogens (7). Daptomycin susceptibility should be monitored, however, because of the potential association between the presence of heteroresistance to vancomycin and the emergence of daptomycin-nonsusceptible (DNS) isolates (8). Although DNS isolates remain relatively uncommon, there have been increasing reports of patients with complicated, often deep-seated, methicillin-resistant S. aureus (MRSA) infections initially treated with vancomycin where DNS isolates have emerged (9–12).
There is a growing concern regarding clinical failure secondary to DNS isolates, resulting in a need to develop novel treatment modalities (13–18). However, many of the alternatives to daptomycin tend to be bacteriostatic, resulting in less-than-optimal clearance of infections such as infective endocarditis and meningitis (19). Combination therapies with various antimicrobials have been evaluated. One combination, daptomycin plus trimethoprim-sulfamethoxazole (TMP-SMX), appears promising and requires further investigation. Two in vitro simulated endocardial vegetation models compared daptomycin alone and in combination with TMP-SMX against DNS isolates (20, 21). Both models demonstrated that the combination was superior to daptomycin alone or in combination with other agents, such as linezolid and beta-lactams. Clinically, there have been two case reports detailing positive clinical outcomes: one with two patients with vertebral osteomyelitis complicated by MRSA bacteremia and one with a single patient diagnosed with infective endocarditis (22, 23). The Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children recommend the use of high-dose daptomycin in combination with TMP-SMX as one of the alternative therapies for persistent infections with vancomycin treatment failure because of the success of these models (24). Since this guideline recommendation, there have been limited anecdotal reports of its use. This case series comprises the largest collection of patients treated with daptomycin and TMP-SMX that has been published to date.
MATERIALS AND METHODS
Study design and population.This retrospective, multicenter case series included adult (≥18 years of age) patients from the Detroit Medical Center, Detroit, Michigan, St. Joseph's Hospital Health Center, Syracuse, New York, and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada, who received the combination daptomycin and TMP-SMX for ≥72 h for the treatment of deep-seated MRSA infections from January 2010 to June 2014. Patients were excluded from the analysis if the causative pathogen was not S. aureus, the primary site of infection was pneumonia, or the patient was receiving TMP-SMX for prophylaxis against Pneumocystis jirovecii pneumonia. A waiver of informed consent was obtained from the participating hospitals' human investigation committees.
Data collection.Patients' demographics, site of infection, comorbid conditions, antimicrobial exposure in the past 30 days, empirical antimicrobial therapy, concomitant antimicrobial therapy, duration of combination therapy, concurrent surgical interventions, presence of bacteremia, date of clearance of bacteremia (as available), length of hospital stay, 30-day all-cause mortality (as available), and overall clinical outcome as judged by the treating medical team were collected. All data were collected and stored securely via a password-protected REDCap database (25).
Safety assessment.Safety data included adverse-event reporting by the medical team and independent evaluation of laboratory values, including creatinine phosphokinase (CPK), serum creatinine, and potassium. Reasons for discontinuation of the combination therapy were assessed to determine the relation to the development of an adverse drug event.
Definitions.Methicillin resistance in S. aureus was defined per the Clinical and Laboratory Standards Institute (CLSI) guidelines as an MIC of ≥4 μg/ml to oxacillin. Daptomycin susceptibility in S. aureus was defined as an MIC of ≤1 μg/ml, and strains with an MIC of >1 μg/ml were referred to as daptomycin nonsusceptible (DNS) (26).
Patient outcomes were categorized as cure, improved, failure, or nonevaluable. Cure was defined as infection clearance, with negative cultures reported, as available, at the end of combination therapy, and resolution of all clinical signs and symptoms with no additional antibiotic therapy necessary. Improvement was defined as a partial resolution of clinical signs and symptoms and/or additional antibiotic therapy necessary at the end of combination therapy. Failure was an inadequate response to daptomycin and TMP-SMX therapy, defined as worsening or new/recurrent signs and symptoms of infection requiring a change in therapy or a positive culture reported at the end of combination therapy. Nonevaluable was defined as cases in which treatment response was unable to be determined at discharge or the end of combination therapy because medical records did not contain appropriate information to determine the clinical outcome.
Safety analysis definitions include adverse effects of either daptomycin or TMP-SMX. CPK elevations possibly caused by daptomycin were defined as >10× the upper limit of normal (ULN) or >5× ULN with symptoms of myopathy. Creatinine elevation was defined as serum creatinine levels with an increase of >1.5× from baseline or a ≥0.5-mg/dl increase in two consecutive measurements. Elevations in potassium secondary to combination therapy were evaluated with the definition of hyperkalemia as >5 meq/liter in the absence of hemolysis.
Susceptibility testing.Organism susceptibility data and baseline blood isolate data were collected from the electronic medical record. MIC values of studied antimicrobials were determined in duplicate by broth microdilution (BMD) at ∼106 CFU/ml per CLSI guidelines for all recovered isolates studied in time-kill experiments (27). All samples were incubated at 35°C for 18 to 24 h in Mueller-Hinton broth (MHB; Difco, Detroit, MI) supplemented with 50 mg/liter calcium and 12.5 mg/liter magnesium as growth media.
Synergy time-kill experiments.Time-kill experiments to determine the presence or absence of synergy were performed in duplicate against 17 recovered isolates in MHB supplemented with 50 mg/liter calcium and 12.5 mg/liter magnesium as growth media. Each macrowell received an initial bacterial inoculum of ∼106 CFU/ml. Bacterial strains were exposed to 0.5× their respective MIC values for daptomycin (Cubist Pharmaceuticals, Lexington, MA) and TMP-SMX (Sigma Chemical, St. Louis, MO) for 24 h. Each agent was tested alone and in combination against all available strains. Aliquots of 100 μl were obtained from each well at 0, 4, 8, and 24 h. Each sample was serially diluted to an appropriate concentration and plated using automatic spiral plating (WASP; DW Scientific, West Yorkshire, England). After 18 to 24 h growth on Trypticase soy agar, bacterial colonies were counted using a laser colony counter (ProtoCOL; Synoptics Limited, Frederick, MD). Time-kill curves were generated by plotting mean colony counts (log10 CFU/ml) versus time to compare 24-hour killing effects of antimicrobial exposures. Synergy was defined as a ≥100-fold increase in bacterial killing compared to the most active single constituent. Bactericidal activity was defined as a ≥1,000-fold reduction from baseline.
Statistical analysis.Patient data (baseline characteristics and clinical outcomes) were analyzed descriptively in terms of numbers, percentages, medians, and interquartile ranges (IQRs). The results of time-kill studies were compared using one-way analysis of variance (ANOVA) with Tukey's post hoc test for comparison of differences among groups. A P value of <0.05 was considered significant.
RESULTS
Twenty-eight patients received the combination of daptomycin and TMP-SMX for the treatment of MRSA infections. Table 1 details patient aggregate demographic and baseline laboratory information. Among the 28 patients, the most common source of infection leading to the use of combination daptomycin and TMP-SMX was bone and joint infections (n = 10, 35.7%). A total of 89.2% (n = 25) received an infectious diseases consult within a median of 2 days of positive blood cultures. Most patients (n = 21, 75.0%) received vancomycin at a median (IQR) maintenance dose of 15.1 mg/kg (13.3 to 16.0 mg/kg) to achieve troughs of 15 to 20 mg/liter prior to the initiation of daptomycin and were changed per hospital policy because of elevated MICs (MIC = 2 μg/ml per automated testing methodology or Etest; n = 17, 60.7%). The median time to daptomycin therapy was 4 days (IQR, 2 to 6 days) and to the addition of TMP-SMX from daptomycin initiation was 5 days (IQR, 1.5 to 9.5 days). Although the reason for combination therapy was not described in many cases (n = 9, 32.1%), the stated reasons included persistent bacteremia (n = 9, 32.1%), evidence of synergy (n = 7, 25.0%), and better central nervous system (CNS) penetration of TMP-SMX (n = 3, 10.7%). The median dose of daptomycin was 9.9 mg/kg daily (IQR, 8.8 to 10.0 mg/kg) and that of TMP-SMX was 8.1 mg/kg daily (IQR, 5.1 to 9.2 mg/kg daily) based on the TMP component.
Baseline demographics and laboratory data
Twenty-six (92.9%) out of 28 patients had positive blood cultures for MRSA during admission. The median total duration of bacteremia was 10 days (IQR, 7 to 16 days). Bacteremia cleared in six patients before or at the time of addition of TMP-SMX; for the remaining patients, bacteremia cleared within a median of 2.5 days (IQR, 1 to 6.75 days) after the initiation of combination therapy. Six isolates were DNS by broth microdilution, and all isolates were susceptible to TMP-SMX. Patients with DNS isolates had cleared bacteremia a median of 6.5 days (IQR, 5 to 7.5 days) after the initiation of TMP-SMX, compared to a median of 2 days (IQR, 1 to 6 days) in those with daptomycin-susceptible isolates. The median length of hospital stay was 24.5 days, and nine patients (33.3%) were admitted to the intensive care unit (ICU) at least once. Twenty-three patients had interventions in addition to antibiotic therapy, the most common being drainage and/or debridement of the source of infection (n = 19, 67.9%). Other interventions included amputation and removal of an infected graft. Among patients who received additional interventions, nine had negative blood cultures upon intervention, and the remainder had a median of 7 days (IQR, 3.5 to 9 days) of bacteremia postintervention. With respect to clinical outcomes, half of the patients had organism eradication without readmission, five patients (17.8%) expired during hospitalization, three (10.7%) were admitted with similar infection-related chief complaints, one (3.5%) was admitted for a nonrelated disease state, and four (14.3%) were lost to follow-up (Table 2). Adverse events relating to the combination of daptomycin and TMP-SMX were not commonly reported. Six patients (21.4%) had an adverse reaction reported in their medical charts (3 CPK elevations, 3 hyperkalemia), of which 50.0% were deemed unlikely to be related to antibiotic therapy. The time to development of adverse events ranged from 0 to 25 days (median, 6.5 days) after the initiation of combination therapy. The median baseline CPK level was 63.0 IU/liter (IQR, 32.7 to 148.3 IU/liter), and the median peak CPK level was 164.0 IU/liter (IQR, 113.0 to 814.0 IU/liter). Two patients had CPK levels of >2,000 IU/liter, but these were their baseline measurements, which decreased during therapy. Ten (35.7%) patients reported electrolyte abnormalities with respect to potassium at a median of 7.5 days after initiation of combination therapy. The median potassium level reported among patients without hemolysis or hemodialysis was 5.1 mg/dl. Among those with reported hyperkalemia, the median potassium level was 5.8 mg/dl. The two highest levels of potassium (6.9 mg/dl and 10.1 mg/dl) were seen in patients with chronic kidney disease on renal replacement therapy, particularly intermittent hemodialysis. All patients had resolution of signs and/or symptoms, and only one patient required discontinuation of TMP-SMX and daptomycin therapy secondary to elevated CPK.
Clinical outcomesa
In vitro time-kill experiments demonstrated that the combination of daptomycin and TMP/SMX was synergistic for 17 of the 17 isolates available for synergy testing (Fig. 1). All isolates were susceptible to TMP-SMX by broth microdilution, while 6 isolates (R6003, R8687, R8869, 232977, SA-H9749-1, and SA-F31774) were nonsusceptible to daptomycin. Of the 6 isolates not susceptible to daptomycin, 5 had a daptomycin MIC value of 4 μg/ml, and 1 (SA-H9749-1) possessed a daptomycin MIC of 2 μg/ml. The combination of daptomycin and TMP-SMX was synergistic and nearly bactericidal against 3 isolates at 24 h (−2.19 ± 0.11, −2.49 ± 0.11, and −2.56 ± 0.01 log10 CFU/ml from initial inoculum for R6003, R8687, and R8869, respectively). The combination was synergistic and bactericidal at 24 h for strains SA-H9749-1, SA-F31774, and 232977 (−3.35 ± 0.03, −3.83 ± 0.08, and −3.27 ± 0.10 log10 CFU/ml, respectively).
Change in log10 CFU/ml from baseline at 24 h by MRSA strain in time-kill studies. DAP and TMP-SMX were given at 0.5× the MRSA of the respective MRSA strains. Black bars, growth control; white bars, DAP; gray bars, TMP-SMX; checkered bars, DAP + TMP-SMX.
DISCUSSION
This case series describes the treatments and outcomes of patients with serious, deep-seated MRSA infections that could not be successfully managed with conventional therapy and were switched to salvage therapy with the novel combination daptomycin plus TMP-SMX. Previous literature demonstrated positive outcomes using this combination in patients with vertebral osteomyelitis and infective endocarditis (22, 23). In the current series, the types of infections were similar, including infective endocarditis, deep-seated abscesses, and bone/joint infections in the majority of cases. As many of these infections were chronic in nature, clinical cure at discharge was rarely definitively established; however, 50.0% of the patients had organism eradication without readmission. Overall, microbiological eradication was demonstrated in 92.8% of patients, with persistence seen in only one patient that could only be managed with source control. Although the doses of daptomycin varied, all but two patients had doses higher than the current FDA-approved 6 mg/kg/day. This higher dose of daptomycin is consistent with current practice recommendations from the IDSA. The optimal dose of TMP-SMX is still unknown; however, the dose of 8 mg/kg/day to 10 mg/kg/day TMP component demonstrated clinical utility in this case series. Adverse events secondary to the combination were minimal, with only three patients experiencing adverse drug reactions that were determined to be attributable to the treatment and only one requiring discontinuation of therapy. Two of the three patients with a daptomycin MIC of 4 μg/ml expired following a myocardial infarction and development of pulmonary embolism.
In this case series, six isolates were DNS, with daptomycin MICs of 2 μg/ml (n = 1) and 4 μg/ml (n = 5), while all were susceptible to TMP-SMX. Our laboratory was one of the first to publish data on this novel combination for multidrug-resistant MRSA, especially for isolates that are DNS. Using an in vitro simulated endocardial vegetation pharmacokinetic/pharmacodynamic (PK/PD) model, we compared daptomycin 6 mg/kg every 24 h alone and in combination with TMP-SMX 160/800 mg every 12 h, linezolid 600 mg every 12 h, cefepime 2 g every 12 h, or nafcillin 4 g every 4 h in two DNS isolates (20). The combination of daptomycin and TMP-SMX proved to be significantly superior to daptomycin alone and was the only regimen to sustain significant bactericidal activity over the 72-hour model. In another simulated endocardial vegetation PK/PD model, the activities of high-dose daptomycin and TMP-SMX were studied alone and in combination against four DNS isolates (21). The regimens studied included daptomycin 10 mg/kg every 24 h for 14 days, TMP-SMX 160/800 mg every 12 h for 14 days, a combination of the two for 14 days, or a combination for 7 days followed by deescalation to one of the antibiotics of interest. The combinations for 14 days or for 7 days followed by deescalation to either daptomycin or TMP-SMX were significantly better than daptomycin monotherapy. Echoing previously published data, synergy occurred in 17 of the 17 isolates tested in this study via time-kill methods. Perhaps most important, synergy extended to the DNS isolates, establishing the efficacy of the daptomycin and TMP-SMX combination against difficult-to-treat strains in vitro. Additionally, previous literature highlighted the importance of TMP-SMX susceptibility in order for the combination to work synergistically (4).
Previous studies evaluated the combination of daptomycin and beta-lactams with positive results (28–34). The combination of daptomycin with rifampin was also evaluated, especially in hardware-associated infections (23, 35–39). Several other agents have been studied with limited applicability in the United States. For instance, the combination of daptomycin with fosfomycin was shown to be favorable, but the intravenous form is not available in the United States (40–42). Published literature on the combination of daptomycin and TMP-SMX is scarce. A case report using high-dose TMP-SMX (15 mg/kg daily TMP component) intravenously in combination with daptomycin at 8 mg/kg demonstrated clinical improvement and microbiological clearance of infective endocarditis that was complicated by embolic stroke (23). After 6 weeks of the combination, the patient was discharged on high-dose TMP-SMX for an additional 6 weeks without complication. Clinical practice guidelines by the IDSA for the treatment of MRSA infections in adults and children recommend using doses of daptomycin greater than those that are currently approved by the FDA in combination with TMP-SMX for persistent infections with vancomycin treatment failure due to the previously mentioned reports, primarily consisting of in vitro data with only several clinical case reports. The recommendation to use this combination in the face of scarce data is secondary to the wide variety of treatment options and the difficulty in successfully treating these patients. Publication of the current study expands the available body of literature to support the recommendation and provides the largest study population to date.
The findings in this retrospective case series are promising, with a high rate of microbiological eradication found in DNS and non-DNS strains. Additionally, the combination demonstrated low rates of toxicity without persistence. The combination of once-daily intravenous daptomycin and oral TMP-SMX allows for ease of administration as an outpatient regimen. Additional investigation into the long-term follow-up of patients with infective endocarditis and bone and joint infections is needed. As more clinicians use this regimen, a larger body of literature can be compiled to determine which patients are optimally amenable to this combination. In addition, it may be of interest to explore the clinical utility of TMP-SMX in other antimicrobial combinations for difficult-to-treat infections.
FOOTNOTES
- Received 22 August 2014.
- Returned for modification 21 October 2014.
- Accepted 9 January 2015.
- Accepted manuscript posted online 20 January 2015.
- Copyright © 2015, American Society for Microbiology. All Rights Reserved.
