Novel cyclic lipopeptides with different acyl tails were synthesized via a semisynthetic approach. Structure activity relationship studies revealed that lipophilicity, chain length, and the location of key aromatic functionalities of the tail modulated activity. The lead compound surotomycin exhibited significantly improved in vitro activity compared with daptomycin (MIC90 0.5 vs 2 mu g/mL) against Clostridium difficile including NAP1 epidemic strains. In hamster efficacy studies, surotomycin protected animals at a dose of 0.5 mg/kg, PO.

ABSTRACT Surotomycin (CB-183,315) is an orally administered, minimally absorbed, selective bactericidal cyclic lipopeptide in phase 3 development for the treatment of Clostridium difficile -associated diarrhea. The aim of this study was to evaluate the emergence of resistance in C. difficile (ATCC 700057 and three recent clinical isolates from the restriction endonuclease analysis groups BI, BK, and K), vancomycin-susceptible (VS) Enterococcus faecalis (ATCC 49452), vancomycin-resistant (VR) E. faecalis (ATCC 700802), VS Enterococcus faecium (ATCC 6569), and VR E. faecium (ATCC 51559) under anaerobic conditions. The rate of spontaneous resistance was below the limit of detection (<10 −8 to <10 −9 ) for surotomycin at 16 and 32× the MIC for all isolates tested. Under selective pressure by serial passage, C. difficile grew in a maximum of 4 μg/ml surotomycin (final MICs of 2 to 8 μg/ml [4- to 16-fold higher than those of the naive control]) at day 15, with the exception of the C. difficile BK strain, which grew in 16 to 32 μg/ml (final MICs of 8 to 32 μg/ml [16- to 64-fold higher than those of the naive control]). Enterococci remained relatively unchanged over 15 days, growing in a maximum of 8 μg/ml surotomycin (final MICs of 2 to 16 μg/ml [8- to 64-fold higher than those of the naive control]). Of the isolates tested, no cross-resistance to vancomycin, rifampin, ampicillin, metronidazole, or moxifloxacin was observed. Surotomycin at 20× MIC demonstrated equally rapid bactericidal activity (≥3-log-unit reduction in CFU/ml in ≤8 h) against naive and reduced-susceptibility isolates of C. difficile , VS Enterococcus (VSE), and VR Enterococcus (VRE), except for C. difficile BK (2.6-log-unit reductions for both). These results suggest that emergence of resistance to surotomycin against C. difficile , E. faecalis , and E. faecium is likely to be rare.

Background: Tedizolid is a novel oxazolidinone antibacterial with potent activity against a wide range of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Although tedizolid is approved by the US Food and Drug Administration (FDA) for treatment of patients with acute bacterial skin and skin structure infection, commercial susceptibility testing products for tedizolid are not currently available. This study evaluated the usefulness of applying linezolid susceptibility test results as a surrogate for predicting susceptibility to tedizolid in clinically significant Gram-positive pathogens.Methods: Gram-positive isolates (N = 10,702) were obtained from annual surveillance programs conducted between 2009 and 2012, from 3 tedizolid clinical trials, and from a preclinical study of the antibacterial activity of tedizolid. Susceptibility testing of linezolid and tedizolid was performed using the reference broth microdilution method in accordance with Clinical and Laboratory Standards Institute methods.Results: The minimum inhibitory concentration (MIC) distribution for tedizolid and linezolid against this set of isolates was consistent with that of previous reports. Scatter plot analysis of relevant subsets of organisms was performed and showed high categorical agreement between linezolid and tedizolid MIC results (>99% for staphylococci and streptococci; >98% for enterococci). Very major error rates (ie, tedizolid false-susceptible errors) were very low and within acceptable limits for a surrogate agent: S. aureus and other staphylococcal species, 0%; Enterococcus spp, 0.2%; and Streptococcus spp, 0%.Conclusions: High categorical agreement between MIC values for tedizolid and linezolid and low very major error rates were shown for all organism groups tested, supporting the use of linezolid as a reliable surrogate for tedizolid susceptibility testing.

Daptomycin has been available as a gram-positive antimicrobial agent in the United States for over 6 years, and during this time there have been developments in daptomycin susceptibility testing. Daptomycin has a unique requirement for calcium; consequently, a standard calcium concentration is needed when performing in vitro testing. The calcium levels in broth and agar are presented, and with the exception of calcium-adjusted Mueller-Hinton broth, demonstrate variation between types and manufacturers. The reference methodology for daptomycin MIC testing is broth microdilution utilizing Mueller-Hinton broth with 50 μg/ml of calcium. Daptomycin is available in several commercial testing systems, which have been shown to be comparable to the reference method. Specific MICs from several Etest studies have been compared to broth microdilution MICs, and essential agreements were 79.1 to 100% (Staphylococcus aureus) and 66.7 to 100% (enterococci). The performance of routine quality control is especially important for in vitro testing of daptomycin, and validation of nonsusceptible daptomycin MICs is recommended.

MIC testing was performed simultaneously by Etest and broth microdilution (BMD) on 587 Staphylococcus aureus isolates submitted by local laboratories to a reference laboratory for confirmatory testing (May 2005 to July 2008). Testing bias was assessed for Etest to BMD MIC ratios. Categoric and essential agreement, very major (BMD nonsusceptible, Etest susceptible), and major (BMD susceptible, Etest nonsusceptible) errors were evaluated. Agar and broth calcium concentrations were consistent with current Clinical and Laboratory Standards Institute and manufacturer recommendations. There was a consistent bias for higher Etest MIC values compared with BMD. Ratios ranged from 0.25 to 4 (average 1.3), with substantial variability noted among the 8 different Etest lots tested. Overall, 6% of all ratios were >2.0. Categoric agreement and essential agreement among the 8 Etest lots ranged from 73% to 96% and 74% to 100%, respectively; very major errors ranged from 3% to 9%, and major errors ranged from 6% to 35%. However, most of the discrepancies were limited to 3 Etest lots.

This review summarizes the in vitro and animal model data available on antibiotic combinations with daptomycin. The majority of studies focus on the clinically relevant combinations of daptomycin with rifampicin or with gentamicin. These studies demonstrate that daptomycin does not adversely affect the activity of other antimicrobial agents that may be administered concomitantly. Overall, additive or indifferent effects with daptomycin combinations were observed; however, synergy was observed for certain isolates of vancomycin-resistant enterococci when exposed to daptomycin and rifampicin. Unexpected synergy was demonstrated against methicillin-resistant Staphylococcus aureus by daptomycin and beta-lactams. Most importantly, no in vitro antagonism of daptomycin with any other agent tested was confirmed in these studies. The most striking in vivo effects were noted in two different complicated infection models; i.e. osteomyelitis and implant infections, where rifampicin combinations with daptomycin increased efficacy and reduced the incidence of rifampicin resistance.

The in vitro activity of daptomycin was evaluated against 360 multidrug-resistant Staphylococcus aureus isolates (including hospital-acquired isolates) and multidrug-susceptible community-acquired methicillin-resistant S. aureus with known virulence genes. All isolates were inhibited at <= 1 mu g/mL, suggesting that daptomycin has excellent activity against both hospital-acquired and community-acquired S. aureus isolates. (C) 2008 Elsevier Inc. All rights reserved.

Two prediffusion methods with daptomycin (DAP) Neo-Sensitabs were evaluated against a challenge set of 30 Staphylococcus aureus isolates and 30 enterococci. DAP Neo-Sensitabs were prediffused for either 8 or 20 h on Mueller-Hinton agar. Inhibition zones were plotted versus Etest MIC values determined on the same prediffused agar. A generalization to the genus level of the manufacturer's suggested Neo-Sensitabs breakpoints for staphylococci and enterococci was used to interpret the results. DAP-susceptible and DAP-nonsusceptible enterococci, Enterococcus faecium in particular, were not reliably discriminated using a 20-h prediffusion method and the manufacturer's suggested breakpoints. Further development of this testing methodology, such as changing the format to a susceptibility screen followed by a confirmatory MIC, is needed to accurately categorize the DAP susceptibility of enterococcal isolates. Prediffusion for either 8 or 20 h with DAP Neo-Sensitabs discriminated between susceptible and nonsusceptible S. aureus with minimal errors. Both prediffusion methods also detected changes in MIC values between isogenic pairs of susceptible and nonsusceptible S. aureus. These results suggest that a multisite evaluation of either prediffusion method with DAP Neo-Sensitabs against a larger collection of S. aureus is warranted.

OBJECTIVE:We sought to compare daptomycin with ceftriaxone for the treatment of patients with community-acquired pneumonia (CAP).METHODS:Two phase-3 randomized, double-blind trials that enrolled adult patients hospitalized with CAP were conducted. Patients received intravenous daptomycin (4 mg/kg) or ceftriaxone (2 g) once daily for 5-14 days. Aztreonam could be added for patients with gram-negative infections. Clinical responses at the test-of-cure visit among patients in the intent-to-treat and clinically evaluable populations were the primary efficacy end points.RESULTS:After combining data from the trials, the intent-to-treat population included 413 daptomycin-treated patients and 421 ceftriaxone-treated patients, and the clinically evaluable population included 369 daptomycin-treated patients and 371 ceftriaxone-treated patients. In the intent-to-treat population, the clinical cure rate among daptomycin-treated patients with CAP was 70.9%, compared with 77.4% among ceftriaxone-treated patients (95% confidence interval for the difference between cure rates, -12.4% to -0.6%). In the clinically evaluable population, the clinical cure rate was lower among daptomycin-treated patients (79.4%) than among ceftriaxone-treated patients (87.9%; 95% confidence interval for the difference between cure rates, -13.8% to -3.2%). A posthoc analysis revealed that, among those who had received up to 24 h of prior effective therapy, cure rates were similar among daptomycin-treated (90.7%) and ceftriaxone-treated patients (88.0%; 95% confidence interval for the difference between cure rates, -6.1% to 11.5%).CONCLUSIONS:Daptomycin is not effective for the treatment of CAP, including infections caused by Streptococcus pneumoniae and Staphylococcus aureus. The observation that as little as 24 h of prior effective therapy may impact clinical outcome suggests that trials to evaluate CAP treatment may need to exclude patients who have received any potentially effective therapy before enrollment.

An initiative was taken to determine the in vitro activity of daptomycin against 85 Gram-positive isolates with reduced susceptibilities to linezolid and quinupristin/dalfopristin. Daptomycin had potent activity against all strains, with a Staphylococcus spp. minimum inhibitory concentration (MIC) ≤2μg/mL and an Enterococcus spp. MIC ≤8μg/mL. Resistance to linezolid and quinupristin/dalfopristin appears to be independent of reduced susceptibility to daptomycin.

ABSTRACT Daptomycin is a novel cyclic lipopeptide that is approved by the U.S. Food and Drug Administration for the treatment of complicated skin and skin structure infections associated with Staphylococcus aureus and other gram-positive pathogens and also staphylococcal bacteremia, including right-sided endocarditis. The Clinical and Laboratory Standards Institute (CLSI) established “susceptible-only” interpretive criteria for broth microdilution (BMD) and disk diffusion (DD) testing of daptomycin in 2005. However, a series of S. aureus isolates have been recovered with daptomycin MICs in the nonsusceptible range (i.e., MICs of >1 μg/ml). The objective of this study was to determine the ability of the Etest and DD methods to differentiate daptomycin-susceptible from nonsusceptible isolates of S. aureus compared to the results of the CLSI BMD reference method. There was a good correlation between Etest MIC results and the results of BMD among laboratories (r = 0.86 to 0.88), with 95.3% of the Etest MICs within a ±1 log2 dilution of the BMD MIC result. A total of 92 of 102 (90.2%) non-daptomycin-susceptible isolates of S. aureus identified by BMD in two participating laboratories were also classified as nonsusceptible by Etest. However, the very major and major error rates reported by one of the participating laboratories were 13.5 and 4.0%, respectively, primarily due to the absence of an intermediate category. The DD method, however, did not reliably differentiate daptomycin-susceptible from non-daptomycin-susceptible isolates. In 2005, daptomycin disks were voluntarily removed from the market by Cubist Pharmaceuticals. The disk diffusion breakpoints were subsequently removed from the CLSI M100 standard in 2006.

OBJECTIVES:To evaluate the activity of daptomycin tested against numerous species of viridans group streptococci and Streptococcus bovis, which are associated with wound infections, sepsis, cellulitis, endocarditis, abscesses and dental caries. The incidence of penicillin-resistant (non-susceptible) and MLS(B)-resistant strains among viridans group streptococci often varies by species.METHODS:The activity of daptomycin was compared with seven other antimicrobial classes using reference broth microdilution and disc diffusion methods tested against 915 bacteraemic isolates of streptococci (815 viridans group strains; 100 S. bovis).RESULTS:Among all species of viridans group streptococci and S. bovis, 99.9% of isolates were susceptible to daptomycin (MIC values, < or = 0.016-2 mg/L). In contrast, penicillin, erythromycin and tetracycline susceptibility varied widely between species. Erythromycin susceptibility was in the range 48.6-88.7%, penicillin susceptibility in the range 65.5-98.1% and tetracycline in the range 35.0-93.9%. The inter-method agreement between daptomycin and linezolid resistance (comparison agent) disc diffusion and broth microdilution test results was high, each showing near complete susceptibility (99.9%).CONCLUSIONS:Daptomycin is an active antimicrobial agent that has a usable potency against eight species of viridans group streptococci, as well as S. bovis, with all MIC values at < or =2 mg/L.

Infections caused by drug-resistant pathogens are on the rise. Daptomycin, a cyclic lipopeptide with activity against most Gram-positive pathogens, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus, is a newly US-FDA approved antimicrobial for complicated skin and skin structure infections (cSSSI). Daptomycin has a unique mechanism of action that results in destruction of the membrane potential. The rapid bactericidal activity of daptomycin makes it an attractive antibiotic for serious Gram-positive infections.

ABSTRACTDaptomycin efficacy against clinical isolates ofEnterococcus faecalis,Enterococcus faecium, and a lab-derived daptomycin-resistant isolate ofE. faecaliswas investigated in a mouse model of renal infection. The daptomycin MICs against these enterococci ranged from 0.5 to 50 μg/ml. The objective of this study was to determine the relationship between the MICs of drugs againstE. faecalisandE. faeciumand the level of daptomycin exposure needed to evaluate the drug's efficacy. Correlating the required therapeutic exposures of mice with the exposures achieved clinically allowed us to project enterococcal breakpoint values. Mice pretreated with carrageenan were infected intravenously with 3 × 108to 4 × 108CFU ofE. faecalisorE. faecium. Daptomycin (5 to 50 mg of drug/kg of body weight) or saline control was administered 4 h postinfection and continued once daily for 2 days (three total doses). On day 4, infected kidneys were harvested, homogenized, and dilution plated. Efficacy was defined as a ≥2-log10(99%) reduction in bacterial burden in infected kidneys. At clinically relevant dosages and exposures (area under the curve, 400 to 600 μg · hr/ml), daptomycin demonstrated similar and marked efficacy against all clinical enterococcal isolates tested. Daptomycin achieved efficacy with comparable doses against both vancomycin-sensitive (MIC, ≤4 μg/ml) and -resistant enterococcal strains tested. Efficacy was also established against the lab-derived daptomycin-resistantE. faecalisisolate. In this murine renal infection model, clinically relevant exposures of daptomycin were effective againstE. faecalisandE. faeciumstrains for which MICs were ≤8 μg/ml. These murine efficacy data for daptomycin, along with surveillance data and human pharmacokinetic exposures achieved, suggest a breakpoint concentration value of ≤8 μg/ml (susceptible) and ≥16 μg/ml (resistant) for daptomycin againstE. faeciumandE. faecalis.

Daptomycin is a novel lipopeptide antibiotic with rapid in vitro bactericidal against activity virtually all gram-positive pathogens. The spectrum of activity includes methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, vancomycin-resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumoniae. Daptomycin has a unique mechanism of action, and there is no cross-resistance with any other drug class. Daptomycin is a natural product derived from the fermentation of Streptomyces roseosporus. Daptomycin is administered intravenously and produces linear pharmacokinetics with an elimination half-life of approximately 8 h in humans. Daptomycin has demonstrated efficacy against drug-susceptible and drug-resistant gram-positive infections in a variety of animal models. Phase 3 studies with a once-daily dosage are under way to study the efficacy of daptomycin against serious infections by gram-positive bacteria, including skin and soft tissue infections, community-acquired pneumonia, and VRE infections.

Inability to Detect Respiratory Syncytial Virus in Peripheral Blood Mononuclear Cells of Infants with Bronchiolitis † 893

Pediatric PulmonologyVolume 26, Issue 5 p. 365-369 Case Report Parvovirus B19-associated interstitial lung disease, hepatitis, and myositis Athos Bousvaros MD, Athos Bousvaros MD Combined Program in Gastroenterology and Nutrition, Children's Hospital, Harvard Medical School, Boston, MassachusettsSearch for more papers by this authorRobert Sundel MD, Robert Sundel MD Division of Rheumatology, Children's Hospital, Boston, MassachusettsSearch for more papers by this authorGrace M. Thorne PhD, Grace M. Thorne PhD Division of Infectious Disease, Children's Hospital, Boston, MassachusettsSearch for more papers by this authorKenneth McIntosh MD, Kenneth McIntosh MD Division of Infectious Disease, Children's Hospital, Boston, MassachusettsSearch for more papers by this authorMark Cohen MD, Mark Cohen MD Acton Medical Associates, Acton, MassachusettsSearch for more papers by this authorDean D. Erdman DrPH, Dean D. Erdman DrPH Division of Viral and Rickettsial Diseases, National Center for Infectious Disease, Centers for Disease Control and Prevention, Atlanta, GeorgiaSearch for more papers by this authorAntonio Perez-Atayde MD, Antonio Perez-Atayde MD Department of Pathology, Children's Hospital, Boston, MassachusettsSearch for more papers by this authorTerri H. Finkel MD, PhD, Terri H. Finkel MD, PhD Division of Rheumatology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, ColoradoSearch for more papers by this authorAndrew A. Colin MD, Corresponding Author Andrew A. Colin MD [email protected] Division of Respiratory Diseases, Children's Hospital, Boston, MassachusettsDivision of Respiratory Diseases, Mailstop 208, Children's Hospital, 300 Longwood Ave., Boston, MA 02115Search for more papers by this author Athos Bousvaros MD, Athos Bousvaros MD Combined Program in Gastroenterology and Nutrition, Children's Hospital, Harvard Medical School, Boston, MassachusettsSearch for more papers by this authorRobert Sundel MD, Robert Sundel MD Division of Rheumatology, Children's Hospital, Boston, MassachusettsSearch for more papers by this authorGrace M. Thorne PhD, Grace M. Thorne PhD Division of Infectious Disease, Children's Hospital, Boston, MassachusettsSearch for more papers by this authorKenneth McIntosh MD, Kenneth McIntosh MD Division of Infectious Disease, Children's Hospital, Boston, MassachusettsSearch for more papers by this authorMark Cohen MD, Mark Cohen MD Acton Medical Associates, Acton, MassachusettsSearch for more papers by this authorDean D. Erdman DrPH, Dean D. Erdman DrPH Division of Viral and Rickettsial Diseases, National Center for Infectious Disease, Centers for Disease Control and Prevention, Atlanta, GeorgiaSearch for more papers by this authorAntonio Perez-Atayde MD, Antonio Perez-Atayde MD Department of Pathology, Children's Hospital, Boston, MassachusettsSearch for more papers by this authorTerri H. Finkel MD, PhD, Terri H. Finkel MD, PhD Division of Rheumatology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, ColoradoSearch for more papers by this authorAndrew A. Colin MD, Corresponding Author Andrew A. Colin MD [email protected] Division of Respiratory Diseases, Children's Hospital, Boston, MassachusettsDivision of Respiratory Diseases, Mailstop 208, Children's Hospital, 300 Longwood Ave., Boston, MA 02115Search for more papers by this author First published: 07 January 1999 https://doi.org/10.1002/(SICI)1099-0496(199811)26:5<365::AID-PPUL11>3.0.CO;2-4Citations: 22AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Heegaard ED, Hornsleth A. 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The spectrum of disease caused by parvovirus B19 has been expanding in recent years because of improved and more sensitive methods of detection. There is evidence to suggest that chronic infection occurs in patients who are not detectably immunosuppressed. We report the case of a young woman with recurrent fever and a syndrome indistinguishable from chronic fatigue syndrome. After extensive investigation, we found persistent parvovirus B19 viremia, which was detectable by polymerase chain reaction (PCR) despite the presence of IgM and IgG antibodies to parvovirus B19. Testing of samples from this patient suggested that in some low viremic states parvovirus B19 DNA is detectable by nested PCR in plasma but not in serum. The patient's fever resolved with the administration of intravenous immunoglobulin.