508272
research-article2013
AOPXXX10.1177/1060028013508272Annals of PharmacotherapyMcDaneld et al
Review Article
Use of Daptomycin to Treat Infections With Methicillin-Resistant Staphylococcus aureus Isolates Having Vancomycin Minimum Inhibitory Concentrations of 1.5 to 2 µg/mL
Annals of Pharmacotherapy XX(X) 1–12 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013508272 aop.sagepub.com
Patrick M. McDaneld, PharmD, BCPS1,2,3, Linda M. Spooner, PharmD, BCPS (AQ ID)1, John F. Mohr, PharmD2, and Paul P. Belliveau, PharmD1
Abstract Objective: To evaluate daptomycin use for the treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) isolates having vancomycin minimum inhibitory concentrations (MICs) of 1.5 to 2 µg/mL. Data Sources: The literature was retrieved through PubMed and EMBASE (January 2006 to August 2013).Study Selection and Data Extraction: English articles were reviewed. Studies that included separate daptomycin data (clinical outcome or in vitro surveillance) for MRSA isolates with vancomycin MICs of 1.5 to 2 µg/mL by any testing methodology were included. Data Synthesis: Clinical and microbiological outcomes associated with daptomycin used as first-line or subsequent therapy for MRSA infections with vancomycin MICs of 1.5 to 2 µg/mL were reported in 7 retrospective clinical studies; susceptibility information involving such isolates was reported from 12 surveillancestudies. Although not all studies demonstrated outcome differences between daptomycin and comparator treatments (usually vancomycin), when differences were reported, they were in favor of daptomycin. Individual studies found lower 60-day (8% vs 20%, P = .046) and 30-day mortality (3.5% vs 12.9%, P = .047) and increased treatment success with daptomycin (68.6% vs 43.1%, P = .008; 76.9% vs 53.8%, P = .048) in bacteremic patients. The median doses used for treatment of bacteremia were greater than that approved by the FDA for this indication (6 mg/kg/d). Conclusions: Current published evidence indicates daptomycin may be an acceptable alternative to vancomycin for MRSA infections, especially bacteremia, involving isolates with vancomycin MIC values of 1.5 to 2 µg/mL. Additional evidence is needed to fully elucidate daptomycin utility in this area. Keywords daptomycin, methicillin-resistant Staphylococcus aureus, MRSA, tolerance, vancomycin, elevated MIC Received September 4, 2013; accepted September 13, 2013
Background Vancomycin has served as the cornerstone of therapy in serious Gram-positive infections for decades, and its activity had been largely preserved, as demonstrated by high and sustained methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S aureus (MRSA) in vitro susceptibility surveillance data.1-4 However, the clinical utility of vancomycin has recently been questioned.5 In 2006, the Clinical and Laboratory Standards Institute lowered the S aureus vancomycin susceptibility breakpoint from ≤4 to ≤2 µg/mL because of evidence that isolates with minimum inhibitory concentrations (MICs) above 2 µg/mL were less responsive to vancomycin therapy.6 This change was also initiated to increase the detection of heterogeneously resistant
S aureus (hVISA).6 Another concern is the identification of a trend of increasing S aureus vancomycin MIC values (MIC creep), something that is not necessarily evident to clinicians because of a lack of changes in the percentage of susceptible 1
Massachusetts College of Pharmacy and Health Sciences, Worcester/ Manchester Lexington, MA, USA 2 Cubist Pharmaceuticals, Lexington, MA, USA 3 Department of Pharmacy, Houston Methodist Hospital, Houston, TX USA Corresponding Author: Patrick M. McDaneld, PharmD, BCPS, Department of Pharmacy, Houston Methodist Hospital, 6565 Fannin St., DB1-09, Houston, TX 77030, USA. Email: [email protected]
Downloaded from aop.sagepub.com at Universitats-Landesbibliothek on December 23, 2013
2
Annals of Pharmacotherapy XX(X)
isolates.7,8 The significance of this trend lies in studies suggesting that patients infected with MRSA isolates that have vancomycin MICs >1 µg/mL have inferior outcomes compared with those patients with isolates ≤1 µg/mL.9-11 This trend has also been identified in MSSA isolates with MIC values >1.5 versus ≤1.5 µg/mL in patients receiving both vancomycin and β-lactam therapy.12 These findings raise the possibility that the elevated vancomycin MIC value itself may be indicative of poor outcomes for S aureus, highlighting the need for evaluation of alternative therapies. The significance of the concerns with vancomycin use is complicated by heterogeneity among MIC results by various testing methodologies.13-16 Etest MICs are reported to be approximately 0.5 to 1.5 µg/mL higher than those generated by broth microdilution.16 The difference between MIC methodologies may in part be attributable to intraoperator/ intramachine variability in test assessment. Much of the data linking vancomycin MIC to outcomes for S aureus infections is based on Etest MICs.17 The Infectious Disease Society of America (IDSA) guideline for MRSA infections suggests considering alternatives to vancomycin for patients not responding to therapy, independent of pathogen MIC.18 However, given data suggesting poorer outcomes in patients infected with vancomycin-susceptible MRSA having elevated MICs, there may be need to consider alternatives for treatment of such pathogens.9-11 Pharmacokinetic/pharmacodynamic modeling, in vitro studies, and limited human data suggest that the area under the curve to MIC (AUC/MIC) ratio for vancomycin needs to be ≥400 to optimize vancomycin exposure and outcomes.19 As the vancomycin MIC rises above 0.5 µg/mL, the probability of reaching the 400 AUC/MIC ratio declines. At an MIC of 2 µg/mL, attainment of this ratio is unlikely with clinically relevant regimens.19 The IDSA vancomycin dosing consensus suggests considering alternatives to vancomycin in patients whose S aureus isolate has a vancomycin MIC ≥2 µg/mL.19 One treatment option in these circumstances may be daptomycin, a lipopeptide antibiotic that is FDA approved for treatment of S aureus bacteremia, right-sided infective endocarditis, and complicated skin and skin structure infections (cSSSIs).20 However, consideration of daptomycin may be complicated by reports suggesting potential vancomycin and daptomycin cross-resistance.21-25 Several mechanisms have been proposed for this cross-resistance, including cell wall thickening, membrane charge changes, and reduced muramic acid O-acetylation.26,27 The relationship between vancomycin and daptomycin S aureus susceptibility has been reviewed by Moise et al.26 Case reports exemplify the potentially disparate outcomes associated with the treatment of S aureus infections with elevated, but susceptible, vancomycin MICs, both with daptomycin and other therapies.28-37 However, their use in evaluating the
safety and efficacy of daptomycin for the treatment of S aureus infections with vancomycin MICs of 1.5 to 2 µg/mL is limited. These represent a single outcome, are subject to publication bias, and typically involve complicated patients (eg, multiple previous antimicrobial therapies and source control failure).28-37 Therefore, the aim of this article is to review patient outcomes and in vitro susceptibility data with daptomycin for vancomycin-susceptible MRSA with MICs of 1.5 to 2 µg/mL.
Literature Review Articles published January 1, 2006, to August 1, 2013 were searched via PubMed and EMBASE utilizing combinations of the search terms Staphylococcus aureus, methicillinresistant Staphylococcus aureus, hVISA, VISA, tolerance, tolerant, resistance, resistant, efficacy, MIC, 1.5, 2, vancomycin, and daptomycin. The search was limited to 2006 to coincide with the Clinical and Laboratory Standards Institute reduction of S aureus vancomycin breakpoint and to maximize the relevance of reviewed articles to current clinical practice.6 These searches generated 964 unique citations. Articles were reviewed; those ineligible for inclusion were eliminated. Articles were excluded if they did not have a breakdown of the isolate numbers with vancomycin MICs of 1.5 to 2 µg/mL; involved use of animal or in vitro pharmacodynamic models, or computer simulations; consisted of surveillance studies not reporting isolate collection years; were review articles; were conference abstracts/proceedings; were not published in English. Articles selected for inclusion were those that included separate information for S aureus isolates with vancomycin MICs of 1.5 to 2 µg/ mL by any testing methodology and described human clinical studies or clinical isolate surveillance. The clinical studies needed to primarily focus on outcomes associated with MRSA infections. Surveillance studies were required to present in vitro activity against MRSA either as the primary focus or a subset of all S aureus. This resulted in 12 in vitro and 7 clinical studies.38-56
In Vitro Studies MRSA susceptibility is routinely assessed in large surveillance studies, but only rarely are MRSA subpopulations with vancomycin MICs of 1.5 to 2 µg/mL analyzed for antimicrobial activity.38-49 Presence of these isolates is often indicated in surveillance data by the MIC range, MIC50 or MIC90.57-59 However, without a subgroup analysis, clinicians are unable to understand the activity of daptomycin against MRSA isolates with vancomycin MICs of 1.5 to 2 µg/mL in the region studied.2,60-62 In all, 12 surveillance studies were identified, which included a subgroup analysis of MRSA isolates with 1.5 to 2 µg/mL vancomycin MICs.38-49 These included isolates from
Downloaded from aop.sagepub.com at Universitats-Landesbibliothek on December 23, 2013
3
McDaneld et al Table 1. Summary of In Vitro Daptomycin Susceptibility for MRSA Isolates With a Vancomycin MIC of 1.5 to 2 µg/mL From Surveillance Programs. Study
Countries Studied
Isolate Source(s)
Isolate Years
Number of Isolates
MIC Testing Methodology
DAP Susceptibility
DAP MIC Range (µg/mL)
DAP MIC50 (µg/mL)
DAP MIC90 (µg/mL)
Sader et al38 (2010) Chong et al39 (2012) Chua et al40 (2008) Samra et al41 (2007) Sancak et al42 (2013) Kao et al43 (2011)
US, Europe Korea US Israel Turkey Taiwan
NR Blood Blood Multiple Blood Blood
2006-2008 2004-2009 2005-2007 2005 1999-2009 2006-2008
410 317 199 165 116 81
97.3% 100% 100% 100% 100% 98.8%
0.12-4 0.125-1 0.25-1 NR NR 0.25-4
0.5 0.25 NR NR NR NR
0.5 0.5 NR NR NR NR
US Spain Canada India Multiple Italy
NR Blood NR Multiple SSSI NR
2007 2008 2007-2011 2011-2012 2004-2007 2006-2007
52 33 28 18 18 8
BMD BMD Etest Etest Etest VAN, agar dilution; daptomycin, BMD Etest Etest BMD Etest BMD BMD
100% 100% 100% 94.4% 100% 100%
NR NR NR 0.125-2 NR 0.25-1
NR NR NR NR NR NR
NR NR NR NR NR NR
Tran et al44 (2009) Picazo et al45 (2009) Zhanel et al46 (2013) Jain et al47 (2013) Mendes et al48 (2010) Marchese et al49 (2009)
Abbreviations: BMD, broth microdilution; DAP, daptomycin; MIC, minimum inhibitory concentration; NR, not reported; SSSI, skin and skin structure infection; VAN, vancomycin.
Canada (n = 28), Europe (n = 128), India (n = 18), Israel (n = 165), Italy (n = 8), Korea (n = 317), Taiwan (n = 81), Spain (n = 33), Turkey (n = 116), the United States (n = 533), and unspecified worldwide (n = 18).38-49 A weighted average from these studies indicated that 99.1% of the isolates were daptomycin susceptible (MIC ≤1 µg/mL). Sader et al38 provided further analysis, which indicated that 128/128 (100%) of the European and 271/282 (96.1%) of the US MRSA isolates with vancomycin MICs of 2 µg/mL were daptomycin susceptible (based on US-approved breakpoints).20 Chong et al39 found that MRSA isolates (Korea) with vancomycin MICs >1 µg/mL were more likely to have a daptomycin MIC ≥0.5 µg/mL (P < .001). Additional information regarding these studies is given in Table 1.
Clinical Studies Limited clinical study information relating specifically to daptomycin for infections caused by MRSA with vancomycin MIC values of 1.5 to 2 µg/mL has been published to date (Table 2); their presence in data sets is often only indicated by MIC ranges.50-56,62 Murray et al50 published a matched, retrospective cohort study comparing the outcomes of early daptomycin use to vancomycin for MRSA bacteremia. Adult patients were included if they had MRSA blood isolates with a vancomycin MIC >1 µg/mL (MicroScan or Etest) and had received either vancomycin or daptomycin for >72 hours. Patients were excluded if they required hemodialysis, the bacteremia source was pneumonia or intravenous catheter related, or they received alternative MRSA therapy for ≥72 hours prior to administration of vancomycin or daptomycin. Following the screening of 1863 consecutive cases at 4 Detroit hospitals from 2005 to 2012, 85 patients receiving daptomycin were matched with 85 patients receiving vancomycin according to age (±5 years), Pitt bacteremia score
(1 µg/mL. Phase I involved a 24-month retrospective analysis of patients admitted to the Detroit Medical Center in 2005-2007 and treated with vancomycin for at least 48 hours. Phase II included a 24-month period (2008-2010) following implementation of a MRSA BSI treatment guideline. This guideline indicated that patients should be treated initially with vancomycin for confirmed or suspected MRSA BSI; if susceptibility testing revealed a MRSA isolate with a vancomycin MIC >1 µg/mL, therapy was to be changed to daptomycin (at least 6 mg/kg/d, based on total body weight and adjusted for renal dysfunction). Phase I MRSA isolates had MICs determined via Etest; phase II MICs were determined by MicroScan. The susceptibility testing of all isolates was repeated by an independent laboratory (methods not specified). Treatment was considered successful in patients with resolution or improvement in baseline signs and symptoms, absence of new signs and symptoms during therapy, and MRSA eradication after the end of a course of therapy of at least 7 days. During phase I, 70 patients met inclusion criteria; 100 patients were included in phase II. The median initial vancomycin trough in phase I was lower than in phase II (11.2 vs 15.2 mg/L, P = .02). The median daptomycin dose in phase II was 7.5 mg/kg/d (IQR = 6-10 mg/kg/d). Patients in phase II received vancomycin for a median of 3 days (IQR = 2-3 days) before being switched to daptomycin. Differences between phase I and phase II patient groups, respectively, included median creatinine clearance (62.5 vs 42.2 mL/min, P = .01) and a history of coronary heart disease (24.3% vs 13.0%, P = .05), diabetes mellitus (18.6 vs 35.0%, P = .01), intravenous drug use (44.3% vs 22.0%, P = .002), and hemodialysis (14.3% vs 33.0%, P = .004). Daptomycin MIC distribution in phase II was as follows: 0.13 µg/mL, 2.2%; 0.25 µg/mL, 15.2%; 0.5 µg/mL, 60.9%; 1 µg/mL, 13%; 2 µg/mL, 4.3%; 4 µg/mL, 4.3%. Treatment success was greater in phase II patients (75% vs 41.4%; P < .001). Continued bacteremia at 7 days of therapy was
Downloaded from aop.sagepub.com at Universitats-Landesbibliothek on December 23, 2013
6
Annals of Pharmacotherapy XX(X)
the most common reason for failure (44.3% vs 21% for phase I and phase II, respectively; P < .001). During the independent laboratory analysis, not all isolates exhibited a vancomycin MIC >1 µg/mL; 58/70 (71.4%) patients in phase I and 51/100 (51%) in phase II were found to have such isolates. An analysis of only these patients did not substantially alter the findings reported from the entire cohort; a greater percentage of phase II patients achieved treatment success (68.6% vs 43.1%, P = .008). The authors concluded that the switch to daptomycin was responsible for the greater clinical success in the treatment of MRSA BSI caused by isolates exhibiting elevated vancomycin MICs but suggested that further studies are needed for confirmation.52 This study was limited by differences in patient characteristics, failure of all isolates to have MICs >1 µg/mL on retesting, and the potential for confounding caused by time period differences in the phases. Campbell et al53 also performed a study in the Detroit Medical Center health system. This retrospective cohort study compared the efficacy and costs of trimethoprim/sulfamethoxazole (TMP/SMX) with that of daptomycin and linezolid in patients with infections from MRSA with vancomycin MICs of 2 µg/mL during 2009. Patients were included if they had received 2 or more doses of TMP/ SMX, daptomycin, or linezolid from 3 days before to 14 days after an initially positive MRSA culture. Susceptibility was determined by MicroScan. Multivariate analysis was used to assess association with several outcomes, including in-hospital mortality, 3-month mortality, length of hospital stay after infection, functional status, need for discharge to a long-term care facility, and readmission within 6 months of discharge. A total of 328 patients were enrolled. The most commonly reported infections were SSSIs and pneumonia (approximately 75% of infections). The remaining infections, in order of decreasing frequency, were BSIs of unknown source, catheter-related BSIs, and urinary tract infections. There were 143 TMP/SMX, 89 daptomycin, and 75 linezolid recipients; 21 patients received TMP/SMX with either daptomycin or linezolid. Vancomycin was used in 73% of patients prior to changing to one of the study drugs because of clinical failure or an elevated vancomycin MIC. The median TMP dose was 4.7 mg/kg/d (range = 1.314.9 mg/kg/d), and the median daptomycin dose was 6.7 mg/kg/d (range = 3.3-12 mg/kg/d) in patients with a creatinine clearance greater than 30 mL/min. In bivariate analysis, TMP/SMX patients demonstrated favorable outcomes compared with patients receiving other treatments for all outcomes inserted into the model. In the multivariate analysis, none of these associations reached statistical significance. There were several significant notable differences in the TMP/SMX patients relative to those receiving comparator treatments (Table 2). Similar patient differences were observed in an analysis limited only to patients with a SSSI.
As may be expected based on the acquisition costs of the treatments, the mean antibiotic cost per patient was significantly lower with TMP/SMX (Table 2). Despite substantial trial limitations, the authors concluded that TMP/SMX demonstrated efficacy and mortality benefits comparable to linezolid and daptomycin and should be considered in the treatment of MRSA infection with MICs of 2 µg/mL.53 This study was limited by the notable intergroup patient differences and the problems that arise from subgroup analyses. Moore et al54 conducted a retrospective case-control study focused on BSI from MRSA isolates with vancomycin MICs of 1.5 or 2 µg/mL treated with vancomycin (n = 118) or daptomycin (n = 59). Vancomycin was dosed to achieve trough values of 10 to 20 µg/mL. MICs were determined via Etest. Patients ≥18 years of age admitted to Henry Ford Hospital (Detroit) during 2005-2009 were included if they had an index MRSA blood culture isolate with a vancomycin MIC of 1.5 to 2 µg/mL, they received active therapy within 48 hours of infection onset, daptomycin was initiated within 14 days of index culture if switched from another therapy, and they received vancomycin or daptomycin for ≥48 hours. Daptomycin patients were matched 1:2 to patients treated with vancomycin based on age, APACHE-II score, and infection source risk level. The primary end point, clinical failure, was defined as a composite that included 60-day mortality, microbiological failure, and/or recurrence. Sixty-day mortality included death in the 60-day period following the index culture. Microbiological failure was defined as a positive MRSA blood culture ≥7 days after index culture for vancomycin patients or after the initiation of daptomycin for daptomycin patients. Recurrence was defined as a MRSA BSI occurring within 30 days after therapy completion. Vancomycin and daptomycin patient groups were similar in terms of mean age (52 vs 51 years, respectively), intravenous drug abuse history (31% vs 39%, respectively), and mean APACHE-II scores (14 for both). There were fewer MRSA isolates with a vancomycin MIC = 2 µg/mL in the vancomycin arm (14% vs 58%, P < .001). The vancomycin and daptomycin groups also differed in terms of the presence of chronic renal disease (6% vs 17%, respectively, P = .022) and immunosuppression (13% vs 27%, respectively, P = .022). The most common BSI sources were CVCs, infective endocarditis, and skin/wound infections. The median definitive vancomycin trough (average of trough values obtained within the hour before the next steady-state dose and at least 72 hours after initiation) was 18 µg/mL (IQR = 15-21 µg/ mL); the median initial daptomycin dose was 6 mg/kg/d (IQR = 6-8 mg/kg/d). In the daptomycin group, 91% of patients had previously received vancomycin therapy. The median time to daptomycin switch from previous therapy was 5 days (IQR = 3-9 days). There was no difference in clinical failure (31% for vancomycin vs 17% for daptomycin, P = .084). However, vancomycin use was associated with an
Downloaded from aop.sagepub.com at Universitats-Landesbibliothek on December 23, 2013
7
McDaneld et al increased risk of failure in a conditional regression analysis (adjusted OR = 3.13; 95% CI = 1-9.76). Regression analysis also identified acute renal failure as associated with failure (adjusted OR = 3.91; 95% CI = 1.05-14.56) and right-sided endocarditis as associated with clinical success (adjusted OR = 0.08; 95% CI = 0.01-0.83). Mortality within 60 days was lower in daptomycin patients (8% vs 20%, P = .046). There was no difference in 30-day recurrence (5% for vancomycin vs 3% for daptomycin, P = .620) or microbiological failure (9% for vancomycin vs 10% for daptomycin, P = .855). The authors concluded that daptomycin use is associated with a better outcome in MRSA BSI for isolates with higher vancomycin MICs.54 This study was limited by a potential patient selection bias in those switched to daptomycin therapy, underlying differences in patient/pathogen characteristics, differences in frequency of infectious diseases’ physician consults, failure to determine daptomycin MICs, and the single-center, retrospective design. Two additional retrospective studies were conducted that included a subgroup of patients with S aureus isolates having vancomycin MIC values of 2 µg/mL.55,56 Jobson et al55 studied outcomes associated with daptomycin and vancomycin when used as initial therapy (≥3 days of treatment) for S aureus infections (excluding endocarditis, osteomyelitis, central nervous system, and respiratory infections) during 2006-2008 at a single California institution. The study enrolled 165 patients; 57 received daptomycin, and 108 received vancomycin. S aureus isolates with an Etest vancomycin MIC of 2 µg/mL accounted for 76% of isolates; the remaining isolates had vancomycin MICs of 0.5 or 1.0 µg/mL. The 2-µg/mL MIC group included 49 daptomycin and 79 vancomycin patients. Baseline characteristics of the study arms (including all isolates) were similar except for mean patient weight (85 kg for daptomycin vs 75 kg for vancomycin, P = .019), urinary tract infection source (9% for daptomycin vs 1% for vancomycin, P = .019), median length of stay before infection onset (8 days for daptomycin vs 5 days for vancomycin, P = .001), percentage of patients with infection onset >3 days after admission (53% for daptomycin vs 25% for vancomycin; P < .001), and distribution of MRSA isolate vancomycin MICs (daptomycin arm, 87% with 2 µg/mL vancomycin MIC; vancomycin arm, 73% with 2 µg/mL vancomycin MIC; P = .028). The primary infection type was SSSI (72% for daptomycin vs 73% for vancomycin). The frequency of MRSA isolates did not differ between groups (81% for daptomycin vs 68% for vancomycin, P = .074). The median daptomycin dose was 4 mg/ kg/d (range = 3.4-7.2 mg/kg/d); the median vancomycin trough was 12.5 mg/L (range = 3.2-30.5 mg/L, 44% between 10 and 14 mg/L). Primary outcomes included antibioticrelated length of stay, 60-day recurrence, and 30-day allcause mortality. In the MRSA subgroup with vancomycin MICs of 2 µg/mL, the median antibiotic length of stay was shorter with daptomycin (7 days vs 10 days, P = .014.
Mortality (8% for daptomycin vs 6% for vancomycin, P = .693) and recurrence (27% for daptomycin vs 19% for vancomycin, P = .316) did not differ between groups among all S aureus infections (data not reported for the MRSA subset). The authors concluded that the initial use of daptomycin for S aureus isolates with vancomycin MICs of 2 µg/mL may be associated with shorter antibiotic-related lengths of stay, but that this must be confirmed by further study.55 This study was limited by a lack of patient baseline characteristic comparison or detailed results in the subgroup whose MRSA isolate had a vancomycin MIC of 2 µg/mL. Additional limitations included the low vancomycin troughs seen in a number of patients, the rounding of half-step MIC values (ie, 1.5 to 2 µg/mL), lack of daptomycin MIC values, and the single-center, retrospective design. The final study was an analysis comparing daptomycin outcomes between patients with infections caused by S aureus isolates having vancomycin MICs
research-article2013
AOPXXX10.1177/1060028013508272Annals of PharmacotherapyMcDaneld et al
Review Article
Use of Daptomycin to Treat Infections With Methicillin-Resistant Staphylococcus aureus Isolates Having Vancomycin Minimum Inhibitory Concentrations of 1.5 to 2 µg/mL
Annals of Pharmacotherapy XX(X) 1–12 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013508272 aop.sagepub.com
Patrick M. McDaneld, PharmD, BCPS1,2,3, Linda M. Spooner, PharmD, BCPS (AQ ID)1, John F. Mohr, PharmD2, and Paul P. Belliveau, PharmD1
Abstract Objective: To evaluate daptomycin use for the treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) isolates having vancomycin minimum inhibitory concentrations (MICs) of 1.5 to 2 µg/mL. Data Sources: The literature was retrieved through PubMed and EMBASE (January 2006 to August 2013).Study Selection and Data Extraction: English articles were reviewed. Studies that included separate daptomycin data (clinical outcome or in vitro surveillance) for MRSA isolates with vancomycin MICs of 1.5 to 2 µg/mL by any testing methodology were included. Data Synthesis: Clinical and microbiological outcomes associated with daptomycin used as first-line or subsequent therapy for MRSA infections with vancomycin MICs of 1.5 to 2 µg/mL were reported in 7 retrospective clinical studies; susceptibility information involving such isolates was reported from 12 surveillancestudies. Although not all studies demonstrated outcome differences between daptomycin and comparator treatments (usually vancomycin), when differences were reported, they were in favor of daptomycin. Individual studies found lower 60-day (8% vs 20%, P = .046) and 30-day mortality (3.5% vs 12.9%, P = .047) and increased treatment success with daptomycin (68.6% vs 43.1%, P = .008; 76.9% vs 53.8%, P = .048) in bacteremic patients. The median doses used for treatment of bacteremia were greater than that approved by the FDA for this indication (6 mg/kg/d). Conclusions: Current published evidence indicates daptomycin may be an acceptable alternative to vancomycin for MRSA infections, especially bacteremia, involving isolates with vancomycin MIC values of 1.5 to 2 µg/mL. Additional evidence is needed to fully elucidate daptomycin utility in this area. Keywords daptomycin, methicillin-resistant Staphylococcus aureus, MRSA, tolerance, vancomycin, elevated MIC Received September 4, 2013; accepted September 13, 2013
Background Vancomycin has served as the cornerstone of therapy in serious Gram-positive infections for decades, and its activity had been largely preserved, as demonstrated by high and sustained methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S aureus (MRSA) in vitro susceptibility surveillance data.1-4 However, the clinical utility of vancomycin has recently been questioned.5 In 2006, the Clinical and Laboratory Standards Institute lowered the S aureus vancomycin susceptibility breakpoint from ≤4 to ≤2 µg/mL because of evidence that isolates with minimum inhibitory concentrations (MICs) above 2 µg/mL were less responsive to vancomycin therapy.6 This change was also initiated to increase the detection of heterogeneously resistant
S aureus (hVISA).6 Another concern is the identification of a trend of increasing S aureus vancomycin MIC values (MIC creep), something that is not necessarily evident to clinicians because of a lack of changes in the percentage of susceptible 1
Massachusetts College of Pharmacy and Health Sciences, Worcester/ Manchester Lexington, MA, USA 2 Cubist Pharmaceuticals, Lexington, MA, USA 3 Department of Pharmacy, Houston Methodist Hospital, Houston, TX USA Corresponding Author: Patrick M. McDaneld, PharmD, BCPS, Department of Pharmacy, Houston Methodist Hospital, 6565 Fannin St., DB1-09, Houston, TX 77030, USA. Email: [email protected]
Downloaded from aop.sagepub.com at Universitats-Landesbibliothek on December 23, 2013
2
Annals of Pharmacotherapy XX(X)
isolates.7,8 The significance of this trend lies in studies suggesting that patients infected with MRSA isolates that have vancomycin MICs >1 µg/mL have inferior outcomes compared with those patients with isolates ≤1 µg/mL.9-11 This trend has also been identified in MSSA isolates with MIC values >1.5 versus ≤1.5 µg/mL in patients receiving both vancomycin and β-lactam therapy.12 These findings raise the possibility that the elevated vancomycin MIC value itself may be indicative of poor outcomes for S aureus, highlighting the need for evaluation of alternative therapies. The significance of the concerns with vancomycin use is complicated by heterogeneity among MIC results by various testing methodologies.13-16 Etest MICs are reported to be approximately 0.5 to 1.5 µg/mL higher than those generated by broth microdilution.16 The difference between MIC methodologies may in part be attributable to intraoperator/ intramachine variability in test assessment. Much of the data linking vancomycin MIC to outcomes for S aureus infections is based on Etest MICs.17 The Infectious Disease Society of America (IDSA) guideline for MRSA infections suggests considering alternatives to vancomycin for patients not responding to therapy, independent of pathogen MIC.18 However, given data suggesting poorer outcomes in patients infected with vancomycin-susceptible MRSA having elevated MICs, there may be need to consider alternatives for treatment of such pathogens.9-11 Pharmacokinetic/pharmacodynamic modeling, in vitro studies, and limited human data suggest that the area under the curve to MIC (AUC/MIC) ratio for vancomycin needs to be ≥400 to optimize vancomycin exposure and outcomes.19 As the vancomycin MIC rises above 0.5 µg/mL, the probability of reaching the 400 AUC/MIC ratio declines. At an MIC of 2 µg/mL, attainment of this ratio is unlikely with clinically relevant regimens.19 The IDSA vancomycin dosing consensus suggests considering alternatives to vancomycin in patients whose S aureus isolate has a vancomycin MIC ≥2 µg/mL.19 One treatment option in these circumstances may be daptomycin, a lipopeptide antibiotic that is FDA approved for treatment of S aureus bacteremia, right-sided infective endocarditis, and complicated skin and skin structure infections (cSSSIs).20 However, consideration of daptomycin may be complicated by reports suggesting potential vancomycin and daptomycin cross-resistance.21-25 Several mechanisms have been proposed for this cross-resistance, including cell wall thickening, membrane charge changes, and reduced muramic acid O-acetylation.26,27 The relationship between vancomycin and daptomycin S aureus susceptibility has been reviewed by Moise et al.26 Case reports exemplify the potentially disparate outcomes associated with the treatment of S aureus infections with elevated, but susceptible, vancomycin MICs, both with daptomycin and other therapies.28-37 However, their use in evaluating the
safety and efficacy of daptomycin for the treatment of S aureus infections with vancomycin MICs of 1.5 to 2 µg/mL is limited. These represent a single outcome, are subject to publication bias, and typically involve complicated patients (eg, multiple previous antimicrobial therapies and source control failure).28-37 Therefore, the aim of this article is to review patient outcomes and in vitro susceptibility data with daptomycin for vancomycin-susceptible MRSA with MICs of 1.5 to 2 µg/mL.
Literature Review Articles published January 1, 2006, to August 1, 2013 were searched via PubMed and EMBASE utilizing combinations of the search terms Staphylococcus aureus, methicillinresistant Staphylococcus aureus, hVISA, VISA, tolerance, tolerant, resistance, resistant, efficacy, MIC, 1.5, 2, vancomycin, and daptomycin. The search was limited to 2006 to coincide with the Clinical and Laboratory Standards Institute reduction of S aureus vancomycin breakpoint and to maximize the relevance of reviewed articles to current clinical practice.6 These searches generated 964 unique citations. Articles were reviewed; those ineligible for inclusion were eliminated. Articles were excluded if they did not have a breakdown of the isolate numbers with vancomycin MICs of 1.5 to 2 µg/mL; involved use of animal or in vitro pharmacodynamic models, or computer simulations; consisted of surveillance studies not reporting isolate collection years; were review articles; were conference abstracts/proceedings; were not published in English. Articles selected for inclusion were those that included separate information for S aureus isolates with vancomycin MICs of 1.5 to 2 µg/ mL by any testing methodology and described human clinical studies or clinical isolate surveillance. The clinical studies needed to primarily focus on outcomes associated with MRSA infections. Surveillance studies were required to present in vitro activity against MRSA either as the primary focus or a subset of all S aureus. This resulted in 12 in vitro and 7 clinical studies.38-56
In Vitro Studies MRSA susceptibility is routinely assessed in large surveillance studies, but only rarely are MRSA subpopulations with vancomycin MICs of 1.5 to 2 µg/mL analyzed for antimicrobial activity.38-49 Presence of these isolates is often indicated in surveillance data by the MIC range, MIC50 or MIC90.57-59 However, without a subgroup analysis, clinicians are unable to understand the activity of daptomycin against MRSA isolates with vancomycin MICs of 1.5 to 2 µg/mL in the region studied.2,60-62 In all, 12 surveillance studies were identified, which included a subgroup analysis of MRSA isolates with 1.5 to 2 µg/mL vancomycin MICs.38-49 These included isolates from
Downloaded from aop.sagepub.com at Universitats-Landesbibliothek on December 23, 2013
3
McDaneld et al Table 1. Summary of In Vitro Daptomycin Susceptibility for MRSA Isolates With a Vancomycin MIC of 1.5 to 2 µg/mL From Surveillance Programs. Study
Countries Studied
Isolate Source(s)
Isolate Years
Number of Isolates
MIC Testing Methodology
DAP Susceptibility
DAP MIC Range (µg/mL)
DAP MIC50 (µg/mL)
DAP MIC90 (µg/mL)
Sader et al38 (2010) Chong et al39 (2012) Chua et al40 (2008) Samra et al41 (2007) Sancak et al42 (2013) Kao et al43 (2011)
US, Europe Korea US Israel Turkey Taiwan
NR Blood Blood Multiple Blood Blood
2006-2008 2004-2009 2005-2007 2005 1999-2009 2006-2008
410 317 199 165 116 81
97.3% 100% 100% 100% 100% 98.8%
0.12-4 0.125-1 0.25-1 NR NR 0.25-4
0.5 0.25 NR NR NR NR
0.5 0.5 NR NR NR NR
US Spain Canada India Multiple Italy
NR Blood NR Multiple SSSI NR
2007 2008 2007-2011 2011-2012 2004-2007 2006-2007
52 33 28 18 18 8
BMD BMD Etest Etest Etest VAN, agar dilution; daptomycin, BMD Etest Etest BMD Etest BMD BMD
100% 100% 100% 94.4% 100% 100%
NR NR NR 0.125-2 NR 0.25-1
NR NR NR NR NR NR
NR NR NR NR NR NR
Tran et al44 (2009) Picazo et al45 (2009) Zhanel et al46 (2013) Jain et al47 (2013) Mendes et al48 (2010) Marchese et al49 (2009)
Abbreviations: BMD, broth microdilution; DAP, daptomycin; MIC, minimum inhibitory concentration; NR, not reported; SSSI, skin and skin structure infection; VAN, vancomycin.
Canada (n = 28), Europe (n = 128), India (n = 18), Israel (n = 165), Italy (n = 8), Korea (n = 317), Taiwan (n = 81), Spain (n = 33), Turkey (n = 116), the United States (n = 533), and unspecified worldwide (n = 18).38-49 A weighted average from these studies indicated that 99.1% of the isolates were daptomycin susceptible (MIC ≤1 µg/mL). Sader et al38 provided further analysis, which indicated that 128/128 (100%) of the European and 271/282 (96.1%) of the US MRSA isolates with vancomycin MICs of 2 µg/mL were daptomycin susceptible (based on US-approved breakpoints).20 Chong et al39 found that MRSA isolates (Korea) with vancomycin MICs >1 µg/mL were more likely to have a daptomycin MIC ≥0.5 µg/mL (P < .001). Additional information regarding these studies is given in Table 1.
Clinical Studies Limited clinical study information relating specifically to daptomycin for infections caused by MRSA with vancomycin MIC values of 1.5 to 2 µg/mL has been published to date (Table 2); their presence in data sets is often only indicated by MIC ranges.50-56,62 Murray et al50 published a matched, retrospective cohort study comparing the outcomes of early daptomycin use to vancomycin for MRSA bacteremia. Adult patients were included if they had MRSA blood isolates with a vancomycin MIC >1 µg/mL (MicroScan or Etest) and had received either vancomycin or daptomycin for >72 hours. Patients were excluded if they required hemodialysis, the bacteremia source was pneumonia or intravenous catheter related, or they received alternative MRSA therapy for ≥72 hours prior to administration of vancomycin or daptomycin. Following the screening of 1863 consecutive cases at 4 Detroit hospitals from 2005 to 2012, 85 patients receiving daptomycin were matched with 85 patients receiving vancomycin according to age (±5 years), Pitt bacteremia score
(1 µg/mL. Phase I involved a 24-month retrospective analysis of patients admitted to the Detroit Medical Center in 2005-2007 and treated with vancomycin for at least 48 hours. Phase II included a 24-month period (2008-2010) following implementation of a MRSA BSI treatment guideline. This guideline indicated that patients should be treated initially with vancomycin for confirmed or suspected MRSA BSI; if susceptibility testing revealed a MRSA isolate with a vancomycin MIC >1 µg/mL, therapy was to be changed to daptomycin (at least 6 mg/kg/d, based on total body weight and adjusted for renal dysfunction). Phase I MRSA isolates had MICs determined via Etest; phase II MICs were determined by MicroScan. The susceptibility testing of all isolates was repeated by an independent laboratory (methods not specified). Treatment was considered successful in patients with resolution or improvement in baseline signs and symptoms, absence of new signs and symptoms during therapy, and MRSA eradication after the end of a course of therapy of at least 7 days. During phase I, 70 patients met inclusion criteria; 100 patients were included in phase II. The median initial vancomycin trough in phase I was lower than in phase II (11.2 vs 15.2 mg/L, P = .02). The median daptomycin dose in phase II was 7.5 mg/kg/d (IQR = 6-10 mg/kg/d). Patients in phase II received vancomycin for a median of 3 days (IQR = 2-3 days) before being switched to daptomycin. Differences between phase I and phase II patient groups, respectively, included median creatinine clearance (62.5 vs 42.2 mL/min, P = .01) and a history of coronary heart disease (24.3% vs 13.0%, P = .05), diabetes mellitus (18.6 vs 35.0%, P = .01), intravenous drug use (44.3% vs 22.0%, P = .002), and hemodialysis (14.3% vs 33.0%, P = .004). Daptomycin MIC distribution in phase II was as follows: 0.13 µg/mL, 2.2%; 0.25 µg/mL, 15.2%; 0.5 µg/mL, 60.9%; 1 µg/mL, 13%; 2 µg/mL, 4.3%; 4 µg/mL, 4.3%. Treatment success was greater in phase II patients (75% vs 41.4%; P < .001). Continued bacteremia at 7 days of therapy was
Downloaded from aop.sagepub.com at Universitats-Landesbibliothek on December 23, 2013
6
Annals of Pharmacotherapy XX(X)
the most common reason for failure (44.3% vs 21% for phase I and phase II, respectively; P < .001). During the independent laboratory analysis, not all isolates exhibited a vancomycin MIC >1 µg/mL; 58/70 (71.4%) patients in phase I and 51/100 (51%) in phase II were found to have such isolates. An analysis of only these patients did not substantially alter the findings reported from the entire cohort; a greater percentage of phase II patients achieved treatment success (68.6% vs 43.1%, P = .008). The authors concluded that the switch to daptomycin was responsible for the greater clinical success in the treatment of MRSA BSI caused by isolates exhibiting elevated vancomycin MICs but suggested that further studies are needed for confirmation.52 This study was limited by differences in patient characteristics, failure of all isolates to have MICs >1 µg/mL on retesting, and the potential for confounding caused by time period differences in the phases. Campbell et al53 also performed a study in the Detroit Medical Center health system. This retrospective cohort study compared the efficacy and costs of trimethoprim/sulfamethoxazole (TMP/SMX) with that of daptomycin and linezolid in patients with infections from MRSA with vancomycin MICs of 2 µg/mL during 2009. Patients were included if they had received 2 or more doses of TMP/ SMX, daptomycin, or linezolid from 3 days before to 14 days after an initially positive MRSA culture. Susceptibility was determined by MicroScan. Multivariate analysis was used to assess association with several outcomes, including in-hospital mortality, 3-month mortality, length of hospital stay after infection, functional status, need for discharge to a long-term care facility, and readmission within 6 months of discharge. A total of 328 patients were enrolled. The most commonly reported infections were SSSIs and pneumonia (approximately 75% of infections). The remaining infections, in order of decreasing frequency, were BSIs of unknown source, catheter-related BSIs, and urinary tract infections. There were 143 TMP/SMX, 89 daptomycin, and 75 linezolid recipients; 21 patients received TMP/SMX with either daptomycin or linezolid. Vancomycin was used in 73% of patients prior to changing to one of the study drugs because of clinical failure or an elevated vancomycin MIC. The median TMP dose was 4.7 mg/kg/d (range = 1.314.9 mg/kg/d), and the median daptomycin dose was 6.7 mg/kg/d (range = 3.3-12 mg/kg/d) in patients with a creatinine clearance greater than 30 mL/min. In bivariate analysis, TMP/SMX patients demonstrated favorable outcomes compared with patients receiving other treatments for all outcomes inserted into the model. In the multivariate analysis, none of these associations reached statistical significance. There were several significant notable differences in the TMP/SMX patients relative to those receiving comparator treatments (Table 2). Similar patient differences were observed in an analysis limited only to patients with a SSSI.
As may be expected based on the acquisition costs of the treatments, the mean antibiotic cost per patient was significantly lower with TMP/SMX (Table 2). Despite substantial trial limitations, the authors concluded that TMP/SMX demonstrated efficacy and mortality benefits comparable to linezolid and daptomycin and should be considered in the treatment of MRSA infection with MICs of 2 µg/mL.53 This study was limited by the notable intergroup patient differences and the problems that arise from subgroup analyses. Moore et al54 conducted a retrospective case-control study focused on BSI from MRSA isolates with vancomycin MICs of 1.5 or 2 µg/mL treated with vancomycin (n = 118) or daptomycin (n = 59). Vancomycin was dosed to achieve trough values of 10 to 20 µg/mL. MICs were determined via Etest. Patients ≥18 years of age admitted to Henry Ford Hospital (Detroit) during 2005-2009 were included if they had an index MRSA blood culture isolate with a vancomycin MIC of 1.5 to 2 µg/mL, they received active therapy within 48 hours of infection onset, daptomycin was initiated within 14 days of index culture if switched from another therapy, and they received vancomycin or daptomycin for ≥48 hours. Daptomycin patients were matched 1:2 to patients treated with vancomycin based on age, APACHE-II score, and infection source risk level. The primary end point, clinical failure, was defined as a composite that included 60-day mortality, microbiological failure, and/or recurrence. Sixty-day mortality included death in the 60-day period following the index culture. Microbiological failure was defined as a positive MRSA blood culture ≥7 days after index culture for vancomycin patients or after the initiation of daptomycin for daptomycin patients. Recurrence was defined as a MRSA BSI occurring within 30 days after therapy completion. Vancomycin and daptomycin patient groups were similar in terms of mean age (52 vs 51 years, respectively), intravenous drug abuse history (31% vs 39%, respectively), and mean APACHE-II scores (14 for both). There were fewer MRSA isolates with a vancomycin MIC = 2 µg/mL in the vancomycin arm (14% vs 58%, P < .001). The vancomycin and daptomycin groups also differed in terms of the presence of chronic renal disease (6% vs 17%, respectively, P = .022) and immunosuppression (13% vs 27%, respectively, P = .022). The most common BSI sources were CVCs, infective endocarditis, and skin/wound infections. The median definitive vancomycin trough (average of trough values obtained within the hour before the next steady-state dose and at least 72 hours after initiation) was 18 µg/mL (IQR = 15-21 µg/ mL); the median initial daptomycin dose was 6 mg/kg/d (IQR = 6-8 mg/kg/d). In the daptomycin group, 91% of patients had previously received vancomycin therapy. The median time to daptomycin switch from previous therapy was 5 days (IQR = 3-9 days). There was no difference in clinical failure (31% for vancomycin vs 17% for daptomycin, P = .084). However, vancomycin use was associated with an
Downloaded from aop.sagepub.com at Universitats-Landesbibliothek on December 23, 2013
7
McDaneld et al increased risk of failure in a conditional regression analysis (adjusted OR = 3.13; 95% CI = 1-9.76). Regression analysis also identified acute renal failure as associated with failure (adjusted OR = 3.91; 95% CI = 1.05-14.56) and right-sided endocarditis as associated with clinical success (adjusted OR = 0.08; 95% CI = 0.01-0.83). Mortality within 60 days was lower in daptomycin patients (8% vs 20%, P = .046). There was no difference in 30-day recurrence (5% for vancomycin vs 3% for daptomycin, P = .620) or microbiological failure (9% for vancomycin vs 10% for daptomycin, P = .855). The authors concluded that daptomycin use is associated with a better outcome in MRSA BSI for isolates with higher vancomycin MICs.54 This study was limited by a potential patient selection bias in those switched to daptomycin therapy, underlying differences in patient/pathogen characteristics, differences in frequency of infectious diseases’ physician consults, failure to determine daptomycin MICs, and the single-center, retrospective design. Two additional retrospective studies were conducted that included a subgroup of patients with S aureus isolates having vancomycin MIC values of 2 µg/mL.55,56 Jobson et al55 studied outcomes associated with daptomycin and vancomycin when used as initial therapy (≥3 days of treatment) for S aureus infections (excluding endocarditis, osteomyelitis, central nervous system, and respiratory infections) during 2006-2008 at a single California institution. The study enrolled 165 patients; 57 received daptomycin, and 108 received vancomycin. S aureus isolates with an Etest vancomycin MIC of 2 µg/mL accounted for 76% of isolates; the remaining isolates had vancomycin MICs of 0.5 or 1.0 µg/mL. The 2-µg/mL MIC group included 49 daptomycin and 79 vancomycin patients. Baseline characteristics of the study arms (including all isolates) were similar except for mean patient weight (85 kg for daptomycin vs 75 kg for vancomycin, P = .019), urinary tract infection source (9% for daptomycin vs 1% for vancomycin, P = .019), median length of stay before infection onset (8 days for daptomycin vs 5 days for vancomycin, P = .001), percentage of patients with infection onset >3 days after admission (53% for daptomycin vs 25% for vancomycin; P < .001), and distribution of MRSA isolate vancomycin MICs (daptomycin arm, 87% with 2 µg/mL vancomycin MIC; vancomycin arm, 73% with 2 µg/mL vancomycin MIC; P = .028). The primary infection type was SSSI (72% for daptomycin vs 73% for vancomycin). The frequency of MRSA isolates did not differ between groups (81% for daptomycin vs 68% for vancomycin, P = .074). The median daptomycin dose was 4 mg/ kg/d (range = 3.4-7.2 mg/kg/d); the median vancomycin trough was 12.5 mg/L (range = 3.2-30.5 mg/L, 44% between 10 and 14 mg/L). Primary outcomes included antibioticrelated length of stay, 60-day recurrence, and 30-day allcause mortality. In the MRSA subgroup with vancomycin MICs of 2 µg/mL, the median antibiotic length of stay was shorter with daptomycin (7 days vs 10 days, P = .014.
Mortality (8% for daptomycin vs 6% for vancomycin, P = .693) and recurrence (27% for daptomycin vs 19% for vancomycin, P = .316) did not differ between groups among all S aureus infections (data not reported for the MRSA subset). The authors concluded that the initial use of daptomycin for S aureus isolates with vancomycin MICs of 2 µg/mL may be associated with shorter antibiotic-related lengths of stay, but that this must be confirmed by further study.55 This study was limited by a lack of patient baseline characteristic comparison or detailed results in the subgroup whose MRSA isolate had a vancomycin MIC of 2 µg/mL. Additional limitations included the low vancomycin troughs seen in a number of patients, the rounding of half-step MIC values (ie, 1.5 to 2 µg/mL), lack of daptomycin MIC values, and the single-center, retrospective design. The final study was an analysis comparing daptomycin outcomes between patients with infections caused by S aureus isolates having vancomycin MICs
