High-dose Daptomycin Research Articles

Effect of dexamethasone on the efficacy of daptomycin in the therapy of experimental pneumococcal meningitis

This study aimed to determine the effect of dexamethasone in combination with low-dose or high-dose daptomycin for the treatment of penicillin- and cephalosporin-resistant pneumococcal meningitis. Efficacy (ΔCFU/mL) and cerebrospinal fluid (CSF) levels of daptomycin at 15mg/kg and 25mg/kg were studied in a rabbit model of pneumococcal meningitis, comparing them with the same doses in combination with dexamethasone at 0.125mg/kg every 12h over a 26-h period against two different Streptococcus pneumoniae strains, HUB 2349 and ATCC 51916 with daptomycin minimum inhibitory concentrations (MICs) of 0.09mg/L and 0.19mg/L, respectively. Daptomycin levels in CSF were lower when dexamethasone was given concurrently. Against strain HUB 2349, therapeutic failure occurred with daptomycin 15mg/kg+dexamethasone; daptomycin 25mg/kg+dexamethasone was better at reducing bacterial counts than the lower dose throughout treatment. Against the highly cephalosporin-resistant ATCC 51916 strain, daptomycin 15mg/kg+dexamethasone achieved a lower bacterial decrease than daptomycin 15mg/kg alone, and therapeutic failure at 24h occurred in the daptomycin 15mg/kg+dexamethasone group. Addition of dexamethasone to a 25mg/kg daptomycin dose did not affect the efficacy of daptomycin: it remained bactericidal throughout treatment. In conclusion, against the studied strains, low-dose (15mg/kg/day) daptomycin is affected by concomitant use of dexamethasone: CSF levels are reduced and its bacterial efficacy is affected. At a higher daptomycin dose (25mg/kg/day), however, the use of dexamethasone does not alter efficacy; the combination appears to be a good choice for the treatment of pneumococcal meningitis.

Daptomycin-induced hyperkalemia in a patient with normal renal function

A case of episodic hyperkalemia associated with daptomycin administration is reported. A 46-year-old African-American woman was hospitalized for treatment of a shoulder abscess. Initially treated with i.v. vancomycin, the patient was switched to daptomycin 9 mg/kg i.v. (500 mg daily) after three days. On day 10 of daptomycin therapy, she was noted to have a serum potassium concentration of 5.4 meq/L, with an increase to 6.1 meq/L on day 11. Reversal of hyperkalemia was achieved with oral sodium polystyrene sulfonate and other agents, and daptomycin was withheld for one day, during which time the patient's serum potassium level normalized. One day after daptomycin therapy was resumed at a lower dose (7 mg/kg), the potassium concentration increased again (to 5.5 meq/L). With a further dosage reduction and continued administration of sodium polystyrene sulfonate, the patient completed the full course of daptomycin therapy. There was a close temporal relationship between daptomycin administrations and the serum potassium fluctuations; other potential causes of hyperkalemia were ruled out. Evaluation of this case using the algorithm of Naranjo et al. yielded a score of 6, indicating that the serum potassium elevations probably constituted an adverse reaction to daptomycin. A literature search identified no other reports of hyperkalemia associated with daptomycin use in a patient with normal renal function. A 46-year-old women with normal renal function developed hyperkalemia after receiving high-dose daptomycin therapy. The potassium levels normalized when daptomycin was withheld but increased again when the patient was rechallenged with the drug.

Tolerability of High Doses of Daptomycin in the Treatment of Prosthetic Vascular Graft Infection: A Retrospective Study.

IntroductionIn treatment of prosthetic vascular graft infection (PVGI), appropriate antimicrobial treatment is crucial for controlling the septic process and preventing re-infection of the new graft. Glycopeptides are the mainstay of treatment for device-related infections by methicillin-resistant Staphylococcus aureus strains, but with some limitations, especially concerning vancomycin-intermediate and glycopeptide-intermediate S. aureus. We report our experience using a high dose of daptomycin (DAP) for treatment of PVGI.MethodsWe reviewed medical reports of 26 patients treated with high doses of DAP (>8 mg/kg) and beta-lactams/aminosides for PVGI, defined as positive bacterial culture of intraoperative specimens or blood samples and/or clinical, biological, and radiological signs of infection. Clinical success was defined by resolution of all clinical signs at the end of follow-up, without the need for additional antibiotic therapy, and/or negative culture in case of new surgery.ResultsCultures of intraoperative samples were positive in 21 patients (80.8%). Blood and intraoperative cultures were concomitantly positive in 10 patients. The main microorganism identified in microbiological samples was S. aureus (n = 18). Surgery was performed in 23 patients (88.4%). The mean duration of the DAP regimen was 12.3 ± 11.9 days. DAP was discontinued in 26 patients [need to switch to microbiological results (n = 19), bacterial pneumonia (n = 2), and increased creatine phosphokinase levels (n = 4)]. One patient had myalgia, while 9 received concomitant statins.ConclusionHigh-dose DAP therapy shows a satisfactory toxicity profile even in severely ill patients with multiple comorbidities, and may favorably compete with vancomycin, especially concerning the risk of induced nephrotoxicity.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0035-9) contains supplementary material, which is available to authorized users.

High-dose daptomycin therapy for staphylococcal endocarditis and when to apply it.

Infective endocarditis (IE) continues to present a large burden to the health-care system. Staphylococcus aureus, the leading pathogen associated with the disease, has always proven difficult to treat. Increasing numbers of S. aureus isolates are demonstrating reduced susceptibility to vancomycin, and therapeutic options are limited. Daptomycin is frequently employed when vancomycin therapy proves unsuccessful or when vancomycin minimum inhibitory concentration (MIC) values rise above 1mg/L. Currently, daptomycin is FDA-approved at a dose of 6mg/kg/day for the treatment of S. aureus bacteremia and associated right-sided endocarditis. However, numerous in vitro and clinical studies suggest that daptomycin doses up to 12mg/kg/day may provide improved efficacy and resistance prevention. Additionally, high-dose daptomycin has demonstrated excellent safety. Together, these data suggest a role for high-dose daptomycin in staphylococcal IE patients who are severely ill, previously failed therapy with vancomycin, or possess a S. aureus isolate with an elevated vancomycin MIC.

High doses of daptomycin (10 mg/kg/d) plus rifampin for the treatment of staphylococcal prosthetic joint infection managed with implant retention: a comparative study

We aimed to analyze the efficacy and safety of high doses of daptomycin (10 mg/kg/d) plus rifampin (D10 + R) for prosthetic joint infection (PJI). This was an observational retrospective multicenter study (2010–2012) including all patients with acute PJI by fluoroquinolone-resistant staphylococci managed with implant retention and D10 + R. Twenty cases were included: 2 (10%) were withdrawn due to toxicity, leaving 18 cases for efficacy evaluation: 13 (72%) women, age 79 years (range 58–90). Clinical failure was observed in 9 (50%) patients: in 5 cases, staphylococci were recovered (28% of microbiological failures); no modification of daptomycin-MIC was observed. These 18 cases were compared with 44 matched historical cases: failure rate was similar, but whereas in the historical series, failure occurred fundamentally during therapy, in the present series, it was recorded after discontinuation of antibiotics. In summary, D10 + R may be the initial treatment of choice for PJI by fluoroquinolone-resistant staphylococci managed with implant retention.

Metabolic and transcriptional activities of Staphylococcus aureus challenged with high-doses of daptomycin

Treatment of stationary growth phase Staphylococcus aureus SA113 with 100-fold of the MIC of the lipopeptide antibiotic daptomycin leaves alive a small fraction of drug tolerant albeit genetically susceptible bacteria. This study shows that cells of this subpopulation exhibit active metabolism even hours after the onset of the drug challenge. Isotopologue profiling using fully 13C-labeled glucose revealed de novo biosynthesis of the amino acids Ala, Asp, Glu, Ser, Gly and His. The isotopologue composition in Asp and Glu suggested an increased activity of the TCA cycle under daptomycin treatment compared to unaffected stationary growth phase cells. Microarray analysis showed differential expression of specific genes 10min and 3h after addition of the drug. Besides factors involved in drug response, a number of metabolic genes appear to shape the signature of daptomycin-tolerant S. aureus cells. These observations will be useful toward the development of new strategies against persisters and related forms of bacterial cells with downshifted physiology.

Right-sided endocarditis in an adult patient with hyperimmunoglobulin-E syndrome successfully treated with high-dose daptomycin

Hyperimmunoglobulin-E syndrome is a syndrome of recurrent staphylococcal abscesses, sinopulmonary infections, and severe eczema, which is characterized by increased IgE and specific facial features. Herein, we describe a patient with hyperimmunoglobulin-E syndrome and right-sided endocarditis due to Staphylococcus aureus, which was successfully treated with high-dose daptomycin.

PKP-015 Optimal dose regimen of antibiotics against methicillin-resistant Staphylococcus aureus in critically ill patients undergoing continuous venovenous hemodiafiltration

BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) is usually involved in nosocomial infections. Acute Kidney Injury (AKI) and a state of high haemodynamic instability are common in ICU patients, thus continuous venovenous haemodiafiltration...

Oral Antibiotic Therapy

Oral Antibiotic Therapy

Lower Daptomycin Concentrations May Occur in Patients with Severe Sepsis

Studies have shown marked variability in the pharmacokinetics of daptomycin in acutely ill patients. Although use of 6 mg/kg daily is suggested for treating infections caused by gram-positive organisms, high-dose (10 mg/kg daily) daptomycin is recommended for persistent methicillin-resistant Staphylococcus aureus bacteremia not responsive to vancomycin. In a recent open-label, prospective study …

Reply to comment “Comment on Jugun et al.: The safety and efficacy of high-dose daptomycin combined with rifampicin for the treatment of Gram-positive osteoarticular infections” by Lu et al.

Dear Prof. Pecina, We thank you for the opportunity to answer the letter commenting on our published article entitled “The safety and efficacy of high-dose daptomycin combined with rifampicin for the treatment of Gram-positive osteoarticular infections”. The colleagues Lu, Zha and Wang have read our paper and highlight some remarks (or opinions as they call it), which we find pertinent and answer them with pleasure. We are aware of the small sample size of 16 patients and this is acknowledged in the manuscript [1]. This is not new. However, Lu and colleagues need to bear in mind that our study addressed the question of the clinical feasibility and tolerance of high-dose daptomycin (8 mg/kg/day) combined with rifampicin, another drug used in orthopaedic surgery with a potentially important side-effect profile. As a general principle, studies targeting the outcome of interventions usually need sample sizes beyond 50 cases in each randomisation arm, as Lu and colleagues correctly remark. These are usually phase III trials or other investigations regarding cure or failure rates. In contrast, tolerability studies in humans, e.g. many phase II trials, are appropriate with a much lower sample size and may be performed within a single centre such as in our study. Therefore, it is not surprising that the local Institutional Review Board and Swissmedic (The Swiss “FDA”) approved our small sample size. Lu et al. ask why we chose daptomycin 8 mg/kg/day combined with rifampicin. Although we explained this in the publication, two reasons predominated. First, daptomycin is under evaluation worldwide for higher doses than the usual 6 mg/kg/day for all types of infections. Theoretical concerns discourage using higher doses, even when a higher dosage could have advantages. Thus, we chose 8 mg as a first step for the investigation. A submission involving a higher jump, e.g. directly from 6 mg/kg to 10 mg/kg, was likely to have been rejected by the Swiss Federal authorities. Second, a combination with rifampicin (or rifampin) is a well-established standard antibiotic regimen for staphylococcal implant infections, the hallmark of orthopaedic infections. Lu et al. regretted the absence of clinical functional recovery data post infection treatment. They would have been correct if the main investigation of our study had been the Therapeutical approach. In our article, we concentrated on the tolerability and safety of a particularly promising antibiotic combination at high doses. Such a manuscript would have been complicated and too long if we had added functional outcomes. Antimicrobial drugs have a range of adverse events, including fatal ones. In most cases however, adverse events usually subside within a few weeks, with absence of long-term sequelae. None of our study patients had antibiotic therapy related sequelae, and any functional impairment depended on the anatomical and orthopaedic conditions predating their infection. We thank again Lu et al. for their thorough reading of our article and their collegial remarks. We remain open for further questions. Yours most sincerely, I. Uckay, MD, and Prof. P. Hoffmeyer, MD

High-Dose Daptomycin Therapy for Left-Sided Infective Endocarditis: a Prospective Study from the International Collaboration on Endocarditis

The use of daptomycin in Gram-positive left-sided infective endocarditis (IE) has significantly increased. The purpose of this study was to assess the influence of high-dose daptomycin on the outcome of left-sided IE due to Gram-positive pathogens. This was a prospective cohort study based on 1,112 cases from the International Collaboration on Endocarditis (ICE)-Plus database and the ICE-Daptomycin Substudy database from 2008 to 2010. Among patients with left-sided IE due to Staphylococcus aureus, coagulase-negative staphylococci, and Enterococcus faecalis, we compared those treated with daptomycin (cohort A) to those treated with standard-of-care (SOC) antibiotics (cohort B). The primary outcome was in-hospital mortality. Time to clearance of bacteremia, 6-month mortality, and adverse events (AEs) ascribable to daptomycin were also assessed. There were 29 and 149 patients included in cohort A and cohort B, respectively. Baseline comorbidities did not differ between the two cohorts, except for a significantly higher prevalence of diabetes and previous episodes of IE among patients treated with daptomycin. The median daptomycin dose was 9.2 mg/kg of body weight/day. Two-thirds of the patients treated with daptomycin had failed a previous antibiotic regimen. In-hospital and 6-month mortalities were similar in the two cohorts. In cohort A, median time to clearance of methicillin-resistant S. aureus (MRSA) bacteremia was 1.0 day, irrespective of daptomycin dose, representing a significantly faster bacteremia clearance compared to SOC (1.0 versus 5.0 days; P < 0.01). Regimens with higher daptomycin doses were not associated with increased incidence of AEs. In conclusion, higher-dose daptomycin may be an effective and safe alternative to SOC in the treatment of left-sided IE due to common Gram-positive pathogens.

Considerations for Higher Doses of Daptomycin in Critically Ill Patients With Methicillin-Resistant Staphylococcus aureus Bacteremia

Higher daptomycin doses are advocated for select methicillin-resistant Staphylococcus aureus (MRSA)-related infections, but the probabilities of target attainment (PTA) and toxicity of these doses have not been characterized in critically ill patients. We evaluated the plasma pharmacokinetics (PK) and clinical outcomes of a cohort of critically ill patients treated with daptomycin 6-8 mg/kg/day for primarily Staphylococcus species-related infections. Daptomycin concentrations were measured intensively over the initial 96-hour dosing period. Data were modeled by population PK analyses, and Monte Carlo simulation was used to estimate the probabilities of effect and toxicity with standard and alternate dosing regimens. Fifty patients with a mean (SD) age of 69.7 (12.2) years, weight 74.5 (20.3) kg, and creatinine clearance 56.8 (38.2) mL/minute were enrolled with measurements of 12 (2.2) daptomycin samples per patient. Significantly lower daptomycin exposures were observed despite comparable doses in a subset of patients (n = 13) with augmented clearance (CL). No covariates of CL were identified, but this subset was significantly more likely to be in severe sepsis or septic shock, have higher Sequential Organ Failure Assessment scores, and MRSA bacteremia. In-hospital mortality was significantly higher (30.7% vs 10.8%) in patients with augmented daptomycin CL. Use of an empiric fixed dose of 750 mg of daptomycin is predicted to achieve a comparable PTA with a lower probability of toxicity as compared to the use of 10 mg/kg in critically ill patients. A reappraisal of current daptomycin dosing recommendations is needed to improve the PTA and reduce toxicity among critically ill patients.

A multicentre evaluation of the effectiveness and safety of high-dose daptomycin for the treatment of infective endocarditis

Despite significant medical advances, infective endocarditis (IE) remains an infection associated with high morbidity and mortality. The objective was to assess the safety and efficacy of high-dose daptomycin, defined as ≥ 8 mg/kg/day, in patients with confirmed or suspected staphylococcal and/or enterococcal IE. This was a multicentre, retrospective observational study (2005-11). Adult patients, not undergoing haemodialysis, with blood cultures positive for staphylococci or enterococci and a definitive or possible diagnosis of IE, who received daptomycin ≥ 8 mg/kg/day (based on total body weight) for ≥ 72 h were included. Seventy patients met the inclusion criteria and comprised 33 (47.1%) with right-sided IE (RIE), 35 (50%) with left-sided IE (LIE) and 2 with both RIE and LIE. Several patients had concomitant sites of infection, with bone/joint infection being most prevalent (12.9%). Sixty-five patients received daptomycin as salvage therapy. Pathogens were isolated from 64 patients, with methicillin-resistant Staphylococcus aureus as the most common organism (84.4%), followed by vancomycin-resistant Enterococcus faecium (7.8%). The median (IQR) daptomycin dose was 9.8 mg/kg/day (8.2-10.0 mg/kg/day), and was similar in RIE and LIE patients (9.8 and 9.3 mg/kg/day, respectively). A total of 24 (34.3%) received combination therapy. For those patients with pathogens isolated (n = 64), the organism was eradicated in 57 (89.1%) patients. Among 64 clinically evaluable patients, 55 (85.9%) achieved clinical success. No patients required discontinuation of high-dose daptomycin due to creatine phosphokinase elevations. Patients with both RIE and LIE had successful outcomes with high-dose daptomycin therapy. Additional clinical trials evaluating high daptomycin dosages in patients with IE are warranted.

Comment on Jugun et al.: The safety and efficacy of high-dose daptomycin combined with rifampicin for the treatment of Gram-positive osteoarticular infections

Dear Editor, In a recent issue of International Orthopaedics, Jugun and his workmates published an article [1] entitled “The safety and efficacy of high-dose daptomycin combined with rifampicin for the treatment of Gram-positive osteoarticular infections”. In this study, the authors indicated that combined therapy with high-dose daptomycin and rifampicin was both safe and effective for the treatment of Gram-positive osteoarticular infections. The conclusion was indeed encouraging for orthopaedic surgeons providing a new method to cure Gram-positive osteoarticular infections. However, we have several opinions that we would like to communicate to the authors. Firstly, the sample size was limited (only 16 patients), which may cause bias. We suggest that more eligible patients should be included in a future study. Secondly, despite the prospective character of the study, the single-centre and the non-comparative design may reduce the persuasiveness and reliability of the conclusion. Therefore, future multi-centre and controlled studies are needed to prove the above conclusion. Thirdly, we would like to know why the authors chose the therapy strategy of intravenous daptomycin (8 mg/kg per day) and oral rifampicin (600 mg/day). Furthermore, the recruitment of patients with different types of osteoarticular infections (Table 1) may also lead to different outcomes. Fourthly, assessment of the clinical efficacy should also focus on the functional recovery of the bone and joint. Therefore, some functional evaluation scales or scores should be applied to evaluate the clinical efficacy. Thanks go to the authors for their contribution to supplying us with a new approach to treating Gram-positive osteoarticular infections.

Multicenter Study of High-Dose Daptomycin for Treatment of Enterococcal Infections

Enterococci are among the leading pathogens isolated in hospital-acquired infections. Current antimicrobial options for vancomycin-resistant enterococci (VRE) are limited. Prior data suggest that daptomycin at >6 mg/kg of body weight/day may be used to treat enterococcal infections. We retrospectively evaluated the effectiveness and safety of high-dose daptomycin (HD-daptomycin) therapy (>6 mg/kg) in a multicenter cohort of adult patients with enterococcal infections to describe the characteristics and outcomes. Two hundred forty-five patients were evaluated. Enterococcus faecium was identified in 175 (71%), followed by Enterococcus faecalis in 49 (20%) and Enterococcus spp. in 21 (9%); overall, 204 (83%) isolates were VRE. Enterococcal infections included bacteremia (173, 71%) and intra-abdominal (35, 14%) and bone and joint (25, 10%) infections. The median dosage and duration of HD-daptomycin were 8.2 mg/kg/day (interquartile range [IQR], 7.7 to 9.7) and 10 days (IQR, 6 to 15), respectively. The overall clinical success rate was 89% (193/218), and microbiological eradication was observed in 93% (177/191) of patients. The median time to clearance of blood cultures on HD-daptomycin was 3 days (IQR, 2 to 5). The 30-day all-cause mortality rate was 27%, and 5 (2%) patients developed daptomycin-nonsusceptible enterococcal strains while on HD-daptomycin. Seven patients (3%) had creatine phosphokinase (CPK) elevation, yet no HD-daptomycin regimen was discontinued due to an elevated CPK and all patients were asymptomatic. Overall, there was a high frequency of clinical success and microbiological eradication in patients treated with HD-daptomycin for enterococcal infections, even in patients with complicated and difficult-to-treat infections. No adverse event-related discontinuation of HD-daptomycin was noted. HD-daptomycin may be an option for the treatment of enterococcal infections.

The safety and efficacy of high-dose daptomycin combined with rifampicin for the treatment of Gram-positive osteoarticular infections

Treatment of Gram-positive osteoarticular infections requires an adequate surgical approach combined with intensive antimicrobial therapy. The aim of this study was to evaluate the safety and efficacy of a combined regimen of high-dose daptomycin and rifampicin, in patients with various types of Gram-positive osteoarticular infections. This single centre, non-comparative, prospective study evaluated the safety and efficacy of a combined regimen of intravenous daptomycin (8 mg/kg/day) and oral rifampicin (600 mg/day) in patients with Gram-positive osteoarticular infections, with a minimal follow-up of one year. Creatine phosphokinase, transaminases, bilirubinaemia, and serum creatinine, were measured at baseline and regular intervals. The median daily doses of daptomycin and rifampicin, administered for a median duration of 21 (range, 10-122) days to 16 patients (median age, 63.5 years; 11 males, five females) presenting with staphylococcal (n = 15) or streptococcal (n = 1) osteoarticular infections, were 8.15 (range, 6.6-8.9) mg/kg/day and 600 (range, 600-900) mg/day, respectively. The combined regimen of daptomycin and rifampicin was well tolerated by all except one patient, without requiring treatment adjustment or discontinuation. One patient developed allergic responses probably due to rifampicin after 42 days. Fifteen (94 %) patients showed favourable clinical and microbiological outcomes. The combined regimen of high-dose daptomycin and rifampicin was well tolerated and may provide a useful alternative to standard glycopeptide therapy for Gram-positive osteoarticular infections.

Editorial Commentary: Early High-Dose Daptomycin for Methicillin-Resistant Staphylococcus aureus Bloodstream Infections With Elevated Vancomycin Minimum Inhibitory Concentrations: Ready for Prime Time?

In this issue of Clinical Infectious Diseases, Murray and colleagues present results from a matched cohort study addressing the clinical conundrum of methicillinresistant Staphylococcus aureus (MRSA) bloodstream infections caused by organisms with elevated vancomycin minimum inhibitory concentrations (MICs) [1]. The investigators conclude that highdose daptomycin treatment led to better outcomes, and they advocate for an early switch from vancomycin to daptomycin based on finding a vancomycin MIC >1 μg/mL. Although the study provides new insight into this important clinical problem, several key questions remain. A growing body of data shows that S. aureus isolates with higher vancomycin MICs are associated with a significant increase in the risk of worse clinical outcomes, including treatment failure and death [2, 3]. It is unknown whether these poor outcomes represent relative resistance to vancomycin, a marker for a more virulent organism, or some undefined third factor associated with worse outcomes. Holmes et al found that the association between higher vancomycin MICs and clinical failure persisted even in patients with methicillin-susceptible S. aureus treated with β-lactam therapy [4]. This makes the decision regarding treatment of patients with MRSA bloodstream infection with an elevated vancomycin MIC even less clear. Should they be switched to an alternative therapy early, based on MIC testing, or wait until they develop persistent bloodstream infection or other signs of clinical failure? Current guidelines from the Infectious Diseases Society of America recommend higher doses of vancomycin based largely on pharmacokinetic and pharmacodynamic data and suggest that “if the patient has

Daptomycin plus trimethoprim/sulfamethoxazole combination therapy in post-neurosurgical meningitis caused by linezolid-resistant Staphylococcus epidermidis

Post-neurosurgical infection is a serious complication that occurs in approx. 4% of all patients undergoing neurosurgical procedures and is associated with high morbidity and mortality rates and prolonged length of intensive care unit (ICU) stay. Coagulase-negative staphylococci (CoNS), especially methicillin-resistant Staphylococcus epidermidis (MRSE), are the most frequent pathogens involved in CNS post-neurosurgical meningitis. Treatment is challenging especially in patients with meningitis due to multidrug- resistant (MDR) CONS. Herein, we report a unique case of post-neurosurgical meningitis due to MRSE resistant to linezolid (a molecular analysis revealed the presence of the mutation G2576T on domain V of the 23S rRNA gene) and with reduced susceptibility to glycopeptides, successfully treated with a combination of daptomycin at 10 mg/kg daily plus trimethoprim/sulfamethoxazole (TMP/SMX). This antibiotic combination showed an indifferent interaction in in vitro studies. Daptomycin serum and cerebrospinal fluid (CSF) concentrations, determined through blood and CSF samples drawn just prior to and 4 h after the third dose, were 18.9–0.78 and 51.65–3.1 mg/L, respectively. These values allowed us to approximate a 5–6% penetration rate of the drug through an inflamed blood–brain barrier. In conclusion, although further studies are needed, combination of high-dose daptomycin plus TMP/SMX is a reasonable option for treatment of meningitis caused by multidrug-resistant S. epidermidis.

Effectiveness and safety of daptomycin in complicated skin and soft-tissue infections and bacteraemia in clinical practice: Results of a large non-interventional study

This retrospective analysis of patients from eight countries included in the European Cubicin® Outcomes Registry and Experience (EU-CORESM) captures the first post-approval years of clinical experience with daptomycin in its licensed indications. Of the total 1127 patients enrolled in EU-CORE between 2006 and 2008, 373 had a primary complicated skin and soft-tissue infection (cSSTI), most commonly surgical-site infection (48%), and 244 had bacteraemia, 55% of which were catheter-related. The most common pathogens were Staphylococcus aureus in cSSTIs (43%) and coagulase-negative staphylococci in bacteraemia (36%). The most frequently prescribed daptomycin doses were 4mg/kg and 6mg/kg for cSSTIs, and 6mg/kg for bacteraemia. The median duration of inpatient and outpatient treatment, respectively, was 13 days and 8 days for cSSTIs and 8 days and 10 days for bacteraemia. Clinical success was reported for 81% of patients with cSSTIs and 77% with bacteraemia, with 82% success overall for infections caused by S. aureus. A trend towards higher clinical success was noted with higher daptomycin doses in bacteraemia (78% for 6mg/kg vs. 90% for doses >6mg/kg). Daptomycin demonstrated a favourable safety profile. Adverse events regardless of relationship to study drug were reported for 11% of patients with cSSTIs and 24% with bacteraemia, most commonly septic shock [7 patients (2%) with cSSTIs and 5 patients (2%) with bacteraemia]. These results demonstrate that daptomycin is effective and well tolerated in the treatment of cSSTIs and bacteraemia caused by Gram-positive bacteria in clinical practice.