Staphylococcus aureus Persisters Tolerant to Bactericidal Antibiotics.

Sept 2012

Lechner S, Lewis K, Bertram R.

Source

Interfakultäres Institut für Mikrobiologie und Infektionsmedizin, Lehrbereich Mikrobielle Genetik, Eberhard Karls Universität Tübingen, Tübingen, Germany.

Abstract

Bacterial persister cells are non- or slow-growing reversible phenotypic variants of the wild type, tolerant to bactericidalantibiotics. We analyzed here Staphylococcus aureus persister levels by monitoring colony-forming unit counts of planktonically grown cells treated with six different antimicrobials over time. The model laboratory strains HG001-HG003, SA113 and the small colony variant (SCV) strains hemB and menD were challenged by the compounds at different logs of minimal inhibitory concentration (MIC) in exponential or stationary growth phase. 

Antibiotic tolerance was usually elevated in SCV strains compared to normally growing cells and in stationary versus exponential phase cultures. Biphasic killing kinetics, typical for persister cell enrichment, were observed in both growth phases under different selective conditions. Treatment of exponential phase cultures of HG001-HG003 with 10-fold MIC of tobramycin resulted in the isolation of persisters which upon cultivation on plates formed either normal or phenotypically stable small colonies. Trajectories of different killing curves indicated physiological heterogeneity within persister subpopulations.

Daptomycin added at 100-fold MIC to stationary phase SA113 cells rapidly isolated very robust persisters. Fractions of antibiotic-tolerant cells were observed with all S. aureus strains and mutants tested. Our results refute the hypothesis that S. aureus stationary phase cells are equivalent to persisters, as not all of these cells showed antibiotic tolerance. Isolation of S. aureus persisters of different robustness seems to depend on the kind and concentration of the antibiotic, as well as on the strain used.

Karger

Comparative antibacterial effects of daptomycin, vancomycin and teicoplanin studied in an in vitro pharmacokinetic model of infection.

Comparative antibacterial effects of daptomycin, vancomycin and teicoplanin studied in an in vitro pharmacokinetic model of infection
J Antimicrob Chemother. 2009 Sep 16

Bowker KE, Noel AR, Macgowan AP.
Bristol Centre for Antimicrobial Research and Evaluation (BCARE), Department of Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK.

* Corresponding author. Tel: +44-(0)1179-9595654; Fax: +44-(0)117-9593217; E-mail: karen.bowker@nbt.nhs.uk

Objectives
To compare the antibacterial effects (ABEs) of the free (f) drugs daptomycin, vancomycin and teicoplanin against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), using high and low inocula in a pharmacokinetic in vitro model. To determine the daptomycin fAUC/MIC ratio for a static effect and 3 log reduction in viable count and relate this target to the clinical breakpoint.

Methods
Five clinical MRSA isolates held at Southmead Hospital were used (SMH 15841, SMH 40289, SMH 40275, SMH 33922 and SMH 33024) together with a VRSA isolate (SMH 19898); inocula of 10(6) and 10(8) cfu/mL were used. Daptomycin (6 mg/kg once daily), vancomycin (1 g twice daily) and teicoplanin (400 mg once daily) regimens were simulated. ABEs were measured using the 24 h area-under-the-bacterial kill curve (AUBKC) and log change in viable count at 24 h (Delta24). For daptomycin, dose escalation was used to determine the relationship between ABE and AUC/MIC.

Results
Daptomycin was bactericidal against the MRSA strains. Daptomycin and vancomycin were active against the VRSA strain; teicoplanin had a static effect. The higher inoculum reduced the ABEs. Analysis of variance (ANOVA) indicated that daptomycin had a superior ABE to teicoplanin and vancomycin. Daptomycin fAUC/MIC was related to AUBKC and Delta24; the fAUC/MIC ratios for a static effect and 1 log and 3 log drop were 37.2 +/- 16.5, 40.6 +/- 17.8 and 49.8 +/- 19.2, respectively.

Conclusions
These data define the fAUC/MIC sizes for daptomycin for bacteriostatic and bactericidal ABEs and indicate that a 6 mg/kg dose of daptomycin is superior to vancomycin and teicoplanin against MRSA and VRSA strains.

Antimicrobial Chemotherapy

Outpatient parenteral antibiotic therapy with daptomycin: insights from a patient registry

Outpatient parenteral antibiotic therapy with daptomycin: insights from a patient registry

Int J Clin Pract. 2008 Aug

Martone WJ, Lindfield KC, Katz DE.
Cubist Pharmaceuticals, Inc., Lexington, MA 02421, USA. william.martone@cubist.com

AIM: To compare and contrast the characteristics and clinical outcomes of patients who have received daptomycin as outpatients and inpatients.

METHODS: The Cubicin Outcomes Registry and Experience (CORE) is a retrospective chart review of patients who have received daptomycin in participating institutions. Patients treated in 2005 were included in this analysis. Demographic characteristics and clinical outcomes (success = cured + improved) were compared among patients who received outpatient parenteral antibiotic therapy (OPAT) and patients who had received inpatient parenteral antibiotic therapy (IPAT).

RESULTS: Of 1172 patients reported by 52 CORE 2005 participating institutions/investigators, 949 (81.0%) patients were evaluable: 539 (56.8%) received OPAT (OPAT patients), and 410 (43.2%) received only IPAT (IPAT patients). Of the 539 OPAT patients, 273 (50.6%) also received some IPAT, usually preceding OPAT therapy. Successful outcomes [no. of successes/(no. of successes + no. of failures)] for OPAT patients vs. IPAT patients were 94.6% and 86.3% respectively (chi-square test, p <>

CONCLUSIONS: Outpatient parenteral antibiotic therapy use was common (539/949 or 56.8%) among patients in CORE 2005. Clinical outcomes among OPAT patients appeared at least as good as or better than IPAT patients. Better outcomes among OPAT patients were most likely because of patient selection for OPAT. Additional studies should focus on clinical characteristics of patients who would be ideal candidates for daptomycin OPAT.

Wiley InterScience

Daptomycin in bone and joint infections: a review of the literature.

Daptomycin in bone and joint infections: a review of the literature.

Arch Orthop Trauma Surg. 2008 Nov 7

Rice DA, Mendez-Vigo L.
St. Joseph's/Candler Health System, Savannah, GA, USA.

INTRODUCTION: To review the pharmacology, pharmacokinetics, efficacy, and safety of daptomycin, a novel antibiotic for the treatment of bone and joint infections, a literature search of relevant articles was conducted.

MATERIALS AND METHODS: A PubMed/MEDLINE search (1990-April 2008) to identify relevant English-language literature was conducted. Search terms included bone and joint infection, osteomyelitis, daptomycin, and methicillin-resistant Staphylococcus aureus (MRSA). Additional articles were identified by reviewing the bibliographies of articles cited. Programs and abstracts from infectious disease meetings were searched, and prescribing information of antibiotics indicated for bone and joint infections consulted. All articles identified from data sources published in English were evaluated.

RESULTS: Caused primarily by Gram-positive pathogens such as S. aureus and, to a lesser extent, Enterococcus faecalis, bone and joint infections are difficult to treat successfully. Surgical intervention and prolonged courses of antibiotics are frequently required, and failure of first-line antibiotic therapy is common. The emergence of S. aureus strains with reduced susceptibility to vancomycin, the longstanding gold standard for bone and joint infections, has complicated the clinical scenario. Few randomized trials comparing the efficacy of different antibiotics for bone and joint infections exist. Daptomycin, a novel intravenous lipopeptide antibiotic, has shown potent in vitro activity against a broad spectrum of Gram-positive bacteria, including many resistant pathogens commonly associated with bone and joint infections such as MRSA and vancomycin-resistant E. faecalis. Early clinical investigation of daptomycin in bone and joint infections unresponsive to antibiotics, such as vancomycin, has found a cure rate of approximately 80%, with a low incidence of adverse events and drug resistance.

CONCLUSION: Further studies are warranted to determine if limited clinical evidence, described in individual case reports and a daptomycin-specific retrospective registry, suggests daptomycin is a promising option for patients with bone and joint infections such as MRSA osteomyelitis.

Springerlink

Prevention of Brain Injury by Daptomycin in Experimental Pneumococcal Meningitis.

Prevention of Brain Injury by the Non Bacteriolytic Antibiotic Daptomycin in Experimental Pneumococcal Meningitis.
Antimicrob Agents Chemother. 2007 Mar 19

Grandgirard D,
Schurch C,
Cottagnoud P,
Leib SL.
Institute for Infectious Diseases, University of Bern, Switzerland, Department of Internal Medicine; and Clinic for Infectious Diseases, University Hospital, Inselspital, Bern, Switzerland.

Background: Bacteriolytic antibiotics cause the release of bacterial components that augment the host inflammatory response which in turn contributes to the pathophysiology of brain injury in bacterial meningitis. In the present study in experimental pneumococcal meningitis, antibiotic therapy with non-bacteriolytic daptomycin vs. bacteriolytic ceftriaxone was evaluated for an effect on inflammation and brain injury.

Methods: Eleven day old rats were injected intracisternally with 1.3 +/- 0.5 x 10(4) colony forming units (cfu) of Streptococcus pneumoniae serotype 3 and randomized for therapy with ceftriaxone (100 mg/kg s.c., n=55) or daptomycin (50 mg/kg s.c., n=56) starting at 18 h after infection. Cerebrospinal fluid was assessed for bacterial count, matrix metalloprotease-9 and TNF-alpha at different time intervals after infection. Cortical brain damage was evaluated at 40 h after infection.

Results: Daptomycin vs. ceftriaxone cleared bacteria more efficiently from the CSF within two hours after initiation of therapy (log10 3.6+/-1.0 vs. log10 6.3+/-1.4 cfu/ml, P<0.02),>

Conclusion: Compared to ceftriaxone, daptomycin cleared bacteria more rapidly from the CSF and caused less CSF inflammation. This combined effect provides an explanation for the observation that daptomycin prevented the development of cortical brain injury in experimental pneumococcal meningitis.

Further research is needed to investigate whether non-bacteriolytic antibiotic therapy with Daptomycin represents an advantageous alternative over current bacteriolytic antibiotics for the therapy of pneumococcal meningitis.

PMID: 17371820 [PubMed - as supplied by publisher]