Treatment of Multidrug-Resistant Gram-Negative Infections in Children

Hsu, Alice J.; Tamma, Pranita D.

doi:10.1093/cid/ciu069

Cited by 141 publications

(133 citation statements)

References 96 publications

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“…73 A few publications propose potential algorithms for treatment of CRE infection based on molecular detection of specific carbapenemases 74 and carbapenem MIC. 75,76 Infection control implications of rapid detection of CP-CRE Timely identification of individuals who are infected or colonized with CP-CRE would enable prompt implementation of infection control interventions, including patient cohorting and isolation, precautions during invasive procedures and patient transport, and appropriate environmental disinfection. This, in turn, is likely to reduce transmission of CP-CRE within healthcare settings.…”

Section: Treatment Implications Of Rapid Detection Of Crementioning

confidence: 99%

Clinical and laboratory considerations for the rapid detection of carbapenem-resistant Enterobacteriaceae

Banerjee

Humphries

2016

Virulence

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Carbapenem resistance among the Enterobacteriaceae has become a significant clinical and public health dilemma. Rapid administration of effective antimicrobials and implementation of supplemental infection control practices is required to both improve patient outcomes and limit the spread of these highly resistant organisms. However, carbapenem-resistant Enterobacteriaceae (CRE)-infected patients are predominantly identified by routine culture methods, which take days to perform. Rapid genomic and phenotypic methods are currently available to accelerate the identification of carbapenemaseproducing CRE. Effective use of these technologies is reliant on close collaboration between clinical microbiology, infection prevention, antimicrobial stewardship and infectious diseases specialists. This review discusses the performance characteristics of these technologies to date, and describes strategies for their optimal implementation.

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Section: Treatment Implications Of Rapid Detection Of Crementioning

confidence: 99%

Clinical and laboratory considerations for the rapid detection of carbapenem-resistant Enterobacteriaceae

Banerjee

Humphries

2016

Virulence

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“…However, identification of organisms producing ESBLs still has important clinical implications. A portion of these organisms retain in vitro susceptibility to piperacillin-tazobactam and cefepime (2), even though these agents are generally considered inferior to carbapenem therapy for the treatment of invasive infections by ESBL-producing organisms (3)(4)(5).…”

mentioning

confidence: 99%

“…Using the current CLSI ceftriaxone breakpoint of 1 g/ml, we previously found that 100% of 96 organisms expressing AmpC ␤-lactamases had ceftriaxone MICs of Ͼ1 g/ml (11). Ceftriaxone has been found to be problematic for the treatment of these organisms, but broader-spectrum ␤-lactams have not demonstrated such problems (5). Therefore, the coexistence of AmpC ␤-lactamases should be unlikely to impact the ceftriaxone MIC used to trigger ESBL testing.…”

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confidence: 99%

Determining the Optimal Ceftriaxone MIC for Triggering Extended-Spectrum β-Lactamase Confirmatory Testing

2014

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As routine testing of clinical isolates for extended-spectrum ␤-lactamase (ESBL) production (screen plus phenotypic confirmatory testing) is no longer required by the Clinical and Laboratory Standards Institute (CLSI), a number of clinical microbiology laboratories use ceftriaxone MICs as a proxy means of identifying bacteria as potential ESBL producers. Data from 1,386 clinical isolates suggest that a ceftriaxone MIC cutoff of 8 g/ml is an excellent predictor of ESBL production, with a positive predictive value and negative predictive value approaching 100% and 99.5%, respectively. In 2010, the Clinical and Laboratory Standards Institute (CLSI) lowered the ceftriaxone (and cefotaxime) breakpoint from 8 g/ml to 1 g/ml, and with that change, the recommendation for screening for extended-spectrum ␤-lactamase (ESBL) production became optional (1). This was in part due to the large workload imposed on clinical microbiology laboratories with phenotypic confirmatory ESBL testing (1). However, identification of organisms producing ESBLs still has important clinical implications. A portion of these organisms retain in vitro susceptibility to piperacillin-tazobactam and cefepime (2), even though these agents are generally considered inferior to carbapenem therapy for the treatment of invasive infections by ESBL-producing organisms (3-5).Without a method of alerting clinicians to the possibility that an agent may be an ESBL producer, potentially suboptimal therapy (e.g., cefepime or piperacillin-tazobactam) may be inadvertently prescribed. In addition, the absence of institutional epidemiological data on ESBLs can hamper efforts to control their spread within health care facilities (6). For these reasons, many clinical microbiology laboratories use ceftriaxone (or other thirdgeneration cephalosporin) MIC thresholds to indicate to clinicians that an organism is a possible ESBL producer or to trigger additional confirmatory phenotypic testing. If the ceftriaxone MIC threshold is lower than necessary, this practice has the potential to lead to the overuse of carbapenems or to needlessly increase the workload of microbiology laboratories (for institutions where confirmatory testing is still performed). If the ceftriaxone MIC threshold for ESBL identification is too high, appropriate infection control and treatment strategies may not be deployed. Our objective was to evaluate the sensitivities and specificities of various ceftriaxone MICs in determining the optimal threshold for identifying an organism as a potential ESBL producer.Microbiology methods. Blood isolates growing Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis obtained from January 2007 to December 2013 were included. These bacteria were selected because the CLSI-recommended method for initial screening and phenotypic confirmatory testing is limited to these organisms (7). Clinical samples were processed at the Johns Hopkins Hospital Microbiology Laboratory according to standard operating procedures. Antimicrobial susceptibility t...

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“…Dosing of colistin in pediatrics is mainly guided by the manufacturer recommendations of a dose of 2.5 mg/kg/dose of colistin base activity (CBA) intravenously every 12 hours. 52 There are no formal studies assessing the use of a loading dose, but several investigators 53 have suggested the use of a loading dose (5 mg/kg of CBA) in order to achieve target serum drug concentration more rapidly. The use of tigecycline in pediatrics is limited by toxicity concerns, and dosing recommendations are based on pharmacokinetic studies (8-11 years: 1.2 mg/kg/dose every 12 hours with a maximum of 50 mg per dose; 12-17 years: 50 mg every 12 hours).…”

Section: Considerations For Pediatricsmentioning

confidence: 99%

“…The use of tigecycline in pediatrics is limited by toxicity concerns, and dosing recommendations are based on pharmacokinetic studies (8-11 years: 1.2 mg/kg/dose every 12 hours with a maximum of 50 mg per dose; 12-17 years: 50 mg every 12 hours). 53 At this time, there are no clinical data or dosing guidance for ceftazidime-avibactam in pediatric patients, although there is an ongoing Phase I study 54 of ceftazidime-avibactam in pediatrics assessing the pharmacokinetics, safety, and tolerability of a single dose in children from 3 months to 18 years of age.…”

Section: Considerations For Pediatricsmentioning

confidence: 99%

Beyond Susceptible and Resistant, Part III: Treatment of Infections due to Gram-Negative Organisms Producing Carbapenemases

Narayanan

Johnson

MacDougall

2016

The Journal of Pediatric Pharmacology and Therapeutics

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Carbapenemases are enzymes that are capable of inactivating all or almost all beta-lactam antimicrobial agents. These enzymes are frequently coexpressed with other resistance mechanisms to non-beta-lactams, leading to extremely drug-resistant pathogens. Once a curiosity, these enzymes have spread into organisms that are among the most common causes of infection, such as Klebsiella pneumoniae and Escherichia coli. Identification of these organisms has proved challenging for clinical microbiology laboratories, leading to revisions in susceptibility standards for carbapenems. Although currently a rare cause of infection in children, these carbapenem-resistant Enterobacteriaceae (CRE) are becoming endemic in a variety of healthcare settings. Management of infections due to CRE is complicated by a lack of effective treatment options and clinical data on their effectiveness. Treatment of CRE infections in children is particularly challenging because therapeutic options for CRE lack adequate data on dosing and safety in children. Use of unconventional combination treatment regimens, including agents to which the organism is resistant in vitro, may provide some benefit in the treatment of severe CRE infection. Fortunately, several agents with the potential for treatment of CRE infections have been recently approved or are in late clinical development, although few data will be available in the short term to inform use in children.

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Treatment of Multidrug-Resistant Gram-Negative Infections in Children

Cited by 141 publications

References 96 publications

Clinical and laboratory considerations for the rapid detection of carbapenem-resistant Enterobacteriaceae

Clinical and laboratory considerations for the rapid detection of carbapenem-resistant Enterobacteriaceae

Determining the Optimal Ceftriaxone MIC for Triggering Extended-Spectrum β-Lactamase Confirmatory Testing

Beyond Susceptible and Resistant, Part III: Treatment of Infections due to Gram-Negative Organisms Producing Carbapenemases

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