<i>Notes from the Field</i>: Pan-Resistant New Delhi Metallo-Beta-Lactamase-Producing <i>Klebsiella pneumoniae</i> — Washoe County, Nevada, 2016

Chen, Lei; Todd, Randall L.; Kiehlbauch, Julia A.; Walters, Maroya Spalding; Kallen, Alexander J.

doi:10.15585/mmwr.mm6601a7

Cited by 167 publications

(133 citation statements)

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“…Recently, a female patient in her 70s from Nevada, USA, diagnosed with systemic inflammatory response syndrome, later developed septic shock and died in September 2016 (179). The causative pathogen, carbapenem-resistant K. pneumoniae, was resistant to all 26 antibiotics approved for her treatment in the United States.…”

Section: Resultsmentioning

confidence: 99%

Intracellular Targeting Mechanisms by Antimicrobial Peptides

Fang

Sekaran

2017

Antimicrob Agents Chemother

431

366

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Antimicrobial peptides (AMPs) are expressed in various living organisms as first-line host defenses against potential harmful encounters in their surroundings. AMPs are short polycationic peptides exhibiting various antimicrobial activities. The principal antibacterial activity is attributed to the membrane-lytic mechanism which directly interferes with the integrity of the bacterial cell membrane and cell wall. In addition, a number of AMPs form a transmembrane channel in the membrane by self-aggregation or polymerization, leading to cytoplasm leakage and cell death. However, an increasing body of evidence has demonstrated that AMPs are able to exert intracellular inhibitory activities as the primary or supportive mechanisms to achieve efficient killing. In this review, we focus on the major intracellular targeting activities reported in AMPs, which include nucleic acids and protein biosynthesis and protein-folding, protease, cell division, cell wall biosynthesis, and lipopolysaccharide inhibition. These multifunctional AMPs could serve as the potential lead peptides for the future development of novel antibacterial agents with improved therapeutic profiles.

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Section: Resultsmentioning

confidence: 99%

Intracellular Targeting Mechanisms by Antimicrobial Peptides

Fang

Sekaran

2017

Antimicrob Agents Chemother

431

366

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“…A recent report from the Centers for Disease Control and Prevention highlighted this risk with the report of the death of a woman in Nevada due to a highly drug-resistant K. pneumoniae infection that was resistant to 26 antibiotics, including all beta-lactams, aminoglycosides, polymyxins, and tigecycline (11). In fact, this isolate was…”

Section: Discussionmentioning

confidence: 99%

In Vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa

Lepak

Zhao

VanScoy

et al. 2017

Antimicrob Agents Chemother

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Fosfomycin is a broad-spectrum agent with activity against Gram-positive and Gram-negative bacteria, including drug-resistant strains, such as extended-spectrumbeta-lactamase (ESBL)-producing and carbapenem-resistant (CR) Gram-negative rods. In the present study, the pharmacokinetic/pharmacodynamic (PK/PD) activity of ZTI-01 (fosfomycin for injection) was evaluated in the neutropenic murine thigh infection model against 5 Escherichia coli, 3 Klebsiella pneumoniae, and 2 Pseudomonas aeruginosa strains, including a subset with ESBL and CR phenotypes. The pharmacokinetics of ZTI-01 were examined in mice after subcutaneous administration of 3.125, 12.5, 50, 200, 400, and 800 mg/kg of body weight. The half-life ranged from 0.51 to 1.1 h, area under the concentration-time curve (AUC 0 -∞ ) ranged from 1.4 to 87 mg · h/liter, and maximum concentrations ranged from 0.6 to 42.4 mg/liter. Dose fractionation demonstrated the AUC/MIC ratio to be the PK/PD index most closely linked to efficacy (R 2 ϭ 0.70). Net stasis and bactericidal activity were observed against all strains. Net stasis was observed at 24-h AUC/MIC ratio values of 24, 21, and 15 for E. coli, K., pneumoniae and P. aeruginosa, respectively. For the Enterobacteriaceae group, stasis was noted at mean 24-h AUC/MIC ratio targets of 23 and 1-log kill at 83. Survival in mice infected with E. coli 145 was maximal at 24-h AUC/MIC ratio exposures of 9 to 43, which is comparable to the stasis exposures identified in the PK/PD studies. These results should prove useful for the design of clinical dosing regimens for ZTI-01 in the treatment of serious infections due to Enterobacteriaceae and Pseudomonas.

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“…These infections are a worldwide problem, with recent reports indicating that CRE are widespread in the United States (7), Europe (8), and China (9). Unfortunately, resistance to "last-line" drugs, such as colistin, is emerging in CRKP strains, and in some cases, isolates are resistant to all antibiotics tested (10). Here, we describe the identification of two multidrug-resistant CRKP isolates exhibiting colistin heteroresistance, a phenomenon in which only a minor subpopulation of genetically identical cells is phenotypically resistant.…”

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confidence: 99%

Carbapenem-Resistant Klebsiella pneumoniae Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection

Band

Satola

Burd

et al. 2018

mBio

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Antibiotic resistance is a growing crisis and a grave threat to human health. It is projected that antibiotic-resistant infections will lead to 10 million annual deaths worldwide by the year 2050. Among the most significant threats are carbapenem-resistant Enterobacteriaceae (CRE), including carbapenem-resistant Klebsiella pneumoniae (CRKP), which lead to mortality rates as high as 40 to 50%. Few treatment options are available to treat CRKP, and the polymyxin antibiotic colistin is often the "last-line" therapy. However, resistance to colistin is increasing. Here, we identify multidrug-resistant, carbapenemase-positive CRKP isolates that were classified as susceptible to colistin by clinical diagnostics yet harbored a minor subpopulation of phenotypically resistant cells. Within these isolates, the resistant subpopulation became predominant after growth in the presence of colistin but returned to baseline levels after subsequent culture in antibiotic-free media. This indicates that the resistance was phenotypic, rather than due to a genetic mutation, consistent with heteroresistance. Importantly, colistin therapy was unable to rescue mice infected with the heteroresistant strains. These findings demonstrate that colistin heteroresistance may cause in vivo treatment failure during K. pneumoniae infection, threatening the use of colistin as a last-line treatment for CRKP. Furthermore, these data sound the alarm for use of caution in interpreting colistin susceptibility test results, as isolates identified as susceptible may in fact resist antibiotic therapy and lead to unexplained treatment failures. IMPORTANCE This is the first report of colistin-heteroresistant K. pneumoniae in the United States. Two distinct isolates each led to colistin treatment failure in an in vivo model of infection. The data are worrisome, especially since the colistin heteroresistance was not detected by current diagnostic tests. As these isolates were carbapenem resistant, clinicians might turn to colistin as a last-line therapy for infections caused by such strains, not knowing that they in fact harbor a resistant subpopulation of cells, potentially leading to treatment failure. Our findings warn that colistin susceptibility testing results may be unreliable due to undetected heteroresistance and highlight the need for more accurate and sensitive diagnostics.KEYWORDS Klebsiella, antibiotic resistance, clonal heteroresistance, colistin, heteroresistance A ntibiotic resistance is an increasingly urgent problem, predicted to cause 10 million annual deaths worldwide by the year 2050 (1). Klebsiella spp., including K. pneumoniae, are responsible for~10% of nosocomial infections in the United States (2),

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Notes from the Field: Pan-Resistant New Delhi Metallo-Beta-Lactamase-Producing Klebsiella pneumoniae — Washoe County, Nevada, 2016

Cited by 167 publications

References 1 publication

Intracellular Targeting Mechanisms by Antimicrobial Peptides

Intracellular Targeting Mechanisms by Antimicrobial Peptides

In Vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa

Carbapenem-Resistant Klebsiella pneumoniae Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection

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