Abstract
Background
Daptomycin is approved by Health Canada for the treatment of Staphylococcus aureus bacteremia and complicated skin and soft tissue infections caused by gram-positive organisms, but is often used for other indications. We aimed to understand the indications, dosing, and safety profile of daptomycin use in a Canadian inpatient setting.
Methods
We included consecutive adult patients who received intravenous daptomycin as inpatients from January 1, 2016, to December 31, 2016, at two tertiary care teaching hospitals in Hamilton, Ontario.
Results
We identified 86 courses in 77 unique patients. S. aureus was the most common pathogen (n = 38, 44%) of which 87% (n = 33) were methicillin-resistant. The most common indications were bloodstream infections (n = 31, 36%). The average treatment duration was 10 days, at an average dose of 7.4 mg/kg. The infectious diseases service was consulted in all but two courses. Less than half of treatment courses were given for an indication approved by Health Canada (n = 41, 48%). Almost half of the unapproved indications (n = 21, 47%) followed Infectious Diseases Society of America (IDSA) recommendations. Creatine kinase elevation of 3 × the upper limit of normal or higher occurred in a small number of courses (n = 7, 8%), with only one instance requiring discontinuation of the drug.
Conclusions
Daptomycin is being used to treat inpatients for a variety of unapproved indications. Importantly, a sizable portion of these are within IDSA guideline recommendations. Most patients are treated with doses higher than the approved 6 mg/kg without major safety concerns.
Key words: antibiotic stewardship, antibiotic therapy, bacterial infections, Staphylococcus aureus
Abstract
Historique
Santé Canada approuve la daptomycine pour le traitement de la bactériémie à Staphylococcus aureus (S. aureus) ainsi que des infections complexes de la peau et des tissus mous causées par des organismes Gram positif, mais ce médicament est souvent utilisé dans d’autres indications. Les auteurs cherchent à comprendre les indications, la posologie et le profil d’innocuité de la daptomycine chez les patients canadiens hospitalisés.
Méthodologie
Les chercheurs ont inclus dans leur étude les adultes hospitalisés consécutifs qui avaient reçu de la daptomycine par voie intraveineuse entre le 1er janvier 2016 et le 31 décembre 2016 dans deux hôpitaux universitaires de soins tertiaires de Hamilton, en Ontario.
Résultats
Les auteurs ont relevé 86 traitements chez 77 patients uniques. Le S. aureus était l’agent pathogène le plus courant (n = 38, 44 %), dont 87 % (n = 33) étaient résistants à la méthicilline. Les indications les plus fréquentes étaient des infections sanguines (n = 31, 36 %). Le traitement était d’une durée moyenne dix jours, à une dose moyenne de 7,4 mg/kg. Le service d’infectiologie a été consulté pour tous les traitements, sauf deux. Moins de la moitié des traitements ont été administrés dans une indication autorisée par Santé Canada (n = 41, 48 %). Près de la moitié des indications non autorisées (n = 21, 47 %) respectait les recommandations de l’Infectious Diseases Society of America (IDSA). Dans quelques traitements (n = 7, 8 %), la créatine kinase était au moins trois fois plus élevée que le seuil supérieur de la normale, et dans un seul cas, le traitement a dû être abandonné.
Conclusions
La daptomycine est utilisée dans diverses indications non approuvées pour traiter les patients hospitalisés. Toutefois, une forte proportion d’entre elles fait partie des recommandations de l’IDSA. La plupart des patients reçoivent des doses supérieures à celle approuvée de 6 mg/kg sans causer d’inquiétudes importantes sur le plan de l’innocuité.
Mots-clés : antibiothérapie, gestion des antibiotiques, infections bactériennes, Staphylococcus aureus
Introduction
The increasing emergence of antibiotic resistance among gram-positive bacteria has led to the development of new agents (1). Daptomycin, a lipopeptide antibiotic initially discovered in the 1980s, was developed as a novel antibiotic for treating infections caused by gram-positive bacteria (2). It has bactericidal activity against gram-positive bacteria, as the lipophilic tail of daptomycin inserts into the cell membrane, leading to rapid membrane depolarization and cell death (3).
Daptomycin was first introduced into clinical practice in the United States in 2003, and has been licenced for use in Canada since 2007. It is comparable to anti-staphylococcal penicillins and vancomycin in the treatment of skin and soft tissue infections (4) and endocarditis (5). In accordance with these studies, its approved indications in adults in Canada are the treatment of complicated skin and soft tissue infections caused by susceptible gram–positive bacteria, and the treatment of Staphylococcus aureus bacteremia (6). In addition to these, daptomycin has several unapproved indications recommended in clinical practice guidelines (CPGs). The Infectious Diseases Society of America (IDSA) CPGs for the treatment of methicillin-resistant S. aureus (MRSA) infections, published in 2011, recommend its use not only for complicated skin and soft tissue infection in hospitalized patients (level A–I) and native valve infective endocarditis (level A–I), but also for treatment of uncomplicated bacteremia (level A–I), complicated bacteremia (level B–III), bone and joint infections (B–II), persistent bacteremia (level B–III), and vancomycin treatment failure (level B–III) (7). In addition to MRSA infections, daptomycin may also be used in the treatment of infections caused by vancomycin-resistant Enterococcus (VRE). Though the treatment of VRE is not currently an approved indication, it has been shown in retrospective studies to be similarly efficacious as linezolid in the treatment of VRE bacteremia (8,9). Hence, it is also recommended for the treatment of VRE infections in the IDSA CPGs for neutropenic patients with cancer (level B–III) (10).
Several studies have examined the use of daptomycin in centres in various countries, but we are unaware of any reports from a Canadian setting. Our study presents the clinical experience with daptomycin use in a Canadian tertiary care setting.
Methods
Study design and population
This was a retrospective chart review conducted at two adult tertiary care teaching hospitals, with 412 and 370 beds, respectively, in Hamilton, Ontario. All consecutive adult patients who received at least one dose of intravenous daptomycin during an inpatient admission between January 1 and December 31, 2016, were included.
Data collection
All data were collected from electronic medical records. Records were reviewed for demographic, clinical, and microbiologic data. A standardized collection form was completed for each daptomycin course. In the event that an individual patient received multiple courses of daptomycin during the study period, each course was analyzed and counted separately, provided that subsequent courses represented separate courses of treatment and were not extensions of the original treatment course. Clinical data included sites of infection, dosing, duration of treatment, and complications of daptomycin therapy. Microbiologic data included pathogens treated, and vancomycin minimum inhibitory concentration (MIC) in the case of MRSA.
Statistical analysis
Indications for daptomycin use were categorized according to their approval by Health Canada (6). Unapproved indications were then categorized according to IDSA CPGs. Categorical variables are expressed as frequencies and percentages.
Ethics approval
The Hamilton Integrated Research Ethics Board approved the study protocol and waived the need for informed consent.
Results
During the study period, 86 courses of at least a single dose of intravenous daptomycin during an inpatient admission were identified in 77 unique patients. Of the 86 courses, 47(55%) were given to male patients. The average age was 59 (SD 18.4; range 20–92) years. Most courses were given to patients admitted to the general medicine (n = 30, 35%), critical care (n = 19, 22%), and malignant hematology services (n = 11, 13%) (Table 1). Consultation from an infectious disease physician was obtained in 84 (98%) of the courses.
Table 1:
Clinical services using daptomycin
| Most responsible physician service | n (%)* |
| General medicine | 30 (35) |
| Critical care | 19 (22) |
| Malignant hematology | 11 (13) |
| Other medical (cardiology, gastroenterology, medical oncology, and neurology) | 9 (10) |
| Surgical | 17 (20) |
| Total | 86 |
* Total percentage may not total 100% due to rounding
Daptomycin was used to treat a variety of pathogens, with S. aureus (n = 38, 44%), Enterococcus faecium ( n = 19, 22%), and coagulase-negative Staphylococcus (n = 14, 16%) being the most common (Table 2). MRSA accounted for most of the S. aureus isolates (n = 33, 87%), while VRE accounted for most of the E. faecium isolates (n = 12, 63%). A substantial number of courses were given for culture-negative infections (n = 17, 20%). The most common indications for daptomycin use were S. aureus bacteremia (n = 32, 37%), followed by complicated skin and soft tissue infection (n = 10, 12%) (Table 3). More than half of the courses were given for unapproved indications (n = 45, 52%), of which almost half were recommended by IDSA guidelines (n = 21, 47%) (Table 3). The most common reasons for using daptomycin over other antibiotics were reactions to vancomycin (n = 21, 24%), acute kidney injury precluding vancomycin use (n = 11, 13%), and treating infections caused by VRE (n = 10, 12%) (Table 4). No positive urine cultures with VRE were treated with daptomycin.
Table 2:
Pathogens treated with daptomycin
| Organism | n (%)* |
| Staphylococcus aureus | 38 (44) |
| Methicillin-resistant | 33 (38) |
| Methicillin-susceptible | 5 (6) |
| Enterococcus | 22 (26) |
| Enterococcus faecalis | 3 (3) |
| Enterococcus faecium | 19 (22) |
| Vancomycin-resistant | 12 (14) |
| Vancomycin-susceptible | 7 (8) |
| Coagulase-negative Staphylococcus | 8 (9) |
| Viridans group Streptococcus | 1 (1) |
| None identified | 17 (20) |
| Total | 86 |
* Total percentage may not total 100% due to rounding
Table 3:
Indications for daptomycin use
| Indication | n (%)* |
| Health Canada approved | 41 (48)** |
| Staphylococcus aureus bacteremia | 32 (37) |
| cSSSI | 10 (12) |
| Unapproved | 45 (52) |
| IDSA recommended | 21 (24) |
| Staphylococcus aureus left-sided endocarditis | 2 (2) |
| Prosthetic joint infection | 4 (5) |
| Intravenous catheter infection | 8 (9) |
| Neutropenic cancer patient | 6 (7) |
| MRSA osteomyelitis | 1 (1) |
| Not IDSA recommended | 24 (28) |
| VRE bacteremia | 8 (9) |
| Other | 16 (19) |
| Total | 86 |
* Total percentage may not total 100% due to rounding
** One course in the same patient was for the treatment of both S. aureus bacteremia and cSSSI
cSSSI = complicated skin and soft tissue infection; IDSA = Infectious Diseases Society of America; MRSA = methicillin-resistant Staphylococcus aureus; VRE = vancomycin-resistant Enterococcus
Table 4:
Rationale for daptomycin use
| Rationale | n (%)* |
| Reaction to vancomycin during treatment | 21 (24) |
| Acute kidney injury necessitating avoidance of vancomycin | 11 (13) |
| VRE infection | 10 (12) |
| Previous daptomycin therapy for similar infection | 10 (12) |
| Persistent bacteremia on initial therapy | 9 (10) |
| Enterococcus infection with known VRE colonization | 5 (6) |
| Antibiotic allergies or intolerances to preferred therapy | 5 (6) |
| MRSA bacteremia with vancomycin MIC ≥2.0 | 5 (6) |
| Other | 10 (12) |
| Total | 86 |
* Total percentage may not total 100% due to rounding
VRE = vancomycin-resistant Enterococcus; MRSA = methicillin-resistant Staphylococcus aureus; MIC = minimum inhibitory concentration
Daptomycin was used at an average dose of 592 mg (SD 236.0 mg), corresponding to 7.4 (SD 2.1; range 3.4–13.9) mg/kg. The average duration of therapy was 10 (SD 12.2; range 1–66) days, with a median of 5 days. A large proportion of courses were only 1–2 days in duration (n = 24, 28%).
Creatine kinase (CK) elevation occurred in only a small proportion of courses, though a CK measurement during therapy was not performed in 23 of the courses (27%). A substantial proportion of these 23 courses (n = 13, 57%) were only 1–2 days long. CK measurement was performed in all courses that were longer than 7 days (n = 38). CK elevation 3–5 × the upper limit of normal (ULN) occurred in one course (1%), 5–10 × ULN in three courses (3%), and >10 × the ULN in a further three courses (3%). These elevations resulted in discontinuation of therapy in one course (1%), where the patient was receiving 9.1 mg/kg, and a dose reduction in another course (1%), where the patient was receiving 8.0 mg/kg. Beyond CK elevation, no other complications of daptomycin therapy were noted.
Interpretation
This study examined the use of daptomycin in adult inpatients over a one-year period. Our results show that daptomycin is used to treat a variety of infections caused by several different gram-positive pathogens. S. aureus was the most common pathogen, with MRSA accounting for the majority of the isolates, and S. aureus bacteremia was the most common indication for daptomycin therapy. A larger than expected proportion of daptomycin courses were used to treat culture-negative infections. The most common reasons for empiric use were that vancomycin could not be used due to an adverse reaction, or that the patients being treated had confirmed recent colonization or infection with resistant pathogens, such as MRSA and/or VRE.
Overall, the most common reasons for using daptomycin over other antibiotics were related to the need to avoid the use of vancomycin. A substantial proportion of daptomycin use was for unapproved indications, with less than half of courses given for a Health Canada approved indication. Of the courses where daptomycin use was for unapproved indications, almost half followed IDSA CPGs. These results show that the approved indications for daptomycin are narrow, and that more studies are needed to potentially expand approved indications in the future to better reflect the indications where daptomycin is needed.
The Health Canada approved dose for daptomycin is 6.0 mg/kg for the treatment of S. aureus. In our study, the average dose used was higher at 7.4 mg/kg, reflecting IDSA CPGs recommending the use of up to 10.0 mg/kg for some infections (7). Despite the higher average dose used, we found very few complications of daptomycin therapy. In clinical practice, CK elevation is the main adverse event of concern. Although we found that CK elevation of at least 3 × ULN occurred in 8% of courses, only one patient required discontinuation of daptomycin therapy. These findings are similar to those observed in other studies (11,19). In our study, a CK was not measured during a substantial proportion of daptomycin courses. All of these courses were a week or less in duration, so the ordering physicians may have not considered it necessary to obtain a CK prior to 1 week of treatment. The creation of an order set for daptomycin ordering, which includes regular CK monitoring, may be a potential solution to address the inconsistent CK monitoring that we observed.
Several studies have examined the use of daptomycin in other countries, including the United States, Spain, Italy, and France (12–15), or examined data from registries that have pooled data from several countries (16–18). In many of these studies, S. aureus was the most common pathogen, and bloodstream infection and skin and soft tissue infections were the most common sites of infection (13–18). Use of daptomycin for unapproved indications was also very common (12,13,15). Overall, the results of our study are consistent with those found in other settings.
The main limitations of our study are the fact that it is reflective of a two-hospital experience, and the retrospective design of the data collection. Furthermore, only inpatient courses were studied, as details relating to continuation of therapy as an outpatient was not readily available. With respect to adverse events, it is possible that minor events were under-reported.
Our study shows that daptomycin is used for a variety of indications to treat many different gram-positive pathogens in a Canadian setting. Use of daptomycin for unapproved indications is very common, with many of these unapproved indications following IDSA CPGs. Daptomycin use is associated with very few adverse events, despite often being used at doses higher than approved by Health Canada.
Competing Interests:
Dr Mertz reports grants from Sunovion during the conduct of the study.
Ethics Approval:
The Hamilton Integrated Research Ethics Board approved the study protocol and waived the need for informed consent.
Informed Consent:
N/A
Registry and the Registration No. of the Study/Trial:
N/A
Animal Studies:
N/A
Funding:
The study was supported by a non-restricted educational grant from Sunovion.
Peer Review:
This article has been peer reviewed.
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