Alexandra M. Hanretty, PharmD*

A wide range of daptomycin doses have been evaluated for the treatment of vanco&shy;mycin-resistant 

bloodstream infections (VRE-BSIs). The US Food and Drug Administration—approved dose of 6 mg/kg/ day is derived from 

infection treatment, but has been shown to be inadequate for the treatment of VRE-BSIs.

A key determinant of poor outcomes is higher daptomycin minimum inhibitory concentrations (MICs) of 

(1 μg/mL), that decrease the probability of achieving optimal pharmacody&shy;namic targets associated with clinical efficacy.

 In vitro study results show MIC90 of 0.5 μg/mL and 4 μg/mL for 

 Indeed, clinical study results have shown that BSIs due to VRE with higher MICs (>2 μg/mL) are associated with higher rates of microbiologic and clinical failure when treated with standard dosing strategies.

may harbor mutations in the LiaFSR 3-component system, which is involved in the cell envelopes’ response to antibiotics, and may result in the emer&shy;gence of daptomycin resistance during treatment or reduced potency.

 Higher MICs may also be a by-product of the testing method since there is variability in MIC results regardless of testing method utilized. This variability may pose problems for clinical interpretation.

 In the 2019 Clinical and Laboratory Standards Institute (CLSI) update, daptomycin breakpoints for 

were changed to reflect the dose-dependent susceptibility observed from previous studies and differentiate 

DAPTOMYCIN DOSING IN ADULTS WITH VRE-BSI 

Although data support higher daptomycin doses, it is unclear what dose is needed to optimally treat VRE-BSIs.

Studies have classified “high-dose” daptomycin with various definitions, including the 8 to 12 mg/kg recommendation by CSLI, leading to the question of what is the optimal dose for VRE-BSIs.

In vitro pharmacokinetic (PK)/pharmacodynamic study results have shown that the dose-dependent effects of dapto&shy;mycin vary based on the MIC, with a minimum AUC0-24 of 1540 to maintain bactericidal activity.

 Models of simulated endocarditis predicted a daptomycin dose >10 mg/kg is neces&shy;sary to obtain AUC24/MIC targets for successful treatment and suppression of resistance development.

A retrospective, multicenter review of adult patients treated with daptomycin doses >6 mg/kg for VRE-BSIs found high rates of overall clinical success and microbiological eradication of 89% and 93%, respectively. The median daptomycin dose was 8.2 mg/kg. As predicted from in vitro models, rates of clinical success decreased as the daptomycin MIC increased.

 Although these results indicate that higher daptomycin doses may be more effective, the study lacked a comparator group and failed to define high-dose.

Chuang and colleagues conducted a prospective, observa&shy;tional study comparing daptomycin doses utilized for treat&shy;ment of VRE-BSIs.

 Investigators compared mortality rates across 3 patient groups based on daptomycin dosing strategy. After dose rounding, higher doses (>9 mg/kg) were associ&shy;ated with lower mortality and better outcomes compared with lower doses (

). The study results did not show an association between MIC and mortality.

Britt and colleagues further stratified dosing by standard (6 mg/kg), medium (8 mg/kg), and high ( 

10 mg/kg) in a retrospective review of VRE-BSIs among Department of Veterans Affairs patients.

 The patients were divided into 3 groups: standard dose (n = 709), medium dose (n = 142), and high dose (n = 60). High-dose daptomycin was associated with an overall survival benefit compared with medium-dose daptomycin after adjusting for confounders. However, there were no differences in the rate of microbiological clearance between the 2 groups (

Limited-isolate MICs were available to further stratify outcomes based on MIC.

 The association with daptomycin MICs and clinical outcomes was evaluated by Shukla and colleagues. This study found that at higher MICs (3-4 μg/mL), there were increased rates of microbiological failure (

= .014). Findings did not support the antici&shy;pated increased daptomycin doses and improved outcomes in this study.

Although not discussed here, the combination of daptomycin with high PBP5 binding affinity β-lactams has shown increased binding affinity of daptomycin through adjustments to the overall charge of the bacterial surface and has shown promising outcomes through in vitro studies and case reports.

Daptomycin is generally well tolerated, with elevations of creatinine phosphokinase and rhab&shy;domyolysis being the primarily reported adverse drug events (ADRs). Based on the available data, there does not seem to be an association with increased dose and muscle toxicity.

 Concomitant statin use and increased risk of ADRs remain uncertain.

Considerations for dosing weight selection in patients considered obese become significant as higher doses are used. The daptomycin package insert recommends dosing based on actual body weight (ABW) in obesity; however, this is based on a 6 mg/kg analysis.

 The concerns are that using ABW may put patients at greater risk for ADRs, given the inherently higher total doses, and using adjusted body weight (AdjBW) or ideal body weight (IBW) could have a negative impact on clinical outcomes. Limited data are available that show the effect of dosing weight on clinical outcomes. A 500-mg fixed dose has been studied, but the investigators did not evaluate outcomes.

 Two studies that eval&shy;uated clinical and safety outcomes in patients clas&shy;sified as obese using ABW versus AdjBW or IBW found no difference in clinical outcomes, and ADRs were similar between groups. Most patients in the 2 studies received 

6 mg/kg; few patients received doses >6 mg/kg.

 Based on available data, dosing based on AdjBW in obesity is reasonable for VRE; however, further studies are warranted.

Dosing varies by type of RRT. In patients receiving continuous renal replacement therapy (CRRT) daily dosing is necessary to achieve similar plasma concentrations and overall exposure as do patients with a creatinine clearance 

30 mL/min. In patients receiving CRRT, a 48-hour dosing interval could result in lower systemic concentrations after the first 24 hours, as drug concentrations are likely to fall below the optimal concentrations needed to maintain bactericidal activity.

 Daptomycin is typically dosed after hemodialysis (HD), and on the longer-interval HD days, the dose should be increased by 50% to account for the 72-hour interval in order to maintain adequate serum levels.32,33 A high dose has not been shown to result in excessive drug exposures or elevated trough levels associated with increased creatine phos&shy;phokinase and therefore should still be utilized in patients receiving RRT.

To date, no studies have evaluated outcomes of high-dose daptomycin for VRE-BSIs in pediatric patients. Available studies are limited to PKs and case series of mixed gram-positive infections.

PK study results demonstrate that serum concen&shy;trations are age-dependent with younger children (2 to 6 years old) and infants (< 24 months) who require higher doses in order to achieve peak serum concentrations similar to those gained with the 4 to 6 mg/kg/day dose used in adult patients, which is reflected in the current dosing recommendations.

 In younger children doses of 8 to 10 mg/kg/day result in concentrations similar to 4 to 6 mg/kg/d in adults.

 Whereas a dose of up to 15mg/kg every 12 hours has been used safely in infants.

Given the variation between pediatric and adults patients, high-dose daptomycin in pediatrics is likely to be different than in adults. In the absence of pediatric clinical outcome data for VRE-BSIs, daptomycin therapeutic drug monitoring may be prudent.

 It is important to note that the updated CLSI susceptible dose-dependent recommenda&shy;tions do not apply to pediatrics.

The current evidence regarding optimal dapto&shy;mycin dosing for the treatment of VRE-BSIs favors the use of high-dose regimens; however, such doses are not well defined in the literature. Targeting strategies to prevent daptomycin resis&shy;tance remain critical to preserve future utiliza&shy;tion in an already limited antimicrobial setting for VRE-BSI treatment. Collaborations between infectious diseases and microbiology teams are necessary for susceptibility interpretations.

Based upon the available literature, a minimum daptomycin dose of 8mg/kg/d should be utilized for the treatment of VRE-BSIs, with higher doses encouraged based upon patient-specific character&shy;istics, including MIC value. Routine monitoring of ADRs is required in the setting of increased doses as well as patients considered obese. Robust studies assessing the optimal dosing of daptomycin are needed for both adult and pediatric populations.

Hanretty is an antimicrobial stewardship pharmacist at Cooper University Healthcare in Camden, New Jersey. *She is an active member of the Society of Infectious Diseases Pharmacists.

Marini is an antimicrobial stewardship pharmacist at the University of Pittsburgh Medical Center (UPMC) Presbyterian Hospital in Pittsburgh, Pennsylvania. *She is an active member of the Society of Infectious Diseases Pharmacists.

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Optimal dosing of daptomycin is unknown, but study results suggest higher doses are required for successful clinical and microbiological outcomes.

The Continued Search for Optimal Daptomycin Dosing Strategies in VRE Bloodstream Infections

Antimicrobial stewardship programs often focus on antimicrobial de-escalation, while less emphasis is placed on treating for the shortest possible duration. Although both are important stewardship initiatives, there is a paucity of data suggesting that de-escalation directly results in less emergence of resistance. Furthermore, antimicrobial de-escalation has not been found to reduce duration of antibiotic therapy.

 However, reducing overall antibiotic exposure is likely to have an impact on decreasing antimicrobial resistance. By shortening antibiotic duration, overall antibiotic exposure is lessened, reducing selection pressure for multidrug resistant organisms. This finding is supported by studies of ventilator-associated pneumonia (VAP).

Hospital-acquired pneumonia (HAP) and VAP account for significant antibiotic use and together are one of the most common health care—associated infections,

 These infections have a large economic burden and are associated with poor patient outcomes, including prolonged mechanical ventilation and hospital stay.

 A justified concern about the poor outcomes that HAP/ VAP cases represent drives antibiotic use because even suspected-but-unproven cases receive broad-spectrum antibiotic therapy.

Historically, HAP and VAP were treated for 14 to 21 days. Although treating these infections for an extended duration seems logical given their severity and the negative patient outcomes, prolonged courses of antibiotics have not been found to improve outcomes but instead to increase the rate of recurrent infections with multidrug- resistant (MDR) organisms.

 In 2005, guidelines by the Infectious Diseases Society of America (IDSA) for the treatment of HAP/VAP recommended treating for either 7 days or 14 days, depending on the causative pathogen. When the causative organism was a non-lactose fermenting gram-negative bacillus (NLFGNB), longer durations were recommended.

Two well-designed, randomized controlled studies have been conducted to evaluate the equivalence of shorter and longer courses of antibiotic therapy in VAP, both comparing 8 and 15 days. The first study was in 401 patients with microbiologically proven VAP. Patients were randomized to 8 days or 15 days of antibiotics selected at the discretion of the treating clinicians. The rate of recurrence and 28-day mortality were similar in both groups: 18.8% (8 d) versus 17.2% (15 d) and 28.9% (8 d) versus 26% (15 d), respectively, and 8 days was found to be noninferior. A finding of this study was that in patients with NLFGNB VAP, there was a higher rate of infection recurrence in the 8-day group (40.6% vs 25.4%), yet there was no difference in in-hospital mortality: 34.4% and 41.3% for 8 and 15 days, respectively. Not only were clinical outcomes similar between groups, but reducing overall antibiotic exposure resulted in a significant reduction of recurrent MDR pulmonary infections. Recurrent pulmonary infections with an MDR organism occurred less frequently in the shorter-treatment group: 42% and 62% for 8 and 15 days, respectively.

 In the second study, 225 patients with early-onset VAP were randomized to receive 8 or 15 days of a beta-lactam plus an aminoglycoside. This study also did not find a difference in clinical cure between the two treatment durations. Clinical cure was 85.3% in the 8-day group and 84.4% in the 15-day group. Similarly, there was no difference in 21-day mortality, which was 8.6% in the 8-day group and 8.3% in the 15-day group.

 One surprising finding was that the rate of secondary infections was higher in the 8-day treatment group (35.3% vs 19.3%; P <.01).

Although secondary infections were more common with short courses, there was no difference in mortality. This difference was explained by the fact that since patients were followed for 21 days, the 8-day group had more time to develop a secondary infection because they were off antibiotics more than twice as long as the 15- day group.

 Patients were not followed after the 21-day period to evaluate for further resistant infections associated with antibiotic use, such as 

infection. A finding that was not surprising in both studies was that there were more antibiotic-free days in the short-course groups, taking into account antibiotics used for the treatment of secondary infections.

 In these 2 studies, a shorter-course of antibiotics did not negatively impact patient outcomes or mortality. In fact, there was the added benefit of less overall antibiotic exposure and although patients were not assessed for the development of a 

 infection, presumably this should decrease the risk of infection.

There have been other attempts to shorten antibiotic therapy that do not fall into the prospective, randomized studies included above. Using objective measures to guide antibiotic duration instead of arbitrarily deciding treatment durations would be optimal for clinicians to individualize treatment based on the stability of the patient, resulting in earlier antibiotic discontinuation for many patients. One study used clinical pulmonary infection scores (CPIS) in patients with radiographic findings suggestive of nosocomial pneumonia to stratify patients at low risk of complications due to short courses of antibiotics. In this study, patients with a low CPIS were randomized to receive either ciprofloxacin for 3 days or standard care (antibiotics for 10-21 days). More severely ill patients were excluded. Clinical outcomes were similar between the 2 groups. As can be expected, in the short-course group, there were significantly more antibiotic-free days, and in the long-course group, there was more resistance and/or super-infections.

 This study was performed in 2000 and is now dated, but the principle is still relevant.

In suspected VAP, using ventilator settings as a surrogate for degree of illness may also be a method to transition patients off empiric antibiotics earlier. In a retrospective study, patients with stable and minimal ventilator settings empirically treated for suspected VAP who received less than 3 days of antibiotics had similar duration of mechanical ventilation, mortality, and time to discharge compared with a longer-duration group (greater than 3 days). However, the majority of patients in this study most likely did not truly have VAP, and therefore this strategy should be used only for stable patients for whom the diagnosis of VAP is uncertain.

Biomarkers such as procalcitonin have also been of interest as a marker to guide antimicrobial duration. There is no clear consensus on the use of procalcitonin to diagnose bacterial infections and data conflicts on whether strategies that utilize this biomarker successfully result in shorter antibiotic durations. A metaanalysis of 14 studies including 4211 patients with acute respiratory infections found that overall, the duration of antibiotics was shorter in the procalcitonin-guided group (7 days vs 10 days; P <.0001). Treatment duration was also shorter in the subset of patients with VAP (11 days vs 14 days; P = .02). Although procalcitonin may have the potential to help guide antimicrobial decisions in HAP/ VAP, these durations of therapy are longer than recommended. It is unclear whether procalcitonin is as useful for antibiotic decision making at earlier time points.

Shortening antimicrobial duration and thereby reducing overall antibiotic exposure is an effective antimicrobial stewardship strategy to slow the emergence of resistance. Current IDSA HAP/VAP guidelines support short-course treatment regardless of the organism and instead favor individualizing treatment and extending therapy when needed based on imaging and/or clinical findings.

 Overall, shorter-treatment durations are associated with more antibiotic-free days and fewer MDR secondary or recurrent infections and do not negatively affect clinical outcomes.

 In this era of antibiotic resistance, reducing overall antibiotic exposure may be a more easily implemented than programs focused on preventing broad-spectrum antibiotic use.

Dr. Hanretty is a clinical pharmacist in infectious diseases at St. Christopher’s Hospital for Children in Philadelphia, Pennsylvania. She completed a PGY1 Pharmacy Residency at UCSF Medical Center in San Francisco, and a PGY2 Residency in Infectious Diseases Pharmacy at Temple University. She is an active member of SIDP.

Dr. Gallagher is a clinical professor at Temple University School of Pharmacy and clinical pharmacy specialist in infectious diseases at Temple University Hospital, both in Philadelphia. He also is the director of the PGY2 Residency in Infectious Diseases Pharmacy at Temple. He is an active member of SIDP.

Tabah A, Cotta MO, Garnacho-Montero J, et al. A systematic review of the definitions, determinants, and clinical outcomes of antimicrobial de-escalation in the intensive care unit. Clin Infect Dis. 2016;62(8):1009-1017. doi: 10.1093/cid/civ1199.

Sullivan A, Edlund C, Nord CE. Effect of antimicrobial agents on the ecological balance of human microflora. Lancet Infect Dis. 2001;1(2):101-114. doi: 10.1016/S1473-3099(01)00066-4.

Pugh R, Grant C, Cooke RP, et al. Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults. Cochrane Database Syst Rev. 2015;(8):CD007577. doi: 10.1002/14651858.CD007577.pub3.

Magill SS, Edwards JR, Fridkin SK, et al. Survey of health care—associated infections. N Engl J Med. 2014;370(26):2542-2543. doi: 10.1056/NEJMc1405194.

Kollef MH, Hamilton CW, Ernst FR. Economic impact of ventilator-associated pneumonia in a large matched cohort. Infect Control Hosp Epidemiol. 2012;33(3):250-256. doi: 10.1086/664049.

Society AT, America IDSo. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416. doi:10.1164/rccm.200405-644ST.

Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290(19):2588-2598. doi: 10.1001/jama.290.19.2588.

Capellier G, Mockly H, Charpentier C, et al. Early-onset ventilator-associated pneumonia in adults randomized clinical trial: comparison of 8 versus 15 days of antibiotic treatment. PLoS One. 2012;7(8):e41290. doi: 10.1371/journal.pone.0041290.

Singh N, Rogers P, Atwood CW, et al. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med. 2000;162(2 Pt 1):505-511. doi: 10.1164/ajrccm.162.2.9909095.

Klompas M, Li L, Menchaca JT, et al. Ultra-short-course antibiotics for patients with suspected ventilator-associated pneumonia but minimal and stable ventilator settings. Clin Infect Dis. 2016; 64(7):870-876. doi: 10.1093/cid/ciw870.

Schuetz P, Briel M, Christ-Crain M, et al. Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis. Clin Infect Dis. 2012;55(5):651-662. doi: 10.1093/cid/cis464.

Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61-e111. doi: 10.1093/cid/ciw353.

Reducing overall antibiotic exposure is likely to have an impact on decreasing antimicrobial resistance.

Alexandra M. Hanretty, PharmD*

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