Teicoplanin pharmacodynamics in reference to the accessory gene regulator (agr) in Staphylococcus aureus using an in vitro pharmacodynamic model

2008 ◽  
Vol 61 (5) ◽  
pp. 1099-1102 ◽  
Author(s):  
W. E. Rose ◽  
G. W. Kaatz ◽  
G. Sakoulas ◽  
M. J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Pharmacodynamic Model ◽  
Accessory Gene ◽  
Accessory Gene Regulator

scholarly journals Evaluation of Accessory Gene Regulator (agr) Group and Function in the Proclivity towards Vancomycin Intermediate Resistance in Staphylococcus aureus

2006 ◽  
Vol 51 (3) ◽  
pp. 1089-1091 ◽  
Author(s):  
Brian T. Tsuji ◽  
Michael J. Rybak ◽  
Kerry L. Lau ◽  
George Sakoulas
Keyword(s):  
Staphylococcus Aureus ◽  
Wild Type ◽  
Accessory Gene ◽  
Time Curve ◽  
Unbound Fraction ◽  
Accessory Gene Regulator ◽  
Intermediate Resistance ◽  
And Function ◽  
Type Strains

ABSTRACT Simulated therapeutic vancomycin exposures were evaluated against agr wild-type and knockout Staphylococcus aureus groups I, II, III, and IV using an in vitro pharmacodynamic model. All agr groups developed intermediate resistance to vancomycin after subtherapeutic exposure. The free unbound fraction of the area under the concentration-time curve (fAUC/MIC) required to suppress resistance was fourfold higher (P < 0.001) in agr dysfunctional strains (112 to 169) than that in parent wild-type strains (28).

scholarly journals Accessory Gene Regulator (agr) Locus in Geographically Diverse Staphylococcus aureus Isolates with Reduced Susceptibility to Vancomycin

2002 ◽  
Vol 46 (5) ◽  
pp. 1492-1502 ◽  
Author(s):  
George Sakoulas ◽  
George M. Eliopoulos ◽  
Robert C. Moellering ◽  
Christine Wennersten ◽  
Lata Venkataraman ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Parent Strain ◽  
Point Mutations ◽  
Loss Of Function ◽  
Accessory Gene ◽  
Accessory Gene Regulator ◽  
Geographic Origins ◽  
Group Ii ◽  
Null Strain

ABSTRACT The majority of infections with glycopeptide intermediate-level resistant Staphylococcus aureus (GISA) originate in biomedical devices, suggesting a possible increased ability of these strains to produce biofilm. Loss of function of the accessory gene regulator (agr) of S. aureus has been suggested to confer an enhanced ability to bind to polystyrene. We studied agr in GISA, hetero-GISA, and related glycopeptide-susceptible S. aureus isolates. All GISA strains from diverse geographic origins belong to agr group II. All GISA strains were defective in agr function, as demonstrated by their inability to produce delta-hemolysin. Hetero-GISA isolate A5940 demonstrated a nonsense mutation in agrA that was not present in a pulsed-field gel electrophoresis-indistinguishable vancomycin-susceptible isolate from the same patient. Various other agr point mutations were noted in several clinical GISA and hetero-GISA isolates. A laboratory-generated agr-null strain demonstrated a small but reproducible increase in vancomycin heteroresistance after growth in vitro in subinhibitory concentrations of vancomycin. This was not seen in the isogenic agr group II parent strain in which agr was intact. The in vitro bactericidal activity of vancomycin was attenuated in the agr-null strain compared to the parent strain. These findings imply that compromised agr function is advantageous to clinical isolates of S. aureus toward the development of vancomycin heteroresistance, perhaps through the development of vancomycin tolerance.

Exploring the Role of Piperacillin and Tazobactam in Combination with Vancomycin against Methicillin-Resistant Staphylococcus aureus

Chemotherapy ◽  
2019 ◽  
Vol 64 (5-6) ◽  
pp. 233-237
Author(s):  
Thomas J. Dilworth ◽  
Daniel Sanchez ◽  
Beverly Anderson ◽  
Haedi DeAngelis ◽  
Renée-Claude Mercier
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Accessory Gene ◽  
Methicillin Resistant ◽  
Accessory Gene Regulator ◽  
Antibiotic Susceptibilities ◽  
Strain Type ◽  
Time Kill

Previous studies have demonstrated synergy between piperacillin (PIP)-tazobactam (TAZ) (TZP) and vancomycin (VAN) against methicillin-resistant Staphylococcus aureus (MRSA). However, it is unknown whether PIP and/or TAZ synergizes with VAN against MRSA. We sought to determine whether PIP and/or TAZ synergizes with VAN against MRSA in vitro. The activity of PIP and/or TAZ with and without VAN (1/2 the minimum inhibitory concentration) was tested against 5 clinical MRSA isolates using a 24-h time-kill methodology. Antibiotic susceptibilities, accessory gene regulator (agr) operon functionality, and US strain type were also determined for the isolates. The combination of VAN and TZP was bactericidal against 3/5 isolates and synergistic against 4/5 isolates tested. Neither PIP nor TAZ alone combined with VAN demonstrated a significant reduction in bacterial growth. The combination of TZP and VAN was less active against the lone isolate with agr dysfunction. In summation, the combination of VAN with both PIP and TAZ was required for synergy against MRSA. This antibiotic combination may not be effective against unique MRSA strain types.

scholarly journals Reduced Susceptibility of Staphylococcus aureus to Vancomycin and Platelet Microbicidal Protein Correlates with Defective Autolysis and Loss of Accessory Gene Regulator (agr) Function

2005 ◽  
Vol 49 (7) ◽  
pp. 2687-2692 ◽  
Author(s):  
George Sakoulas ◽  
George M. Eliopoulos ◽  
Vance G. Fowler ◽  
Robert C. Moellering ◽  
Richard P. Novick ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Treated Patient ◽  
Accessory Gene ◽  
Accessory Gene Regulator ◽  
Vancomycin Mics ◽  
Platelet Microbicidal Protein ◽  
Triton X ◽  
Level Resistance

ABSTRACT Loss of agr function, vancomycin exposure, and abnormal autolysis have been linked with both development of the GISA phenotype and low-level resistance in vitro to thrombin-induced platelet microbicidal proteins (tPMPs). We examined the potential in vitro interrelationships among these parameters in well-characterized, isogenic laboratory-derived and clinical Staphylococcus aureus isolates. The laboratory-derived S. aureus strains included RN6607 (agrII-positive parent) and RN6607V (vancomycin-passaged variant; hetero-GISA), RN9120 (RN6607 agr::tetM; agr II knockout parent), RN9120V (vancomycin-passaged variant), and RN9120-GISA (vancomycin passaged, GISA). Two serial isolates from a vancomycin-treated patient with recalcitrant, methicillin-resistant S. aureus (MRSA) endocarditis were also studied: A5937 (agrII-positive initial isolate) and A5940 (agrII-defective/hetero-GISA isolate obtained after prolonged vancomycin administration). In vitro tPMP susceptibility phenotypes were assessed after exposure of strains to either 1 or 2 μg/ml. Triton X-100- and vancomycin-induced lysis profiles were determined spectrophotometrically. For agrII-intact strain RN6607, vancomycin exposure in vitro was associated with modest increases in vancomycin MICs and reduced killing by tPMP, but no change in lysis profiles. In contrast, vancomycin exposure of agrII-negative RN9120 yielded a hetero-GISA phenotype and was associated with defects in lysis and reduced in vitro killing by tPMP. In the clinical isolates, loss of agrII function during prolonged vancomycin therapy was accompanied by emergence of the hetero-GISA phenotype and reduced tPMP killing, with no significant change in lysis profiles. An association was identified between loss of agrII function and the emergence of hetero-GISA phenotype during either in vitro or in vivo vancomycin exposure. In vitro, these events were associated with defective lysis and reduced susceptibility to tPMP. The precise mechanism(s) underlying these findings is the subject of current investigations.

scholarly journals Repression of the Staphylococcus aureus Accessory Gene Regulator in Serum and In Vivo

2002 ◽  
Vol 184 (4) ◽  
pp. 1095-1101 ◽  
Author(s):  
Jeremy M. Yarwood ◽  
John K. McCormick ◽  
Michael L. Paustian ◽  
Vivek Kapur ◽  
Patrick M. Schlievert
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Dna Microarrays ◽  
Expression Profiles ◽  
Rabbit Serum ◽  
Accessory Gene ◽  
Experimental Conditions ◽  
Accessory Gene Regulator

ABSTRACT Subgenomic DNA microarrays were employed to evaluate the expression of the accessory gene regulator (agr locus) as well as multiple virulence-associated genes in Staphylococcus aureus. Gene expression was examined during growth of S. aureus in vitro in standard laboratory medium and rabbit serum and in vivo in subcutaneous chambers implanted in either nonimmune rabbits or rabbits immunized with staphylococcal enterotoxin B. Expression of RNAIII, the effector molecule of the agr locus, was dramatically repressed in serum and in vivo, despite the increased expression of secreted virulence factors sufficient to cause toxic shock syndrome (TSS) in the animals. Statistical analysis and clustering of virulence genes based on their expression profiles in the various experimental conditions demonstrated no positive correlation between the expression of agr and any staphylococcal virulence factors examined. Disruption of the agr locus had only a minimal effect on the expression in vivo of the virulence factors examined. An effect of immunization on the expression of agr and virulence factors was also observed. These results suggest that agr activation is not necessary for development of staphylococcal TSS and that regulatory circuits responding to the in vivo environment override agr activity.

scholarly journals Activity of Gatifloxacin in an In Vitro Pharmacokinetic-Pharmacodynamic Model against Staphylococcus aureus Strains either Susceptible to Ciprofloxacin or Exhibiting Various Levels and Mechanisms of Ciprofloxacin Resistance

2006 ◽  
Vol 50 (6) ◽  
pp. 1931-1936 ◽  
Author(s):  
Boubakar B. Ba ◽  
Corinne Arpin ◽  
Céline Vidaillac ◽  
Arnaud Chausse ◽  
Marie-Claude Saux ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Goodness Of Fit ◽  
Reference Strain ◽  
Pharmacodynamic Model ◽  
Bacterial Killing ◽  
Β Phase ◽  
Ciprofloxacin Resistance ◽  
Total Elimination ◽  
Gram Positive Cocci

ABSTRACT Gatifloxacin (GAT) is a new 8-methoxy fluoroquinolone with enhanced activity against gram-positive cocci. Its activity was studied in an in vitro pharmacokinetic-pharmacodynamic model against five Staphylococcus aureus strains, either susceptible to ciprofloxacin or exhibiting various levels and mechanisms of ciprofloxacin (CIP) resistance: the ATCC 25923 reference strain (MICs of CIP and GAT: 0.5 and 0.1 μg/ml, respectively), its efflux mutant SA-1 (16 and 0.5 μg/ml; mutation in the norA promoter region), and three clinical strains, Sa2102 (2 and 0.2 μg/ml), Sa2667 (4 and 0.5 μg/ml), and Sa2669 (16 and 1 μg/ml), carrying mutations in the grlA (Ser80Tyr or Phe) and gyrA (Ser84Ala) quinolone resistance-determining regions (QRDRs) for Sa2669. Plasmatic pharmacokinetic profiles after daily 1-h perfusion of 400 mg for 48 h were accurately simulated. Thus, mean maximum concentration of drug in serum values for the two administration intervals were 5.36 and 5.80 μg/ml, respectively, and the corresponding half-life at β-phase values were 8.68 and 7.80 h (goodness of fit coefficient, >0.98). Therapeutic concentrations of GAT allowed the complete eradication of the susceptible strain within 12 h (difference between the bacterial counts at the beginning of the treatment and at a defined time: −2.18 at the 1-h time point [t 1] and −6.80 at t 24 and t 48; the bacterial killing and regrowth curve from 0 to 48 h was 30.2 h × log CFU/milliliter). However, mutants (M) with GAT MICs increased by 4- to 40-fold were selected from the other strains. They acquired mutations either supplementary (MSa2102 and MSa2667) or different (Ala84Val for MSa2669) in gyrA or in both gyrA and grlA QRDRs (MSA-1). MSa2667 additionally overproduced efflux system(s) without norA promoter modification. Thus, GAT properties should allow the total elimination of ciprofloxacin-susceptible S. aureus, but resistant mutants might emerge from strains showing reduced susceptibility to older fluoroquinolones independently of the first-step mutation(s).

scholarly journals Finding of Agr Phase Variants in Staphylococcus aureus

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Vishal Gor ◽  
Aya J. Takemura ◽  
Masami Nishitani ◽  
Masato Higashide ◽  
Veronica Medrano Romero ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Phase Variation ◽  
Accessory Gene ◽  
Content Type ◽  
Accessory Gene Regulator ◽  
Immune Mediated ◽  
A Minor ◽  
First Time ◽  
Phase Variants

ABSTRACT Staphylococcus aureus is an important human pathogen whose success is largely attributed to its vast arsenal of virulence factors that facilitate its invasion into, and survival within, the human host. The expression of these virulence factors is controlled by the quorum sensing accessory gene regulator (Agr) system. However, a large proportion of clinical S. aureus isolates are consistently found to have a mutationally inactivated Agr system. These mutants have a survival advantage in the host but are considered irreversible mutants. Here we show, for the first time, that a fraction of Agr-negative mutants can revert their Agr activity. By serially passaging Agr-negative strains and screening for phenotypic reversion of hemolysis and subsequent sequencing, we identified two mutational events responsible for reversion: a genetic duplication plus inversion event and a poly(A) tract alteration. Additionally, we demonstrate that one clinical Agr-negative methicillin-resistant S. aureus (MRSA) isolate could reproducibly generate Agr-revertant colonies with a poly(A) tract genetic mechanism. We also show that these revertants activate their Agr system upon phagocytosis. We propose a model in which a minor fraction of Agr-negative S. aureus strains are phase variants that can revert their Agr activity and may act as a cryptic insurance strategy against host-mediated stress. IMPORTANCE Staphylococcus aureus is responsible for a broad range of infections. This pathogen has a vast arsenal of virulence factors at its disposal, but avirulent strains are frequently isolated as the cause of clinical infections. These isolates have a mutated agr locus and have been believed to have no evolutionary future. Here we show that a fraction of Agr-negative strains can repair their mutated agr locus with mechanisms resembling phase variation. The agr revertants sustain an Agr OFF state as long as they exist as a minority but can activate their Agr system upon phagocytosis. These revertant cells might function as a cryptic insurance strategy to survive immune-mediated host stress that arises during infection.

scholarly journals Impact of agr Functionality on the Outcome of Patients with Methicillin-Susceptible Staphylococcus aureus Bacteremia

2021 ◽  
Author(s):  
Jeong Eun Lee ◽  
Shinwon Lee ◽  
Sohee Park ◽  
Soon O. Lee ◽  
Sun H. Lee
Keyword(s):  
Staphylococcus Aureus ◽  
Accessory Gene ◽  
Content Type ◽  
Accessory Gene Regulator ◽  
Staphylococcus Aureus Bacteremia ◽  
Mssa Infection

Few studies have examined the association between methicillin-susceptible Staphylococcus aureus (MSSA) infection and accessory gene regulator ( agr ) functionality. We evaluated the association between agr dysfunction and mortality in patients with MSSA bacteremia.

scholarly journals In VitroPharmacodynamics of Human Simulated Exposures of Ceftaroline and Daptomycin against MRSA, hVISA, and VISA with and without Prior Vancomycin Exposure

2013 ◽  
Vol 58 (2) ◽  
pp. 672-677 ◽  
Author(s):  
Amira A. Bhalodi ◽  
Mao Hagihara ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Staphylococcus Aureus ◽  
Body Weight ◽  
Sequential Therapy ◽  
Free Drug ◽  
Pharmacodynamic Model ◽  
Prior Exposure ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Infection

ABSTRACTThe effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistantStaphylococcus aureus(MRSA) have not been widely studied. Humanized free-drug exposures of vancomycin at 1 g every 12 h (q12h), ceftaroline at 600 mg q12h, and daptomycin at 10 mg/kg of body weight q24h were simulated in a 96-hin vitropharmacodynamic model against three MRSA isolates, including one heteroresistant vancomycin-intermediateS. aureus(hVISA) isolate and one VISA isolate. A total of five regimens were tested: vancomycin, ceftaroline, and daptomycin alone for the entire 96 h, and then sequential therapy with vancomycin for 48 h followed by ceftaroline or daptomycin for 48 h. Microbiological responses were measured by the changes in log10CFU during 96 h from baseline. Control isolates grew to 9.16 ± 0.32, 9.13 ± 0.14, and 8.69 ± 0.28 log10CFU for MRSA, hVISA, and VISA, respectively. Vancomycin initially achieved ≥3 log10CFU reductions against the MRSA and hVISA isolates, followed by regrowth beginning at 48 h; minimal activity was observed against VISA. The change in 96-h log10CFU was largest for sequential therapy with vancomycin followed by ceftaroline (−5.22 ± 1.2,P= 0.010 versus ceftaroline) and for sequential therapy with vancomycin followed by ceftaroline (−3.60 ± 0.6,P= 0.037 versus daptomycin), compared with daptomycin (−2.24 ± 1.0), vancomycin (−1.40 ± 1.8), and sequential therapy with vancomycin followed by daptomycin (−1.32 ± 1.0,P> 0.5 for the last three regimens). Prior exposure of vancomycin at 1 g q12h reduced the initial microbiological response of daptomycin, particularly for hVISA and VISA isolates, but did not affect the response of ceftaroline. In the scenario of poor vancomycin response for high-inoculum MRSA infection, a ceftaroline-containing regimen may be preferred.

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