Association between the Presence of Aminoglycoside-Modifying Enzymes and
            <i>In Vitro</i>
            Activity of Gentamicin, Tobramycin, Amikacin, and Plazomicin against Klebsiella pneumoniae Carbapenemase- and Extended-Spectrum-β-Lactamase-Producing Enterobacter Species

Haidar, Ghady; Alkroud, Ammar; Cheng, Shaoji; Churilla, Travis M.; Churilla, Bryce M.; Shields, Ryan K.; Doi, Yohei; Clancy, Cornelius J.; Nguyen, M. Hong

doi:10.1128/aac.00869-16

Cited by 41 publications

(33 citation statements)

References 49 publications

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“…Among the aminoglycosides, amikacin usually provides better coverage against ESBL and AmpC producers (110). Plazomicin is a new aminoglycoside with good activity against ESBL and AmpC producers (111,112) and is reviewed in the section on carbapenemase producers.…”

Section: Aminoglycosidesmentioning

confidence: 99%

“…It escapes the activity of aminoglycoside-modifying enzymes and is therefore active against a greater proportion of CRE than those with gentamicin, tobramycin, and amikacin. Nonetheless, like all other aminoglycosides, it is affected by 16S rRNA methyltransferases (111,(361)(362)(363). The results of a phase 3 randomized trial comparing plazomicin (15 mg/kg/ day) and meropenem (1 g/8 h) for treatment of cUTI, including pyelonephritis, have been reported; 388 patients were included in the microbiological modified intentionto-treat (mMITT) population, and plazomicin showed a higher rate of microbiological response (87.4% versus 72.1%) (364).…”

Section: Pipeline Of Drugs Against Crementioning

confidence: 99%

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Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

et al. 2018

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Therapy of invasive infections due to multidrug-resistant (MDR-E) is challenging, and some of the few active drugs are not available in many countries. For extended-spectrum β-lactamase and AmpC producers, carbapenems are the drugs of choice, but alternatives are needed because the rate of carbapenem resistance is rising. Potential active drugs include classic and newer β-lactam-β-lactamase inhibitor combinations, cephamycins, temocillin, aminoglycosides, tigecycline, fosfomycin, and, rarely, fluoroquinolones or trimethoprim-sulfamethoxazole. These drugs might be considered in some specific situations. AmpC producers are resistant to cephamycins, but cefepime is an option. In the case of carbapenemase-producing (CPE), only some "second-line" drugs, such as polymyxins, tigecycline, aminoglycosides, and fosfomycin, may be active; double carbapenems can also be considered in specific situations. Combination therapy is associated with better outcomes for high-risk patients, such as those in septic shock or with pneumonia. Ceftazidime-avibactam was recently approved and is active against KPC and OXA-48 producers; the available experience is scarce but promising, although development of resistance is a concern. New drugs active against some CPE isolates are in different stages of development, including meropenem-vaborbactam, imipenem-relebactam, plazomicin, cefiderocol, eravacycline, and aztreonam-avibactam. Overall, therapy of MDR-E infection must be individualized according to the susceptibility profile, type, and severity of infection and the features of the patient.

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Section: Aminoglycosidesmentioning

confidence: 99%

Section: Pipeline Of Drugs Against Crementioning

confidence: 99%

Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

et al. 2018

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“…Aminoglycosides are an important component of the current antibacterial arsenal due to their broad spectrum of activity, rapid bactericidal action, and favorable chemical and pharmacokinetic (PK) properties . Although resistance to aminoglycosides has been increasing, these antibiotics are used as first‐line agents in the empirical therapy of severe sepsis and as second‐line agents for directed therapy of infections due to multidrug‐resistant Gram‐negative bacteria that lack therapeutic alternatives…”

mentioning

confidence: 99%

A Phase 1 Study of Intravenous Plazomicin in Healthy Adults to Assess Potential Effects on the QT/QTc Interval, Safety, and Pharmacokinetics

Gall¹,

Choi²,

Riddle³

et al. 2019

Clinical Pharm in Drug Dev

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Plazomicin is an aminoglycoside with in vitro activity against multidrug‐resistant Enterobacteriaceae. A phase 1, randomized, double‐blind, crossover study assessed the potential effects of plazomicin on cardiac repolarization (NCT01514929). Fifty‐six healthy adults (24 men, 32 women) received a single therapeutic dose of plazomicin (15 mg/kg administered by 30‐minute intravenous infusion), a single supratherapeutic dose of plazomicin (20 mg/kg administered by 30‐minute intravenous infusion), placebo, or oral moxifloxacin (400 mg). The primary end point was the baseline‐adjusted, placebo‐corrected QTc interval using the Fridericia formula (ΔΔQTcF). Assay sensitivity was concluded if the lower limit of a 1‐sided 95%CI (adjusted for multiplicity using the Hochberg procedure) for moxifloxacin ΔΔQTcF was >5 milliseconds at ≥1 prespecified time points. No QT prolongation effect for plazomicin was concluded if the largest mean effect was <5 milliseconds, and the upper limit of a 2‐sided 90%CI for plazomicin ΔΔQTcF was <10 milliseconds at all time points. Assay sensitivity was demonstrated based on moxifloxacin ΔΔQTcF. No QT prolongation effect for plazomicin was concluded because the largest mean ΔΔQTcF for plazomicin was 3.5 milliseconds, and the highest upper limit was 5.6 milliseconds. No clinically relevant changes were observed in electrocardiograms. For the 15‐ and 20‐mg/kg dose levels of plazomicin, mean peak plasma concentration values were 76.0 and 96.6 mg/L, and mean values of the area under the concentration‐time curve over 24 hours were 263 and 327 mg·h/L, respectively. Model‐derived pharmacokinetic parameters and safety findings were generally consistent with previously reported plazomicin studies. In conclusion, therapeutic and supratherapeutic doses of plazomicin had no clinically significant effect on cardiac repolarization and were generally well tolerated.

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“…All five antibioticsdceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, plazomicin and eravacyclinedare improved derivatives of well-known antibiotic classes and address class-specific resistance mechanisms. The recent approval of plazomicin prompted us to discuss the clinical development process of these antibiotics and the challenges involved in generating clinical evidence on their efficacy and safety in patients with infections caused by extensively drug-resistant (XDR) or pan-drugeresistant (PDR) Gram-negative bacteria.Plazomicin, a new aminoglycoside related to sisomycin, has been designed to withstand the most common aminoglycosidemodifying enzymes in Enterobacteriaceae, thus providing a new treatment option for carbapenem-resistant Enterobacteriaceae (CRE), which are more likely than others to possess aminoglycoside-modifying enzymes [1]. Its activity against CRE is unrelated to the carbapenem resistance mechanism (unlike the new b-lactam/b-lactamase inhibitor combinations), inhibiting 99% of 97 patient-unique clinical CRE isolates at an MIC of 4 mg/mL, most of which were Klebsiella pneumoniae carbapenemase producers, in a recent survey [2].…”

mentioning

confidence: 99%

“…Plazomicin, a new aminoglycoside related to sisomycin, has been designed to withstand the most common aminoglycosidemodifying enzymes in Enterobacteriaceae, thus providing a new treatment option for carbapenem-resistant Enterobacteriaceae (CRE), which are more likely than others to possess aminoglycoside-modifying enzymes [1]. Its activity against CRE is unrelated to the carbapenem resistance mechanism (unlike the new b-lactam/b-lactamase inhibitor combinations), inhibiting 99% of 97 patient-unique clinical CRE isolates at an MIC of 4 mg/mL, most of which were Klebsiella pneumoniae carbapenemase producers, in a recent survey [2].…”

mentioning

confidence: 99%

Developing a new antibiotic for extensively drug-resistant pathogens: the case of plazomicin

Theuretzbacher¹

2018

Clinical Microbiology and Infection

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After a long void in the development of new antibiotics against Gram-negative pathogens, five new antibiotics have been approved over the last 4 years. All five antibioticsdceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, plazomicin and eravacyclinedare improved derivatives of well-known antibiotic classes and address class-specific resistance mechanisms. The recent approval of plazomicin prompted us to discuss the clinical development process of these antibiotics and the challenges involved in generating clinical evidence on their efficacy and safety in patients with infections caused by extensively drug-resistant (XDR) or pan-drugeresistant (PDR) Gram-negative bacteria.Plazomicin, a new aminoglycoside related to sisomycin, has been designed to withstand the most common aminoglycosidemodifying enzymes in Enterobacteriaceae, thus providing a new treatment option for carbapenem-resistant Enterobacteriaceae (CRE), which are more likely than others to possess aminoglycoside-modifying enzymes [1]. Its activity against CRE is unrelated to the carbapenem resistance mechanism (unlike the new b-lactam/b-lactamase inhibitor combinations), inhibiting 99% of 97 patient-unique clinical CRE isolates at an MIC of 4 mg/mL, most of which were Klebsiella pneumoniae carbapenemase producers, in a recent survey [2]. However, CRE producing New Delhi metallo-b-lactamase (NDM) are most likely to co-carry the genes for 16S rRNA methylases which affect all aminoglycosides including plazomicin and thus are resistant to these drugs [3]. Plazomicin has less or insufficient activity against Pseudomonas aeruginosa or Acinetobacter baumannii (Castanheira MS et al., 'Activity of plazomicin and comparator agents tested against recent clinical isolates collected in Asia-Pacific, Europe and Latin America,' paper presented at the 27th European Congress of Clinical Microbiology and Infectious Diseases, 2017).Plazomicin was recently approved by the US Food and Drug Administration (FDA) for complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). Approval was based on a single phase 3 randomized controlled trial (RCT), which was a 1:1 noninferiority RCT comparing plazomicin to meropenem, both followed by oral levofloxacin if needed (EPIC study) [4,5]. Plazomicin (306 patients randomized, 191 evaluated) was noninferior to meropenem (303 randomized, 197 evaluated) with respect to a coeprimary outcome of clinical and microbiologic cure at a 15% noninferiority margin. A phase 2 RCT was also completed, recruiting 98 patients with cUTI or AP to different doses of plazomicin (63 evaluated) vs. 47 patients to intravenous levofloxacin (29 evaluated). The high dose of plazomicin (51 patients) resulted in comparable efficacy to levofloxacin. Thus, approval for cUTI and AP was based on these two studies [5].However, the indication of bloodstream infections (BSI) caused by documented or presumed CRE was rejected by the FDA after the failure of the RCT to complete the planned enrolment (CARE study; ClinicalTrials.gov NCT019703...

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Association between the Presence of Aminoglycoside-Modifying Enzymes and In Vitro Activity of Gentamicin, Tobramycin, Amikacin, and Plazomicin against Klebsiella pneumoniae Carbapenemase- and Extended-Spectrum-β-Lactamase-Producing Enterobacter Species

Cited by 41 publications

References 49 publications

Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

A Phase 1 Study of Intravenous Plazomicin in Healthy Adults to Assess Potential Effects on the QT/QTc Interval, Safety, and Pharmacokinetics

Developing a new antibiotic for extensively drug-resistant pathogens: the case of plazomicin

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