Combination Of Daptomycin Research Articles

Daptomycin and Its Immunomodulatory Effect: Consequences for Antibiotic Treatment of Methicillin-Resistant Staphylococcus aureus Wound Infections after Heart Surgery

Infections by methicillin-resistant Staphylococcus aureus (MRSA) play an increasing role in the postoperative course. Although wound infections after cardiac surgery are rare, the outcome is limited by the prolonged treatment with high mortality. Not only surgical debridement is crucial, but also antibiotic support. Next to vancomycin and linezolid, daptomycin gains increasing importance. Although clinical evidence is limited, daptomycin has immunomodulatory properties, resulting in the suppression of cytokine expression after host immune response stimulation by MRSA. Experimental studies showed an improved efficacy of daptomycin in combination with administration of vitamin E before infecting wounds by MRSA.

Evaluation of Double- and Triple-Antibiotic Combinations for VIM- and NDM-Producing Klebsiella pneumoniae by In Vitro Time-Kill Experiments

Combination therapy is recommended for infections with carbapenemase-producing Klebsiella pneumoniae. However, limited data exist on which antibiotic combinations are the most effective. The aim of this study was to find effective antibiotic combinations against metallo-beta-lactamase-producing K. pneumoniae (MBL-KP). Two VIM- and two NDM-producing K. pneumoniae strains, all susceptible to colistin, were exposed to antibiotics at clinically relevant static concentrations during 24-h time-kill experiments. Double- and triple-antibiotic combinations of aztreonam, ciprofloxacin, colistin, daptomycin, fosfomycin, meropenem, rifampin, telavancin, tigecycline, and vancomycin were used. Synergy was defined as a ≥2 log10 decrease in CFU/ml between the combination and its most active drug after 24 h, and bactericidal effect was defined as a ≥3 log10 decrease in CFU/ml after 24 h compared with the starting inoculum. Synergistic or bactericidal activity was demonstrated for aztreonam, fosfomycin, meropenem, and rifampin in double-antibiotic combinations with colistin and also for aztreonam, fosfomycin, and rifampin in triple-antibiotic combinations with meropenem and colistin. Overall, the combination of rifampin-meropenem-colistin was the most effective regimen, demonstrating synergistic and bactericidal effects against all four strains. Meropenem-colistin, meropenem-fosfomycin, and tigecycline-colistin combinations were not bactericidal against the strains used. The findings of this and other studies indicate that there is great potential of antibiotic combinations against carbapenemase-producing K. pneumoniae. However, our results deviate to some extent from those of previous studies, which might be because most studies to date have included KPC-producing rather than MBL-producing strains. More studies addressing MBL-KP are needed.

Oral Antibiotic Therapy

Oral Antibiotic Therapy

A pilot study of the efficacy and safety of empiric daptomycin therapy in oncology patients with fever and severe neutropenia.

Patients with extended periods of time spent with low or absent absolute neutrophil counts (ANCs) are at risk for bacterial infections. Febrile neutropenia is a complication in this patient population, requiring administration of antibiotics. The use of daptomycin in treating patients with febrile neutropenia is not well described. Our objective was to describe the clinical course of febrile neutropenic patients that received daptomycin therapy. This was an open-labeled, pilot study of 30 patients with documented febrile neutropenia treated with empiric daptomycin. Eligible patients received daptomycin 6 mg/kg/day, in addition to concomitant broad-spectrum antimicrobials. The Kaplan-Meier method was used to estimate the median days to reach an afebrile state and negative bacterial cultures. A total of 30 febrile neutropenic patients were enrolled and received daptomycin as part of an empiric antimicrobial regimen. All patients had severe neutropenia with ANC <100 cells/mm(3). Two patients were removed from study due to the development of pneumonia. Clinically, 87% patients improved on daptomycin in combination with Gram-negative coverage, with 73% of patients succeeding therapy. A total of 18 of 19 (95%) subjects with positive blood cultures had microbiological eradication, with the median time to reach an afebrile state of 4.3 days (range 1-13). Four patients were discontinued from daptomycin due to a suspected related adverse event or to clinical failure. This pilot study supports future evaluation of the use of empiric daptomycin therapy in combination with Gram-negative coverage compared with vancomycin in patients with neutropenic fever in a large, randomized controlled trial.

Bactericidal synergism between daptomycin and the phage lysin Cpl-1 in a mouse model of pneumococcal bacteraemia

Combination therapy may improve the outcome of Streptococcus pneumoniae-induced bacteraemia. Here we tested the combination of two antipneumococcal agents, daptomycin and Cpl-1 (the pneumococcal Cp-1 bacteriophage lysin), in a mouse model of pneumococcal bacteraemia. Mice were challenged intraperitoneally (i.p.) with 106CFU of the extremely virulent serotype 2 S. pneumoniae D39 isolate. Subtherapeutic doses of daptomycin (0.4mg/kg) and Cpl-1 (0.4mg/kg and 1mg/kg) were administrated i.p. either alone or in combination by a single bolus injection 1h after bacterial challenge. Survival rates of animals were followed over a period of 7 days. Daptomycin (0.4mg/kg) in combination with Cpl-1 (0.4mg/kg) significantly increased the percentage of surviving mice at Day 7 (80%) compared with the untreated control (0%) and daptomycin or Cpl-1 monotherapy (35% and 0%, respectively). Whilst increasing the concentration of Cpl-1 to 1.0mg/kg did not improve survival when injected alone, its combination with 0.4mg/kg daptomycin further increased the survival rate to 95%. Thus, it was found that the combination of daptomycin with Cpl-1 was synergistic and bactericidal against S. pneumoniae in a mouse model of pneumococcal bacteraemia. To our knowledge, this is the first report of synergism between daptomycin and a phage lysin demonstrated in vivo. Such a combination could represent an interesting alternative therapy for the treatment of pneumococcal bacteraemia/sepsis and possibly other severe pneumococcal infections.

In vitro activity of daptomycin in combination with low-dose colistin against a diverse collection of Gram-negative bacterial pathogens

The activity of colistin in combination with daptomycin was assessed using 30 Gram-negative type strains and multidrug-resistant isolates with defined mechanisms of resistance. Daptomycin minimum inhibitory concentrations (MICs) were determined with and without sub-inhibitory concentrations of colistin. The activity of daptomycin was not affected with respect to Escherichia coli, Klebsiella pneumoniae or Pseudomonas aeruginosa. For colistin-susceptible Acinetobacter baumannii, sensitisation factors ranged from 8 to 128 (median 32), with the daptomycin MIC being reduced to the Clinical and Laboratory Standards Institute (CLSI) enterococci susceptibility breakpoint of 4μg/ml for the ATCC 19606 type strain. A combination of daptomycin and colistin may be useful for the treatment of A. baumannii but not infections due to other Gram-negative species.

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.

Evaluation of the combination of daptomycin and nafcillin against vancomycin-intermediate Staphylococcus aureus

Continued selective pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus, including vancomycin-intermediate S. aureus (VISA). Though relatively uncommon, VISA presents a particularly difficult clinical challenge when it arises. Pertinent to this investigation is the correlation between vancomycin intermediacy and daptomycin non-susceptibility. The aim of this study was to evaluate the potential for synergy between daptomycin and nafcillin against VISA. Twenty VISA strains were evaluated for daptomycin and nafcillin MICs by broth microdilution in duplicate. Potential for synergy was assessed by time-kill at 0.5× MIC in triplicate. Four strains displaying synergy in time-kill analysis were analysed in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model in duplicate over 72 h. In time-kill experiments, 55% of strains (11/20) displayed synergy with the combination. In the PK/PD model, no differences between daptomycin-alone and combination regimens were observed for the strain with the lowest daptomycin MIC (0.5 mg/L). For the strain with a daptomycin MIC of 1 mg/L, 6 mg/kg daptomycin+nafcillin was superior to 6 mg/kg daptomycin alone (P=0.002) and 10 mg/kg daptomycin+nafcillin was superior to all other regimens (P ≤ 0.004). When the daptomycin MIC increased to 2 mg/L, 10 mg/kg daptomycin+nafcillin was superior to 6 mg/kg daptomycin+nafcillin, which was superior to both 6 and 10 mg/kg daptomycin alone (P ≤ 0.019). Daptomycin and nafcillin in combination significantly improved antibacterial activity against VISA. This effect was more pronounced as the daptomycin susceptibility of the strain declined.

Ceftaroline Increases Membrane Binding and Enhances the Activity of Daptomycin against Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus in a Pharmacokinetic/Pharmacodynamic Model

New antimicrobial agents and novel combination therapies are needed to treat serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to daptomycin and vancomycin. The purpose of this study was to evaluate the combination of ceftaroline plus daptomycin or vancomycin in an in vitro pharmacokinetic/pharmacodynamic model. Simulations of ceftaroline-fosamil at 600 mg per kg of body weight every 8 h (q8h) (maximum free-drug concentration in serum [fC(max)], 15.2 mg/liter; half-life [t(1/2)], 2.3 h), daptomycin at 10 mg/kg/day (fC(max), 11.3 mg/liter; t(1/2), 8 h), vancomycin at 2 g q12h (fC(max), 30 mg/liter; t(1/2), 6 h), ceftaroline plus daptomycin, and ceftaroline plus vancomycin were evaluated against a clinical, isogenic MRSA strain pair: D592 (daptomycin susceptible and heterogeneous vancomycin intermediate) and D712 (daptomycin nonsusceptible and vancomycin intermediate) in a one-compartment in vitro pharmacokinetic/pharmacodynamic model over 96 h. Therapeutic enhancement of combinations was defined as ≥2 log(10) CFU/ml reduction over the most active single agent. The effect of ceftaroline on the membrane charge, cell wall thickness, susceptibility to killing by the human cathelicidin LL37, and daptomycin binding were evaluated. Therapeutic enhancement was observed with daptomycin plus ceftaroline in both strains and vancomycin plus ceftaroline against D592. Ceftaroline exposure enhanced daptomycin-induced depolarization (81.7% versus 72.3%; P = 0.03) and killing by cathelicidin LL37 (P < 0.01) and reduced cell wall thickness (P < 0.001). Fluorescence-labeled daptomycin was bound over 7-fold more in ceftaroline-exposed cells. Whole-genome sequencing and mutation analysis of these strains indicated that change in daptomycin susceptibility is related to an fmtC (mprF) mutation. The combination of daptomycin plus ceftaroline appears to be potent, with rapid and sustained bactericidal activity against both daptomycin-susceptible and -nonsusceptible strains of MRSA.

Vancomycin-resistant Enterococcus faecium meningitis in adults: Case series and review of the literature

Vancomycin-resistant Enterococcus faecium (VR E. faecium) is a rare cause of meningitis and is associated with substantial mortality. Limited therapeutic options are available for the treatment of VR E. faecium meningitis. The optimum therapy has not been established. We retrospectively identified adult cases of meningitis due to VR E. faecium that occurred at the Massachusetts General Hospital from 1999 to 2011 and performed a literature search for published adult cases using Medline and Embase. At our institution, 4 cases of meningitis due to VR E. faecium were identified. Three out of our 4 cases were successfully treated with linezolid in combination with rifampicin, or with daptomycin in combination with quinupristin-dalfopristin (QD), and 1 out of 4 with linezolid monotherapy. The literature search yielded 18 cases published to date. Published cases showed bacterial cure with linezolid, chloramphenicol or QD (intravenous (IV) and intrathecal (IT)) monotherapy, or linezolid in combination with ampicillin, gentamicin, rifampicin or chloramphenicol, or daptomycin in combination with gentamicin or QD. Bacterial cure of meningitis due to VR E. faecium can be achieved with various antimicrobial drugs used as monotherapy or in combination. IT in addition to IV therapy should be considered dependent on the pharmacological properties of the drugs. We also reported the successful treatment of a case with a vancomycin-resistant, linezolid-intermediate isolate with QD and daptomycin. The paucity of cases with this clinical syndrome does not allow the identification of an optimal treatment regimen.

β-Lactams Increase the Antibacterial Activity of Daptomycin against Clinical Methicillin-Resistant Staphylococcus aureus Strains and Prevent Selection of Daptomycin-Resistant Derivatives

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged to be one of the most important pathogens both in health care and in community-onset infections. Daptomycin (DAP) is a cyclic anionic lipopeptide recommended for treatment of skin infections, bacteremia, and right-sided endocarditis caused by MRSA. Resistance to DAP (DAP(r)) has been reported in MRSA and is mostly accompanied by a parallel decrease in oxacillin resistance, a process known as the "seesaw effect." Our study provides evidence that the seesaw effect applies to other β-lactams and carbapenems of clinical use, including nafcillin (NAF), cefotaxime (CTX), amoxicillin-clavulanic (AMC), and imipenem (IMP), in heterogeneous DAP(r) MRSA strains but not in MRSA strains expressing homogeneous β-lactam resistance. The antibacterial efficacy of DAP in combination with β-lactams was evaluated in isogenic DAP-susceptible (DAP(s))/Dap(r) MRSA strains originally obtained from patients that failed DAP monotherapy. Both in vitro (MIC, synergy-kill curve) and in vivo (wax worm model) approaches were used. In these models, DAP and a β-lactam proved to be highly synergistic against both heterogeneous and homogeneous clinical DAP(r) MRSA strains. Mechanistically, β-lactams induced a reduction in the cell net positive surface charge, reverting the increased repulsion provoked by DAP alone, an effect that may favor the binding of DAP to the cell surface. The ease of in vitro mutant selection was observed when DAP(s) MRSA strains were exposed to DAP. Importantly, the combination of DAP and a β-lactam prevented the selection of DAP(r) variants. In summary, our data show that the DAP-β-lactam combination may significantly enhance both the in vitro and in vivo efficacy of anti-MRSA therapeutic options against DAP(r) MRSA infections and represent an option in preventing DAP(r) selection in persistent or refractory MRSA infections.

Daptomycin Therapy for Vancomycin-Resistant Enterococcus Bacteremia in Neutropenic Patients With Hematologic Malignancies and Hematopoietic Cell Transplantation Recipients

Background: Vancomycin-resistant Enterococcus fascium (VRE) are rapidly emerging nosocomial pathogens in the United States and worldwide. Vancomycin resistance is recognized to be an independent risk factor for increased morbidity and mortality among patients with enterococcal bloodstream infections (BSI); thus, early appropriate therapy is vital in improving outcomes. We report our experience in treating VRE BSI in patients with hematologic malignancies with daptomycin, a cyclic lipopeptide antibiotic with bactericidal activity against VRE. Methods: We performed retrospective chart review for patients with hematologic malignancies treated with daptomycin for a VRE BSI from January 2005 to May 2009. Patients were assessed for microbiological cure and survival. Patients were identified using a computerized clinical microbiology laboratory records. Results: Of 74 patients with a VRE BSI, 40 patients (31 male patients; median age, 61 years) met criteria and were included in the study. In this series, 35.6% of the patients had received a hematopoietic stem cell transplant, and 57.8% of the patients were neutropenic. Vancomycinresistant Enterococcus BSI occurred at a median of 20 days (4Y109 days) of neutropenia among these patients. The patients were treated with daptomycin monotherapy (62.5%) or daptomycin plus other antimicrobial(s) (37.5%). For those who were successfully treated with daptomycin alone, the median duration of therapy was 9 days (1Y36 days). Overall, 92.3% of the patients achieved a microbiological cure, which was evident at a median of 1 day (1Y16 days) after the initiation of therapy. Conclusion: Daptomycin is an effective agent for the treatment of VRE BSI. For both daptomycin monotherapy or combination therapy, we would recommend an intravenous dose of 8 mg/kg once daily for 10 to 14 days.

Addition of Ceftaroline to Daptomycin after Emergence of Daptomycin-Nonsusceptible Staphylococcus aureus during Therapy Improves Antibacterial Activity

Antistaphylococcal beta-lactams enhance daptomycin activity and have been used successfully in combination for refractory methicillin-resistant Staphylococcus aureus (MRSA) infections. Ceftaroline possesses MRSA activity, but it is unknown if it improves the daptomycin potency comparably to other beta-lactams. We report a complex patient case of endocarditis who was treated with daptomycin in combination with ceftaroline, which resulted in clearance of a daptomycin-nonsusceptible strain. An in vitro pharmacokinetic/pharmacodynamic model of renal failure was used to simulate the development of daptomycin resistance and evaluate the microbiologic effects of daptomycin plus ceftaroline treatment. Combination therapy with daptomycin and ceftaroline restored daptomycin sensitivity in vivo and resulted in clearance of persistent blood cultures. Daptomycin susceptibility in vitro was increased in the presence of either ceftaroline or oxacillin. Daptomycin at 6 mg/kg of body weight every 48 h was bactericidal in the model but resulted in regrowth and daptomycin resistance (MIC, 2 to 4 μg/ml) with continued monotherapy. The addition of ceftaroline at 200 mg every 12 h after the emergence of daptomycin resistance enhanced bacterial killing. Importantly, daptomycin plus ceftaroline as the initial combination therapy produced rapid and sustained bactericidal activity and prevented daptomycin resistance. Both in vivo- and in vitro-derived daptomycin resistance resulted in bacteria with more fluid cell membranes. After ceftaroline was added in the model, fluidity was restored to the level of the initial in vivo isolate. Daptomycin-resistant isolates required high daptomycin exposures (at least 10 mg/kg) to optimize cell membrane damage with daptomycin alone. Ceftaroline combined with daptomycin was effective in eliminating daptomycin-resistant MRSA, and these results further justify the potential use of daptomycin plus beta-lactam therapy for these refractory infections.

Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus Vertebral Osteomyelitis Cases Complicated by Bacteremia Treated with High-Dose Daptomycin and Trimethoprim-Sulfamethoxazole

We report two cases of daptomycin (DAP)-nonsusceptible (DNS) vancomycin-intermediate Staphylococcus aureus (VISA) vertebral osteomyelitis cases complicated by bacteremia treated with high-dose daptomycin and trimethoprim-sulfamethoxazole. Both patients responded rapidly and favorably to this combination. The clinical isolates from the two patients were tested post hoc in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model to confirm the bactericidal activity and enhancement of daptomycin and trimethoprim-sulfamethoxazole. The combination of high-dose daptomycin and trimethoprim-sulfamethoxazole should be explored further for the treatment of DNS VISA strains.

Activity of linezolid and high-dose daptomycin, alone or in combination, in an in vitro model of Staphylococcus aureus biofilm

The aim of the study was to assess the in vitro activity of linezolid and daptomycin, alone and in combination, against three Staphylococcus aureus isolates using a pharmacokinetic/pharmacodynamic (PK/PD) model of biofilm for 3 days. One non-clinical methicillin-resistant S. aureus isolate (N315) and two clinical methicillin-resistant S. aureus isolates were evaluated. Simulated regimens included high-dose daptomycin (10 mg/kg once daily) and linezolid (600 mg twice daily), alone and in combination. Against all three strains, neither linezolid nor daptomycin alone was bactericidal against biofilm-embedded bacteria (BB). Against planktonic bacteria (PB) only daptomycin was bactericidal. In contrast, the combination of linezolid and daptomycin demonstrated greater activity than either of the two agents alone, being bactericidal against both PB and BB, almost reaching the limit of detection at 72 h. In this in vitro PK/PD model of mature biofilms, a combination of linezolid plus daptomycin was more effective than each agent alone, representing another potential option to treat S. aureus biofilm-associated infections.

In vitro activities of antimicrobial cationic peptides; melittin and nisin, alone or in combination with antibiotics against Gram-positive bacteria

The in vitro activities of two antimicrobial cationic peptides, melittin and nisin alone and in combination with frequently used antibiotics (daptomycin, vancomycin, linezolid, ampicillin, and erythromycin), were assessed against clinical isolates of methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus and Enterococcus faecalis. Using the broth microdilution method, minimum inhibitory concentration (MIC) ranges of melittin and nisin against all strains were 2–8 μg/ml and 2–32 μg/ml respectively. In combination studies performed with the microdilution checkerboard method using a fractional inhibitory concentration index of ⩽0·5 as borderline, synergistic interactions occurred more frequently with nisin–ampicillin combination against MSSA and nisin–daptomycin combination against E. faecalis strains. The results of the time-killing curve analysis demonstrated that the concentration dependent rapid bactericidal activity of nisin, and that synergism or early synergism was detected in most strains when nisin or melittin was used in combination with antibiotics even at concentrations of 0·5×MIC.

Vancomycin-Resistant Enterococcus faecium (VRE) Bacteremia in Infective Endocarditis Successfully Treated with Combination Daptomycin and Tigecycline

(2011). Vancomycin-Resistant Enterococcus faecium (VRE) Bacteremia in Infective Endocarditis Successfully Treated with Combination Daptomycin and Tigecycline. Journal of Chemotherapy: Vol. 23, No. 4, pp. 240-241.

Treatment of Cardiovascular Implantable Electronic Device Infection with Daptomycin

We describe a case of 83-year-old man who was admitted to our department for treatment of recurrent device-pocket infections. Our report shows that in a case of high-risk patient with a complicated cardiac implantable electric devices infection involving multidrug-resistent gram-positive pathogen, the application of daptomycin in combination with staged surgical therapy can be efficient and safe.

Antibiotic Combinations with Daptomycin for Treatment of Staphylococcus aureus Infections

Daptomycin is a lipopeptide antibiotic with a unique mechanism of action on Gram-positive bacteria. It is approved for treatment of skin and soft-tissue infections with Gram-positive bacteria, bacteraemia and right-sided infective endocarditis caused by Staphylococcus aureus. Diminishing susceptibility of S. aureus to daptomycin during treatment of complicated infections and clinical failure have been described. Combinations of daptomycin with other antibiotics including gentamicin, rifampin, beta-lactams, trimethoprim/sulfamethoxazole (TMP-SMX), or clarithromycin present a new approach for therapy. In vitro and animal studies have shown that such combinations may, in some cases, be superior to daptomycin monotherapy. In this paper we focus on the antibiotic combinations for complicated S. aureus infections.

Vancomycin-Resistant Enterococcus faecium Meningitis Successfully Treated With Daptomycin in Combination With Doxycycline and Linezolid

Vancomycin-Resistant Enterococcus faecium Meningitis Successfully Treated With Daptomycin in Combination With Doxycycline and Linezolid