Ceftaroline-Resistant, Daptomycin-Tolerant, and Heterogeneous Vancomycin-Intermediate Methicillin-Resistant Staphylococcus aureus Causing Infective Endocarditis

Nigo, Masayuki; Diaz, Lorena; Carvajal, Lina P; Tran, Truc T.; Ríos, Rafael; Panesso, Diana; Garavito, Juan David; Miller, William R.; Wanger, Audrey; Weinstock, George M.; Munita, José M.; Arias, César A.; Chambers, Henry F.

doi:10.1128/aac.01235-16

Cited by 27 publications

(19 citation statements)

References 34 publications

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“…This work, provides a mechanistic explanation for efficacy in these studies, although there have been previous conflicting reports 9 . While it is unlikely that penicillins and β-lactamase inhibitor combinations would be used as a monotherapy, they would be attractive additional therapeutic option for hard-to-treat infections such as multidrug-resistant MRSA 48 , particularly as β-lactams synergise with vancomycin and daptomycin 49,50 . PK/PD modelling studies, including an assessment of highly resistant cells during treatment is now needed to determine the optimum dosing strategy required for sustained efficacy before appropriate clinical trial could be conducted.…”

Section: Discussionmentioning

confidence: 99%

Genomic identification of cryptic susceptibility to penicillins and β-lactamase inhibitors in methicillin-resistant Staphylococcus aureus

Harrison

Coll

et al. 2019

Nat Microbiol

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Antibiotic resistance in bacterial pathogens threatens the future of modern medicine. One such resistant pathogen is methicillin-resistant Staphylococcus aureus (MRSA), which is resistant to nearly all β-lactam antibiotics, limiting treatment options. Here, we show that a significant proportion of MRSA isolates from different lineages, including the epidemic USA300 lineage, are susceptible to penicillins when used in combination with β-lactamase inhibitors such as clavulanic acid. Susceptibility is mediated by a combination of two different mutations in the mecA promoter region that lowers mecA-encoded penicillin binding protein 2a (PBP2a) expression, and in the majority of isolates by either one of two substitutions in PBP2a (E246G or M122I) that increase the affinity of PBP2a for penicillin in the presence of clavulanic acid. Treatment of S. aureus infections in wax moth and mouse models demonstrate that penicillin/β-lactamase inhibitor susceptibility can be exploited as an effective therapeutic choice for 'susceptible' MRSA infection. Finally, we show that isolates with the PBP2a E246G substitution have a growth advantage in the presence of penicillin, but the absence of clavulanic acid, which suggests that penicillin/βlactamase susceptibility is an example of collateral sensitivity (resistance to one antibiotic increases sensitivity to another). Our findings suggest that widely available and currently disregarded antibiotics could be effective in a significant proportion of MRSA infections.

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Section: Discussionmentioning

confidence: 99%

Genomic identification of cryptic susceptibility to penicillins and β-lactamase inhibitors in methicillin-resistant Staphylococcus aureus

Harrison

Coll

et al. 2019

Nat Microbiol

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“…15 Synergy has been demonstrated in vitro with both DAP/CPT and VAN/CPT, with groups employing various assays including time-kill analyses and modified E-test techniques. 15,21,28,29 Figure 1 provides an illustrated summary of the proposed synergy mechanisms present with DAP/CPT and VAN/CPT.…”

Section: Discussionmentioning

confidence: 99%

Adjunctive ceftaroline in combination with daptomycin or vancomycin for complicated methicillin-resistant Staphylococcus aureus bacteremia after monotherapy failure

Hornak

Anjum

Reynoso

2019

Therapeutic Advances in Infection

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Background: Methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) may fail to improve with standard monotherapy, particularly in patients with multifocal infection, incomplete source control, or persistent bacteremia. Synergy observed in vitro between ceftaroline (CPT) and daptomycin (DAP) or vancomycin (VAN) may translate into clinical benefit. Here, we describe our experience with DAP/CPT and VAN/CPT for complicated MRSA-B after monotherapy failure. Methods: Single-center, retrospective review of consecutive patients treated with DAP/CPT or VAN/CPT for MRSA-B after monotherapy failure from 1 January 2016 to 30 November 2018. Results: We identified 11 instances of combination therapy in 10 patients (DAP/CPT = 6, VAN/CPT = 5) with 1 patient receiving VAN/CPT followed by DAP/CPT. Rates of multifocal infection, incomplete source control, persistent bacteremia, and infective endocarditis were high (100%, 80%, 60%, and 60%, respectively). Combination therapy was initiated most commonly for persistent bacteremia (60%). When patients were persistently bacteremic, median preceding duration was 13 days and median time to clearance was 3 days. Total microbiologic cure rate was 100%. There were zero instances of bacteremia relapse at 30 days (30D) or 60 days (60D). All-cause 30D and 60D mortality rates were 11.1% and 33.3%, respectively. Conclusions: Combination therapy demonstrated success in diverse cases of refractory MRSA-B, including instances of persistent bacteremia paired with incomplete source control. Optimal timing and therapeutic cadence for combination therapy remain unclear. Our findings suggest that DAP/CPT and VAN/CPT can be considered for complicated MRSA bacteremia when other treatment options fail or are unavailable. We propose persistent bacteremia with incomplete source control to be a clinical niche particularly worthy of further investigation.

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“… Please note that the table includes ONLY those antibiotics which are deleted or newly added since 2010 . = Antibiotics deleted from CLSI guidelines between 2010 and 2018; 1, New antibiotics added in the CLSI guidelines since 2010 ; = No resistance reported till date ; = Resistance reported; Ef, E. faecium; S, S. aureus; K, K. pneumoniae; A, A. baumannii; P, P. aeruginosa; E= Enterobacter spp . S = (Long et al, 2014; Chan et al, 2015; Nigo et al, 2017); K = (Zowawi et al, 2015; Vuotto et al, 2017; Stanley et al, 2018); A = (Göttig et al, 2014; Goic-Barisic et al, 2017; Nowak et al, 2017; Caio et al, 2018; Chuang and Ratnayake, 2018); P = (Prakash et al, 2014; Gill et al, 2016; Alipour et al, 2017; Mohapatra et al, 2018; Palavutitotai et al, 2018) ; E = (Lee et al, 2015; Babouee Flury et al, 2016; Zeng et al, 2016; Kulengowski et al, 2018) .…”

Section: Introductionmentioning

confidence: 99%

“…S = (Long et al, 2014; Chan et al, 2015; Nigo et al, 2017); K = (Zowawi et al, 2015; Vuotto et al, 2017; Stanley et al, 2018); A = (Göttig et al, 2014; Goic-Barisic et al, 2017; Nowak et al, 2017; Caio et al, 2018; Chuang and Ratnayake, 2018); P = (Prakash et al, 2014; Gill et al, 2016; Alipour et al, 2017; Mohapatra et al, 2018; Palavutitotai et al, 2018) ;…”

Section: Introductionmentioning

confidence: 99%

Emerging Strategies to Combat ESKAPE Pathogens in the Era of Antimicrobial Resistance: A Review

et al. 2019

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The acronym ESKAPE includes six nosocomial pathogens that exhibit multidrug resistance and virulence: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa , and Enterobacter spp. Persistent use of antibiotics has provoked the emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) bacteria, which render even the most effective drugs ineffective. Extended spectrum β-lactamase (ESBL) and carbapenemase producing Gram negative bacteria have emerged as an important therapeutic challenge. Development of novel therapeutics to treat drug resistant infections, especially those caused by ESKAPE pathogens is the need of the hour. Alternative therapies such as use of antibiotics in combination or with adjuvants, bacteriophages, antimicrobial peptides, nanoparticles, and photodynamic light therapy are widely reported. Many reviews published till date describe these therapies with respect to the various agents used, their dosage details and mechanism of action against MDR pathogens but very few have focused specifically on ESKAPE. The objective of this review is to describe the alternative therapies reported to treat ESKAPE infections, their advantages and limitations, potential application in vivo , and status in clinical trials. The review further highlights the importance of a combinatorial approach, wherein two or more therapies are used in combination in order to overcome their individual limitations, additional studies on which are warranted, before translating them into clinical practice. These advances could possibly give an alternate solution or extend the lifetime of current antimicrobials.

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Ceftaroline-Resistant, Daptomycin-Tolerant, and Heterogeneous Vancomycin-Intermediate Methicillin-Resistant Staphylococcus aureus Causing Infective Endocarditis

Cited by 27 publications

References 34 publications

Genomic identification of cryptic susceptibility to penicillins and β-lactamase inhibitors in methicillin-resistant Staphylococcus aureus

Genomic identification of cryptic susceptibility to penicillins and β-lactamase inhibitors in methicillin-resistant Staphylococcus aureus

Adjunctive ceftaroline in combination with daptomycin or vancomycin for complicated methicillin-resistant Staphylococcus aureus bacteremia after monotherapy failure

Emerging Strategies to Combat ESKAPE Pathogens in the Era of Antimicrobial Resistance: A Review

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