Activity of Telavancin against Staphylococcus aureus Isolates, Including Those with Decreased Susceptibility to Ceftaroline, from Cystic Fibrosis Patients

Roch, Mélanie; Varela, Maria Celeste; Taglialegna, Agustina; Rose, Warren E.; Rosato, Adriana E.

doi:10.1128/aac.00956-18

Cited by 6 publications

(2 citation statements)

References 28 publications

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“…Although neither 10 mg/kg nor higher doses of 12.5 mg/kg or 750 mg achieved optimal PTA for those MICs above the susceptibility breakpoint in adults with CF, this is unlikely to be clinically relevant. In a collection of 333 S. aureus strains cultured from patients with CF, 100% had a telavancin MIC of less than or equal to 0.06 mg/liter (28), which a 10-mg/kg dose is predicted to adequately treat even if any of these MICs were underestimated by 1 doubling dilution. Attempts to overcome telavancin resistance (MIC Ͼ 0.12 mg/liter) by using doses above 12.5 mg/kg would necessarily increase the chances of reaching the toxicity threshold AUC of 763 mg • h • liter Ϫ1 associated with AKI beyond 12.2% (17), creating an unacceptable risk of a serious adverse event while providing little to no benefit.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation

Kidd

Sakon

Oleksiuk

et al. 2019

Antimicrob Agents Chemother

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Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus. Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92 ± 0.76 liters · kg−1; CLNR, 0.59 ± 0.30 liters · h−1; CLθ, 5.97 × 10−3 ± 1.24 × 10−3; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h−1. The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter−1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.)

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation

Kidd

Sakon

Oleksiuk

et al. 2019

Antimicrob Agents Chemother

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“… 1 , 2 Despite the continuous improvement of effective antimicrobial and patient care conditions, many cases of S. aureus bacteremia or sepsis with significant morbidity and mortality have been reported worldwide. 3 , 4 With the widespread use or even misuse of antibacterial agents, S. aureus has shown the resistance to a broad range of antibiotics, such as vancomycin and daptomycin. In particular, the widespread emergence of multidrug-resistant S. aureus and methicillin-resistant S. aureus (MRSA) has resulted in a limited number of therapeutic options against S. aureus infections increasingly.…”

Section: Introductionmentioning

confidence: 99%

Resistance Profiles and Biological Characteristics of Rifampicin-Resistant Staphylococcus aureus Small-Colony Variants

Zheng¹,

Fang²,

Wang³

et al. 2021

IDR

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Background Staphylococcus aureus ( S. aureus ) is a major contributor to nosocomial and community-acquired infections. S. aureus small colony variants (SCVs) which changed in relevant phenotype have made more limited and difficult for therapeutic options against S. aureus infections increasingly. Rifampicin is considered as the “last-resort” antibiotic against S. aureus . Our study investigated resistance profiles and biological characteristics of rifampicin-resistant S. aureus SCVs. Methods We collected S. aureus SCVs that were selected from 41 rifampicin-resistant clinical isolates. Then, biological characteristics, resistance spectrum, and rifampicin resistance mechanisms of tested S. aureus SCVs and corresponding parental strains were investigated by classic microbiological methods, agar dilution method, polymerase chain reaction (PCR). Moreover, the fitness cost of S. aureus SCVs, including growth, biofilm formation ability, and virulence profile, was also determined by bacterial growth curve assay, biofilm formation assay, and Galleria mellonella infection model. Results There were three S. aureus SCVs (JP310 SCVs, JP1450 SCVs, JP1486 SCVs) that were selected from 41 rifampicin-resistant S. aureus. S. aureus SCVs colonies were tiny, with decreased pigmentation, and the hemolysis circle was not obvious compared with corresponding parental strains. And SCVs could not be restored to normal-colony phenotype after hemin, menaquinone, or thymidine supplementation. Different rpoB mutations occurred in JP1486 SCVs. Antimicrobial susceptibility testing revealed MICs of SCVs were higher than corresponding parental strains. Besides, the growth ability and virulence of SCVs were lower, and biofilm formation ability of which increased compared with parental strains. Conclusion S. aureus SCVs share the rifampicin resistance mechanisms with parental strains, although there were some differences in the position of rpoB mutations. Moreover, we found that the biological characteristics of SCVs were significantly different from corresponding parental strains. In contrast, decreased susceptibility to other antibiotics of SCVs was observed during phenotype switch. Furthermore, SCVs incur the fitness cost.

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Methicillin-Resistant Staphylococcus aureus Infection and Treatment Options

Chalmers

Wylam

2019

Methods in Molecular Biology

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Activity of Telavancin against Staphylococcus aureus Isolates, Including Those with Decreased Susceptibility to Ceftaroline, from Cystic Fibrosis Patients

Cited by 6 publications

References 28 publications

Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation

Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation

Resistance Profiles and Biological Characteristics of Rifampicin-Resistant Staphylococcus aureus Small-Colony Variants

Methicillin-Resistant Staphylococcus aureus Infection and Treatment Options

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