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PubMed2004

Daptomycin: a cyclic lipopeptide antimicrobial agent.

OBJECTIVES: The aims of this article were: to summarize the pharmacology, pharmacokinetics, and efficacy of daptomycin; to explore its safety profile; and to discuss its current and potential roles as an antimicrobial therapy. METHODS: A literature search was conducted using the MEDLINE (1966-August 2004) and International Pharmaceutical Abstracts (1970-August 2004) databases with the search terms daptomycin, LY146032, and lipopeptide antibiotics. Abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy and documents submitted to the US Food and Drug Administration were also reviewed. RESULTS: Phase III study results suggest no difference in efficacy or tolerability between daptomycin 4 mg/kg IV QD and vancomycin or semisynthetic penicillins for complicated skin and skin-structure infections. Animal studies suggest daptomycin may be useful for the treatment of endocarditis. Daptomycin is not indicated for pneumonia, with poorer outcomes than conventional treatment It is available as an IV medication and exhibits 92% plasma protein binding in vitro. In healthy adult humans, daptomycin has a volume of distribution of 0.1 L/kg and a plasma elimination half-life of approximately 9 hours, and is eliminated primarily by renal excretion (approximately 54%). In patients with reduced renal function, including those receiving hemodialysis and peritoneal dialysis, the dose interval should be 48 hours. No dosage adjustment appears to be necessary for mild to moderate hepatic impairment. The use of daptomycin in patients with severe hepatic impairment has not been assessed. The most commonly reported adverse events include constipation, nausea, injection-site reactions, headache, and diarrhea. Patients should also be monitored regularly for skeletal muscle toxicity. CONCLUSIONS: Daptomycin may be useful for complicated skin and skin-structure infections and gram-positive pathogens resistant to conventional antimicrobials. However, limited data are currently available for duration of treatment beyond 14 days and at doses >4 mg/kg QD.

Animals↗
PubMed2004

Release of daptomycin from polymethylmethacrylate beads in a continuous flow chamber.

Because daptomycin is active against Gram-positive cocci, it may be useful in the treatment and prevention of bone and joint infections when incorporated into polymethylmethacrylate (PMMA). The release kinetics of daptomycin from PMMA were studied in a continuous flow chamber designed to simulate in vivo conditions. Three-millimeter beads containing 2.5%, 7.5%, and 15.0% daptomycin (weight daptomycin per weight PMMA) were individually placed in a chamber with 1 mL Krebs Ringer buffer flowing at 1 mL/hour. The majority of daptomycin was released in the first 24 hours. The mean peak concentrations were 13.4, 62.3, and 146.7 microg/mL; the mean AUC0-infinity were 30, 272, and 1204 h x microg/mL; and the mean percentages of daptomycin released were 6%, 18%, and 42% for the beads containing 2.5%, 7.5%, and 15.0% daptomycin, respectively. Daptomycin is released from PMMA in a continuous flow chamber at a rate similar to that previously determined by our laboratory for vancomycin.

Anti-Bacterial Agents↗
PubMed2004

Antimicrobial activity of daptomycin against multidrug-resistant Gram-positive strains collected worldwide.

Daptomycin is a cyclic lipopeptide recently released for clinical use in the treatment of serious Gram-positive infections in hospitalized patients. We evaluated the in vitro activity of daptomycin tested against recently isolated multidrug-resistant Gram-positive clinical strains. A total of 386 isolates were selected from a large collection of strains from more than 70 centers located in Europe, North America, and South America. The strains were tested by reference broth microdilution methods in Mueller-Hinton broth with 50 mg/L Ca++ against daptomycin. Daptomycin was the most potent compound tested against penicillin-resistant Streptococcus pneumoniae with MIC50/90 values at < or =0.12 and 0.25 microg/mL, respectively. Daptomycin was also highly active against vancomycin-resistant enterococci and staphylococcal strains with various resistance patterns. Enterococcus faecium showed higher daptomycin MIC values (MIC90, 4 microg/mL) when compared to E. faecalis (MIC90, 1 microg/mL). In summary, resistance to vancomycin, teicoplanin, quinupristin/dalfopristin, or penicillin among the Gram-positive isolates did not adversely influence daptomycin activity. Daptomycin showed a significant potency and spectrum against Gram-positive species, including multidrug-resistant strains, and may represent a reasonable therapeutic option for infections caused by these important pathogens.

Anti-Bacterial Agents↗
PubMed2003

Daptomycin against multiple drug-resistant staphylococcus and enterococcus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations.

Daptomycin is a lipopeptide antibiotic that exhibits bactericidal activity against Gram-positive bacteria. In pursuit of potential clinical dosing regimens for endocarditis, we evaluated two, once-daily daptomycin regimens against multiple, drug-resistant Gram-positive pathogens. Daptomycin susceptibility was determined in the absence and presence of physiologic concentrations of albumin. An in vitro pharmacodynamic model with simulated endocardial vegetations incorporating protein was used to simulate regimens of daptomycin at 6 and 8 mg/kg/day and vancomycin at 1 g every 12 h against methicillin-resistant S. aureus (MRSA-67 and 494) and S. epidermidis (MRSE-R227 and R617), glycopeptide-intermediate S. aureus and S. epidermidis (GISA-992 and GISE-12333), and vancomycin-resistant E. faecium (VREF-SF12047 and 12366). Bacterial quantification occurred over 72 h. Daptomycin MIC results for study isolates in the absence or presence of albumin ranged from 0.125 to 4 and 1 to 8, respectively. Both daptomycin regimens achieved greater than 99.9% kill by 8 h and demonstrated greater bacterial reduction than vancomycin against all tested isolates at 24, 48, and 72 h (p < 0.05). Undetectable limits of bacterial quantification was achieved and maintained by 8 mg/kg/day against MRSA-494 and 67, GISA-992, and VREF-590 for the study duration. Although slight regrowth was noted only for 6 mg/kg/day against MRSA-67, 99.9% kill was maintained throughout the study period without development of resistance. Pharmacodynamic profiles and drug exposure of daptomycin at 6 mg/kg/day corresponds to previously reported AUC/MIC requirements. These results suggest that 6 and 8 mg/kg/day of daptomycin represent potential regimens for further clinical evaluation in drug-resistant Gram-positive endocarditis.

Anti-Bacterial Agents↗
PubMed2006

Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to daptomycin and vancomycin in an in vitro dynamic model.

OBJECTIVES: To extend the mutant selection window (MSW) hypothesis to include antibiotics in addition to fluoroquinolones, the pharmacodynamics of daptomycin (DAP) and vancomycin (VAN) and their ability to prevent the selection of resistant Staphylococcus aureus were studied in an in vitro model that simulates antibiotic concentrations below the MIC, between the MIC and the mutant prevention concentration (MPC), and above the MPC. METHODS: Two clinical isolates of S. aureus, S. aureus 866 (MIC(DAP) 0.35, MIC(VAN) 0.7, MPC(DAP) 1.1, MPC(VAN) 2.4 mg/L) and S. aureus 10 (MIC(DAP) 1.1, MIC(VAN) 1.3, MPC(DAP) 5.5, MPC(VAN) 11 mg/L), were exposed for five consecutive days to once-daily daptomycin (half-life 9 h) and twice-daily vancomycin (half-life 6 h) at the ratio of 24 h area under the concentration-time curve (AUC24) to MIC that varied over a 16- to 30-fold range. The cumulative antimicrobial effect was expressed by its intensity (I(E)). Changes in susceptibility and numbers of surviving organisms on agar plates containing 2x and 4x MIC of daptomycin or vancomycin were monitored daily. RESULTS: The I(E)-log AUC24/MIC plots were bacterial strain- and antibiotic-independent. This allowed combination of data obtained with both antibiotics and both organisms. Based on the sigmoid relationship between I(E) and the AUC24/MIC (r2 = 0.9), the antistaphylococcal effect of the therapeutic doses of daptomycin (4 and 6 mg/kg) against a hypothetical S. aureus with MIC equal to the MIC90 (AUC24/MIC90 380 and 570 h, respectively) was predicted to be similar to the effect of two 1 g doses of vancomycin given at a 12 h interval (AUC24/MIC90 200 h). AUC24/MIC relationships of the final-to-initial MIC ratio and logarithm of the ratio of maximal-to-initial numbers of organisms resistant to 2x and 4x MIC of daptomycin or vancomycin were bell-shaped and bacterial strain- and antibiotic-independent. Based on these relationships, an AUC24/MIC ratio that protects against the selection of resistant mutants was predicted at > or = 200 h. This protective value is less than the AUC24/MIC90s provided by the 4 mg/kg dose and considerably less than the 6 mg/kg dose of daptomycin, but it is close to the AUC24/MIC90 provided by two 1 g doses of vancomycin. CONCLUSIONS: These findings support the MSW hypothesis and suggest comparable antistaphylococcal effects of clinically achievable AUC24/MIC90s of daptomycin and vancomycin but slightly better prevention against the selection of resistant S. aureus by daptomycin.

Anti-Bacterial Agents↗
PubMed2006

The efficacy and safety of daptomycin: first in a new class of antibiotics for Gram-positive bacteria.

In the face of increasing resistance to currently available antibiotics, there is a continued interest in the development of new drugs to treat Gram-positive infections. One such agent is the cyclic lipopeptide daptomycin-licensed in the USA for treatment of Gram-positive complicated skin and skin structure infections (cSSSIs) in 2003 and currently awaiting European approval for a similar indication (complicated skin and soft tissue infections). Daptomycin exerts its rapid bactericidal effect through insertion into and subsequent depolarisation of the bacterial cell membrane, a mode of action unlike that of any other available antibiotic. This novel mechanism of action makes the development of cross-resistance between daptomycin and other antibiotic classes unlikely. Daptomycin is highly active in vitro against a range of Gram-positive pathogens, including both susceptible and multidrug-resistant staphylococci and enterococci. Bactericidal activity has also been demonstrated against both growing and stationary-phase organisms, suggesting potential utility in the treatment of deep-seated infections. Two pivotal clinical studies comparing daptomycin 4 mg/kg per day intravenously with vancomycin or oxacillin-class antibiotics demonstrated the efficacy of daptomycin for treatment of cSSSIs. Daptomycin was well tolerated, with most adverse events considered to be unrelated to study medication, of mild-to-moderate intensity, and with a frequency and distribution similar to those associated with comparator antibiotics. The favourable clinical profile and low potential for development of resistance combine to make daptomycin a promising alternative to current agents for treatment of Gram-positive bacterial infections.

Anti-Bacterial Agents↗
PubMed2006

In vitro activities of daptomycin, vancomycin, and penicillin against Clostridium difficile, C. perfringens, Finegoldia magna, and Propionibacterium acnes.

Daptomycin has in vitro activity against gram-positive anaerobic bacteria, although limited numbers of species have been tested. We studied the in vitro activities of daptomycin, vancomycin, and penicillin against more than 100 strains each of Clostridium difficile, C. perfringens, Finegoldia magna, and Propionibacterium acnes. Daptomycin Etest MICs and results from time-kill studies were determined for selected strains. For 392 of 421 strains (93%), daptomycin was inhibitory at < or =1 microg/ml, including 15 of 16 strains of C. difficile with elevated linezolid MICs of 8 and 16 microg/ml, all 32 strains with moxifloxacin MICs of > or =4 microg/ml, and all 16 strains resistant to clindamycin. Daptomycin MICs were also < or =1 microg/ml for all 16 F. magna strains resistant to clindamycin and all 32 strains resistant to tetracycline. Only one strain, a C. perfringens strain, had a MIC of >2 microg/ml to daptomycin. Eighty-five and 92.5% of the Etest MICs were within 1 dilution of the agar dilution method for all drugs at 24 and 48 h, respectively. In time-kill studies, a C. difficile strain was inhibited by both daptomycin and vancomycin at 1, 2, 4, 8, and 24 h; colony counts were decreased by 2.3 to 2.9 log at 24 h. Vancomycin was not bactericidal for C. perfringens; however, daptomycin showed bactericidal activity as early as 1 h at four and eight times the MIC and at 2 and 4 h at two and four times the MIC.

Anti-Bacterial Agents↗
PubMed2006

Daptomycin bactericidal activity and correlation between disk and broth microdilution method results in testing of Staphylococcus aureus strains with decreased susceptibility to vancomycin.

A total of 207 Staphylococcus aureus strains, including 105 well-characterized strains with decreased susceptibility to vancomycin (17 vancomycin-intermediate S. aureus [VISA] and 88 heteroresistant VISA [hVISA] strains) and 102 wild-type methicillin-resistant S. aureus (MRSA-WT) strains were tested by reference/standardized broth microdilution and disk diffusion methods, as well as by Etest (AB BIODISK, Solna, Sweden), against daptomycin and vancomycin. The lowest concentration of antimicrobial agent that killed > or = 99.9% of the initial inoculum was defined as the minimum bactericidal concentration (MBC) endpoint, and time-kill curves were performed in selected strains to further evaluate bactericidal activity. All MRSA-WT and hVISA strains were inhibited by < or = 1 microg/ml of daptomycin, while the VISA strains showed slightly higher daptomycin MICs (range, 0.5 to 4 microg/ml). All daptomycin MBC results were at the MIC or twofold higher. In contrast, 14.7% of MRSA-WT, 69.3% of hVISA, and all VISA strains showed a vancomycin MBC/MIC ratio of > or = 32 or an MBC of > or = 16 microg/ml (tolerant). The correlation coefficients between broth microdilution and disk diffusion method results were low for daptomycin (0.07) and vancomycin (0.11). Eight (3.8%) strains (all hVISA or VISA) were "nonsusceptible" to daptomycin by broth microdilution methods but susceptible by the disk diffusion method. For vancomycin, 35 (16.9%) strains were nonsusceptible by broth microdilution methods but susceptible by disk diffusion methods. In conclusion, daptomycin was highly bactericidal against S. aureus strains, and its bactericidal activity was not affected by decreased susceptibility to vancomycin. In contrast, many (one in seven) contemporary MRSA-WT, the majority of hVISA, and all VISA strains showed vancomycin MBC/MIC ratios consistent with tolerance, a predictor of poor clinical response. Disk diffusion tests generally failed to detect strains categorized as nonsusceptible to daptomycin or vancomycin by the reference broth microdilution method or Etest, and reassessment of breakpoints should be immediately attempted for MIC methods suggested as the test of choice.

Anti-Bacterial Agents↗
PubMed1989

Ex vivo study of serum bactericidal titers and killing rates of daptomycin (LY146032) combined or not combined with amikacin compared with those of vancomycin.

Twelve volunteers, in two groups of six, received daptomycin at a dose of 1 or 2 mg/kg. In addition, they received in a randomly allocated order amikacin (500 mg), daptomycin-amikacin, and vancomycin (500 mg). Thirty-five clinical isolates, including Staphylococcus aureus, S. epidermidis, Corynebacterium sp. group JK, and Enterococcus faecalis, were tested in vitro for the measure of the serum bactericidal titers and killing rates. The mean peak concentrations of daptomycin in serum 1 h after the administration of 1 and 2 mg/kg were 11 and 20 micrograms/ml, respectively. At 24 h after the administration of 2 mg/kg, the mean level in serum was 1.9 micrograms/ml, which is higher than the MICs for susceptible pathogens. Daptomycin and amikacin provided identical concentrations in serum whether given alone or in combination. Among the six regimens tested, those including daptomycin provided the highest and the most prolonged serum bactericidal titers against S. aureus, S. epidermidis, and E. faecalis. The killing rates measured by the killing curves were correlated with the concentration/MIC and concentration/MBC ratios of daptomycin for all strains tested. Significant killing occurred once the concentration of daptomycin in the serum 4- to 6-fold the MIC or 1- to 1.2-fold the MBC. The combination of daptomycin and amikacin had no effect on either the serum bactericidal titers or the rates of killing. Only vancomycin provided significant killing of the strains of Corynebacterium sp. group JK.

Amikacin↗
PubMed1989

In vitro synergism between daptomycin and fosfomycin against Enterococcus faecalis isolates with high-level gentamicin resistance.

Daptomycin and fosfomycin are two agents which inhibit different steps in peptidoglycan synthesis. We studied the in vitro activities of these drugs, alone and in combination, by time-kill techniques against 21 clinical isolates of Enterococcus (Streptococcus) faecalis demonstrating high-level resistance to gentamicin. Combinations of fosfomycin and daptomycin exhibited synergistic bactericidal activity (100-fold decrease in CFU per milliliter at 24 h compared with daptomycin alone) against all strains (mean +/- standard deviation of increment in killing = 2.7 +/- 0.7 log10 CFU/ml). In a subgroup of strains against which daptomycin (5 micrograms/ml) alone was bactericidal (greater than 3 log10 killing), synergistic activity was demonstrable only when the concentration of daptomycin was lowered to 0.25 to 0.5 microgram/ml. A 50% dilution of human serum diminished the bactericidal activity of daptomycin alone at 24 h but did not affect killing observed with the daptomycin-fosfomycin combination. The inhibition of peptidoglycan synthesis by the combination was greater than the inhibition observed with either drug alone. The combination of daptomycin and fosfomycin exhibited consistent synergistic bactericidal activity against strains of E. faecalis possessing high-level resistance to gentamicin. This synergism may be the result of sequential inhibition of early steps in peptidoglycan synthesis.

Anti-Bacterial Agents↗
PubMed1990

Daptomycin compared with teicoplanin and vancomycin for therapy of experimental Staphylococcus aureus endocarditis.

The efficacies of daptomycin, teicoplanin, and vancomycin were compared in the therapy of experimental Staphylococcus aureus endocarditis. Rabbits infected with either of two methicillin-susceptible strains (SA-12871 or its moderately teicoplanin-resistant derivative SA-12873) or a methicillin-resistant S. aureus strain (MRSA-494) were treated with daptomycin, 8 mg/kg of body weight, every 8 h; teicoplanin, 12.5 mg/kg (low-dose teicoplanin [teicoplanin-LD], excluding MRSA-494) or 40 mg/kg (high-dose teicoplanin [teicoplanin-HD]) every 12 h; or vancomycin, 17.5 mg/kg every 6 h, for 4 days. Compared with no treatment daptomycin, teicoplamin-HD, and vancomycin significantly reduced bacterial counts of all test strains in vegetations and renal and splenic tissues (P less than 0.001). Teicoplanin-LD was equally effective against SA-12871 but failed against SA-12873, with three of six animals still being bacteremic at the end of therapy. For SA-12871, daptomycin was as effective as teicoplanin-HD and was superior to teicoplanin-LD and vancomycin (P = 0.02) in lowering vegetation bacterial counts. There were no differences between daptomycin, teicoplanin-HD, or vancomycin in the reduction of bacterial counts in tissues for any of the test strains. In rabbits infected with SA-12871, vegetations from 33% of teicoplanin-LD-treated, 6% of teicoplanin-HD-treated, and 13% of daptomycin-treated animals yielded organisms for which there were up to eightfold increases in the MICs. Resistance may have contributed to early death in one daptomycin-treated animal. No increases in the MICs for the test strain were detected in animals infected with SA-12873 or MRSA-494. We conclude that in this model and against these strains of S. aureus, daptomycin and teicoplanin-HD are as efficacious as vancomycin, but diminished susceptibility to both can develop during therapy.

Animals↗
PubMed2000

In vitro activities of daptomycin, arbekacin, vancomycin, and gentamicin alone and/or in combination against glycopeptide intermediate-resistant Staphylococcus aureus in an infection model.

Daptomycin, a lipopeptide antibiotic, has broad activity against gram-positive organisms, similar to vancomycin; however, its mechanism of action differs, resulting in interference with cell membrane transport and a more rapid bactericidal activity. In light of increasing need for alternative treatments against intermediate-resistant Staphylococcus aureus, there is revitalized interest in this antibiotic. We, therefore, evaluated the activity of daptomycin alone or in combination in an in vitro infection model against two glycopeptide intermediate-resistant S. aureus (GISA) isolates. Newly designed regimens of daptomycin at 4 and 6 mg/kg of body weight every 24 h (q24h) were compared to the previous regimen of 3 mg/kg q12h. Daptomycin MICs and minimal bactericidal concentrations (MBCs) (MIC/MBC) for Mu-50, HIP5836 (992), and MRSA-67 were 0.5/1.0, 0.5/1.0, and 0.125/0.5 microgram/ml, respectively. MICs and MBCs of arbekacin for the three strains were 2.0/8.0, 0. 125/0.5, and 0.125/0.25 microgram/ml, respectively. Vancomycin and gentamicin MICs and MBCs for the three strains were 8.0/8.0, 8.0/8.0, and 0.5/1.0 microgram/ml and 128/128, 0.5/1.0, and 0.25/0.5 microgram/ml, respectively. Our experience with daptomycin in an in vitro infection model has shown significant kill against the two GISA strains (Mu-50 and 992) (P < 0.03). We also noted that kill was related to a total dose effect for 992, in which simulated daptomycin in vivo dosages of 6 mg/kg q24h and 3 mg/kg q12h produced similar kill and 4 mg/kg q24h resulted in significant regrowth (P </= 0.05). Combination therapy with arbekacin resulted in synergistic activity against Mu-50. Daptomycin area under the concentration-time curve/MIC and C(max)/MIC ranges for GISA isolates were 80 to 116 and 6 to 12, respectively, and ranges for MRSA-67 were 320 to 461 and 24 to 48, respectively, and appeared to have an association with kill (i.e., decreased CFU/milliliter) at 24 and 48 h. Therefore, these experiments suggest that daptomycin alone or in combination could provide an alternative for the treatment of GISA.

Aminoglycosides↗
PubMed2001

Bactericidal activities of two daptomycin regimens against clinical strains of glycopeptide intermediate-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations.

Daptomycin is an investigational lipopeptide antibiotic active against gram-positive organisms. The mechanism of action is unique, resulting in interference with cell membrane transport. The bactericidal activity of daptomycin was evaluated against glycopeptide-intermediate susceptible Staphylococcus aureus (GISA), vancomycin-resistant Enterococcus faecium (VREF), and methicillin-resistant S. aureus (MRSA) in an in vitro infection model with simulated endocardial vegetations. Simulated regimens of daptomycin at 6 mg/kg/day (D6) and 10 mg/kg/day (D10) were utilized. MICs and MBCs for daptomycin were determined in the absence and in the presence of albumin with the following results (MIC/MBC): for GISA-992, 0.5/1.0 and 16/16; for VREF-590, 2.0/2.0 and 32/32; and for MRSA-494, 0.25/0.25 and 1.0/4.0 microg/ml, respectively. During the first 8 h daptomycin significantly reduced the inoculum for all organisms. Daptomycin at 6 mg/kg/day and 10 mg/kg/day had log(10) CFU/g reductions of 5 and 6, 3.4 and 5, and 6.4 and 6.5 by 8 h for GISA-992, VREF-590, and MRSA-494, respectively. Against both GISA-992 and VREF-590, the D10 regimen achieved the limit of detection at 72 h, with D6 regimens showing slight regrowth. A concentration-dependent killing effect was noted to occur, with daptomycin demonstrating a more rapid and greater kill from the D10 versus the D6 regimen. The results of this study suggest that daptomycin demonstrates significant (P < 0.05) activity against gram-positive organisms in a simulated sequestered infection site.

Anti-Bacterial Agents↗
PubMed2002

In vitro and in vivo activities of tigecycline (GAR-936), daptomycin, and comparative antimicrobial agents against glycopeptide-intermediate Staphylococcus aureus and other resistant gram-positive pathogens.

Tigecycline (GAR-936) and daptomycin are potent antibacterial compounds in advanced stages of clinical trials. These novel agents target multiply resistant pathogenic bacteria. Daptomycin is principally active against gram-positive bacteria, while tigecycline has broad-spectrum activity. When tested by the standard protocols of the National Committee for Clinical Laboratory Standards in Mueller-Hinton broth II, tigecycline was more active than daptomycin (MICs at which 90% of isolates tested are inhibited, 0.12 to 1 and 0.5 to 16 microg/ml, respectively) against staphylococcal, enterococcal, and streptococcal pathogens. Daptomycin demonstrated a stepwise increase in activity corresponding to an increase in the supplemental concentration of calcium. When tested in base Mueller-Hinton broth supplemented with 50 mg of calcium per liter, daptomycin demonstrated improved activity (MIC(90)s, 0.015 to 4 microg/ml). The activity of daptomycin, however, equaled that of tigecycline against the glycopeptide-intermediate Staphylococcus aureus (GISA) strains only when the test medium was supplemented with excess calcium (75 mg/liter). Tigecycline and daptomycin demonstrated in vivo efficacies against GISA, methicillin-resistant S. aureus, and methicillin-susceptible S. aureus strains in an intraperitoneal systemic murine infection model. These data suggest that tigecycline and daptomycin may offer therapeutic options against clinically relevant resistant pathogens for which current alternatives for treatment are limited.

Animals↗
PubMed2006

Assessment of two commercial susceptibility test methods for determination of daptomycin MICs.

Daptomycin is a lipopeptide antibiotic with activity against several important gram-positive bacterial pathogens, including drug-resistant staphylococci and enterococci. Because the mechanism of action of daptomycin is calcium-dependent depolarization of the cell membrane, susceptibility testing requires medium supplemented with a physiological level of calcium. This study assessed two Food and Drug Administration-cleared commercial test devices for determination of daptomycin MICs, Etest and JustOne. A collection of 220 selected isolates, including Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, E. faecium, E. avium, E. durans, E. casseliflavus, and E. gallinarum, were tested by both methods. Included in the collection were 22 S. aureus and 14 Enterococcus sp. isolates that were recovered from patients and were nonsusceptible on the basis of the daptomycin MICs. As the reference method for comparison, all isolates were tested by the Clinical and Laboratory Standards Institute broth microdilution method incorporating cation-adjusted Mueller-Hinton broth with 50 microg/ml calcium. Daptomycin MICs agreed, within 1 twofold dilution, for 97% of the isolates by Etest and for 100% by JustOne. However, daptomycin MICs determined by Etest were 1 dilution lower than the reference MICs for 65% of the Enterococcus sp. isolates tested. This resulted in 28.5% very major (VM) errors (4/14) with enterococci (all E. faecium) but none (0/22) with staphylococci. Use of JustOne yielded MICs that were 1 dilution lower than the reference MICs for 69% of the staphylococci and 25% of the enterococci. This resulted in 13.6% VM errors (3/22) with staphylococci and 14.3% VM errors (2/14) with enterococci. The manufacturer-recommended JustOne inoculum preparation resulted in mean colony counts of only 5 x 10(4) to 1 x 10(5) CFU/ml in the wells of the strip. Increasing the inoculum to 3 x 10(5) to 4 x 10(5) CFU/ml eliminated two of five VM errors upon retesting. No major interpretive errors occurred with either device. In summary, daptomycin MICs generated by the Etest or JustOne method generally agreed within 1 dilution of the reference daptomycin MICs. However, both devices produced slightly lower MICs that resulted in some VM errors.

Anti-Bacterial Agents↗
PubMed2005

Daptomycin in vitro activity tested against Gram-positive strains collected from European and Latin American medical centers in 2003.

Daptomycin, a cyclic lipopeptide, was susceptibility tested against clinical bacterial isolates consecutively collected in hospitals located in Europe (4,731 strains) and Latin America (1,007 strains) in 2003 as part of a continuing surveillance program. The bacterial isolates tested were Gram-positive pathogens that included staphylococci, streptococci and enterococci. The isolates were tested for susceptibility using broth microdilution methods (broth with 50 mg/L Ca++ for testing daptomycin). All isolates, except two Enterococcus faecium strains from Europe, were inhibited at daptomycin MIC of < or = 4 mg/L. In addition, 99.4 and 97.3% of isolates were inhibited at daptomycin MIC of < or = 2 and < or = 1 mg/L, respectively. Except for one Staphylococcus aureus and one viridans group streptococci from Europe and one coagulase-negative staphylococci from Latin America, all staphylococcal and streptococcal isolates were inhibited by 1 mg/L of daptomycin. Resistance to other compounds (vancomycin, oxacillin, and penicillin) did not influence daptomycin activity. The activity of daptomycin was very similar in both geographic regions evaluated and demonstrated the same MIC distribution as isolates evaluated in studies in the United States. The results of this study showed that daptomycin continues to be very active against clinical isolates of Gram-positive cocci isolated in Europe and Latin America.

Anti-Bacterial Agents↗
PubMed2004

Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin.

Daptomycin is a cyclic anionic lipopeptide antibiotic recently approved for the treatment of complicated skin infections (Cubicin). Its function is dependent on calcium (as Ca2+). Circular dichroism spectroscopy indicated that daptomycin experienced two structural transitions: a transition upon interaction of daptomycin with Ca2+, and a further transition upon interaction with Ca2+ and the bacterial acidic phospholipid, phosphatidyl glycerol. The Ca2+-dependent insertion of daptomycin into model membranes promoted mild and more pronounced perturbations as assessed by the increase of lipid flip-flop and membrane leakage, respectively. The NMR structure of daptomycin indicated that Ca2+ induced a conformational change in daptomycin that increased its amphipathicity. These results are consistent with the hypothesis that the association of Ca2+ with daptomycin permits it to interact with bacterial membranes with effects that are similar to those of the cationic antimicrobial peptides.

Anti-Bacterial Agents↗
PubMed2005

Comparative in vitro activities of daptomycin, linezolid, and quinupristin/dalfopristin against Gram-positive bacterial isolates from a large cancer center.

Our objective was to evaluate and compare the in vitro activity of daptomycin, linezolid, and quinupristin/dalfopristin against clinical bloodstream isolates of Gram-positive pathogens from a large cancer center in the Northeastern United States. Minimum inhibitory concentrations (MICs) were determined for daptomycin, quinupristin/dalfopristin, and linezolid against 258 isolates; bactericidal activity was evaluated using time-kill experiments against 14 representative pathogens. Vancomycin-resistant enterococci represented the largest proportion of bacteria tested (32% of the isolates), followed by methicillin-resistant coagulase-negative staphylococci (23%), and vancomycin sensitive enterococci (14%). Against staphylococci, the MIC90 was 1 microg/mL for both daptomycin and quinupristin/dalfopristin and 4 microg/mL for linezolid. Against enterococci, the MIC90 for both daptomycin and linezolid was 4 microg/mL and was 16 microg/mL for quinupristin/dalfopristin. The quinupristin/dalfopristin MIC90 for Enterococcus faecium was 2 microg/mL. Two enterococci were linezolid resistant and remained susceptible to daptomycin. In vitro time-kill studies found daptomycin to be rapidly bactericidal against the majority of organisms tested, killing 99.9% of bacteria within 6 h. Quinupristin/dalfopristin was bactericidal against staphylococci and bacteriostatic against most enterococci. Linezolid was bacteriostatic against all organisms evaluated. Daptomycin, quinupristin/dalfopristin, and linezolid each demonstrated in vitro activity against this collection of organisms. Future clinical studies to evaluate a potential role for these agents in the management of infections in cancer patients, including the treatment of febrile neutropenia, appear warranted.

Acetamides↗