<i>In Vitro</i>
            Activity of Ceftaroline against Staphylococcus aureus Isolates Collected in 2012 from Latin American Countries as Part of the AWARE Surveillance Program

Biedenbach, Douglas J.; Hoban, Daryl J.; Reiszner, E; Lahiri, S. C.; Alm, Richard A.; Sahm, Daniel F.; Bouchillon, S.; Ambler, Jane E.

doi:10.1128/aac.01833-15

Cited by 15 publications

(15 citation statements)

References 35 publications

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“…Significantly, it is perhaps the drug's most important and distinguishing feature within the class of beta-lactams, its activity against MRSA, that has been met with the most skepticism. In particular, concerns over the appropriateness of the currently recommended dosage of 600 mg twice daily for the treatment of infections caused by S. aureus isolates with MIC values above the current EUCAST breakpoint of 1 mg/liter (14) have been raised, given that CPT MIC 90 values of 2 mg/liter for MRSA have been reported in certain countries within Europe, in Latin America, and in Asia (15)(16)(17)(18)(19)(20). These concerns have driven the initiation of additional clinical trials evaluating an increased frequency of administration (every 8 h) and an extension of the duration of the intravenous infusion of the drug from 1 to 2 h as a potential future mode of administration for infections caused by less susceptible organisms.…”

Section: Discussionmentioning

confidence: 99%

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

Matzneller

Lackner

Lagler

et al. 2016

Antimicrob Agents Chemother

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bCeftaroline fosamil (CPT-F) is currently approved for use for the treatment of complicated skin and soft tissue infections and community-acquired pneumonia at 600 mg twice daily (q12h), but other dosing regimens are under evaluation. To date, very limited data on the soft tissue pharmacokinetics (PK) of the active compound, ceftaroline (CPT), are available. CPT concentrations in the plasma, muscle, and subcutis of 12 male healthy volunteers were measured by microdialysis after single and repeated intravenous administration of 600 mg CPT-F q12h or three times daily (q8h) in two groups of 6 subjects each. Relevant PK and PK/pharmacodynamic (PD) parameters were calculated and compared between groups. In plasma, the area under the concentration-time curve (AUC) from 0 to 24 h for total CPT and the cumulative percentage of the dosing interval during which the free drug concentrations exceeded the MIC (fT MIC ) for unbound CPT for the currently established threshold of 1 mg/liter were significantly higher in the group receiving CPT-F q8h. Exposure to free drug in soft tissues was higher in the group receiving CPT-F q8h, but high interindividual variability in relevant PK parameters was observed. The mean ratios of the AUC from time zero to the end of the dosing interval (AUC 0-) for free CPT in soft tissues and the AUC 0-for the calculated free fraction in plasma at steady state ranged from 0.66 to 0.75. Administration of CPT-F q8h led to higher levels of drug exposure in all investigated compartments. When MIC values above 1 mg/liter were assumed, the calculated fT MIC after dosing q12h was markedly lower than that after dosing q8h. The clinical implications of these differences are discussed in light of recently completed clinical phase III and PK/PD studies. Ceftaroline fosamil (CPT-F; brand names, Zinforo in Europe and Teflaro in the United States) was recently approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of complicated skin and soft tissue infections (cSSTIs) and community-acquired pneumonia (CAP) in adults. Ceftaroline (CPT) is a cephalosporin antibiotic and acts, like all beta-lactam agents, via inhibition of peptidoglycan synthesis. In contrast to other cephalosporins, CPT is active against some resistant microorganisms, such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-nonsusceptible Streptococcus pneumoniae (PNSP), and is therefore often referred to as a "fifth generation," or advanced-generation, cephalosporin. CPT-F, a water soluble N-phosphono prodrug, is converted to the active CPT in human plasma, and CPT is further converted into the inactive ring-opened metabolite CPT M-1.Although CPT-F was shown to be effective against both approved indications, CAP and cSSTIs (1-5), precise information regarding the pharmacokinetics (PKs) of CPT in the interstitial space fluid of soft tissues is very limited to date. However, this information is considered to be highly relevant as a key input for PK/pharmacodynamic (PD) cal...

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Section: Discussionmentioning

confidence: 99%

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

Matzneller

Lackner

Lagler

et al. 2016

Antimicrob Agents Chemother

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“…Current treatment of critical S. aureus infections can be carried out by ceftaroline, a highly advanced β-lactam drug that received FDA approval in 2010. Several recent clinical surveillance studies however suggest that ceftaroline non-susceptibility in S. aureus is on the rise, which is mainly due to PBP2a point mutations [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

PBP4: A New Perspective on Staphylococcus aureus β-Lactam Resistance

et al. 2018

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β-lactam antibiotics are excellent drugs for treatment of staphylococcal infections, due to their superior efficacy and safety compared to other drugs. Effectiveness of β-lactams is severely compromised due to resistance, which is widespread among clinical strains of Staphylococcus aureus. β-lactams inhibit bacterial cells by binding to penicillin binding proteins (PBPs), which perform the penultimate steps of bacterial cell wall synthesis. Among PBPs of S. aureus, PBP2a has received the most attention for the past several decades due to its preeminent role in conferring both high-level and broad-spectrum resistance to the entire class of β-lactam drugs. Studies on PBP2a have thus unraveled incredible details of its mechanism of action. We have recently identified that an uncanonical, low molecular weight PBP of S. aureus, PBP4, can also provide high-level and broad-spectrum resistance to the entire class of β-lactam drugs at a level similar to that of PBP2a. The role of PBP4 has typically been considered not so important for β-lactam resistance of S. aureus, and as a result its mode of action remains largely unknown. In this article, we review our current knowledge of PBP4 mediating β-lactam resistance in S. aureus.

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“…Besides, d-Ser also had sensitization activity in combination with ceftaroline. Ceftaroline, currently used as treatment of critical S. aureus infections, received FDA approval several years ago, now facing challenges that non-susceptible S. aureus is on the rise worldwide35., 36.. We studied and found that addition of 40 mmol/L d-Ser could enhance the antibacterial activity of ceftaroline against MRSA strains, with the MICs reduced by 2–16 times (data not shown).…”

Section: Discussionmentioning

confidence: 94%

“…Ceftaroline, currently used as treatment of critical S. aureus infections, received FDA approval several years ago, now facing challenges that non-susceptible S. aureus is on the rise worldwide 35. , 36. .…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo activity of d-serine in combination with β-lactam antibiotics against methicillin-resistant Staphylococcus aureus

Wang

Pang

et al. 2019

Acta Pharmaceutica Sinica B

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As d-amino acids play important roles in the physiological metabolism of bacteria, combination of d-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate in vitro and in vivo activity of d-serine alone and in combination with β -lactams against methicillin-resistant Staphylococcus aureus (MRSA) strains, and to explore the possible sensitization mechanisms. The activity of d-serine, β -lactams alone and in combinations was evaluated both in vitro by standard MICs, time–kill curves and checkerboard assays, and in vivo by murine systemic infection model as well as neutropenic thigh infection model. An in vitro synergistic effect was demonstrated with the combination of d-serine and β -lactams against MRSA standard and clinical strains. Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared to β -lactam alone groups. Initial mechanism study suggested possible revision of d-alanine-d-alanine residue to d-alanine-d-serine in peptidoglycan by adding of d-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, d-serine had synergistic activity in combination with β -lactams against MRSA strains both in vitro and in vivo . Considering the relatively good safety of d-serine alone or in combination with β -lactams, d-serine is worth following up as new anti-MRSA infection strategies.

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In Vitro Activity of Ceftaroline against Staphylococcus aureus Isolates Collected in 2012 from Latin American Countries as Part of the AWARE Surveillance Program

Cited by 15 publications

References 35 publications

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

PBP4: A New Perspective on Staphylococcus aureus β-Lactam Resistance

In vitro and in vivo activity of d-serine in combination with β-lactam antibiotics against methicillin-resistant Staphylococcus aureus

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