Once-daily aminoglycoside dosing: An update on current literature

Stankowicz, Matthew S.; Ibrahim, Jad; Brown, Daniel L.

doi:10.2146/ajhp140564

Cited by 57 publications

(25 citation statements)

References 49 publications

(97 reference statements)

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“…Current clinical guidelines suggest high-dose extended-interval administration of aminoglycosides, reconciling toxicity concerns with efficacy (29,38). Theoretically, such fluctuating stress conditions are predicted to promote the evolution of antibiotic tolerance through increased persister cell formation, rather than to select for resistant mutants (39).…”

Section: Resultsmentioning

confidence: 99%

In Vitro Emergence of High Persistence upon Periodic Aminoglycoside Challenge in the ESKAPE Pathogens

Michiels

Bergh

Verstraeten

et al. 2016

Antimicrob Agents Chemother

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bHealth care-associated infections present a major threat to modern medical care. Six worrisome nosocomial pathogens-Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.-are collectively referred to as the "ESKAPE bugs." They are notorious for extensive multidrug resistance, yet persistence, or the phenotypic tolerance displayed by a variant subpopulation, remains underappreciated in these pathogens. Importantly, persistence can prevent eradication of antibiotic-sensitive bacterial populations and is thought to act as a catalyst for the development of genetic resistance. Concentration-and time-dependent aminoglycoside killing experiments were used to investigate persistence in the ESKAPE pathogens. Additionally, a recently developed method for the experimental evolution of persistence was employed to investigate adaptation to high-dose, extended-interval aminoglycoside therapy in vitro. We show that ESKAPE pathogens exhibit biphasic killing kinetics, indicative of persister formation. In vitro cycling between aminoglycoside killing and persister cell regrowth, evocative of clinical high-dose extended-interval therapy, caused a 37-to 213-fold increase in persistence without the emergence of resistance. Increased persistence also manifested in biofilms and provided cross-tolerance to different clinically important antibiotics. Together, our results highlight a possible drawback of intermittent, high-dose antibiotic therapy and suggest that clinical diagnostics might benefit from taking into account persistence.

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Section: Resultsmentioning

confidence: 99%

In Vitro Emergence of High Persistence upon Periodic Aminoglycoside Challenge in the ESKAPE Pathogens

Michiels

Bergh

Verstraeten

et al. 2016

Antimicrob Agents Chemother

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“…However, this uptake is saturable, and studies have shown that less frequent aminoglycoside administration results in less aminoglycoside uptake and less nephrotoxicity (45). Additionally, once daily dosing provides a higher ratio of peak concentration of drug to minimum inhibitory concentration (MIC), which allows for rapid bacterial killing, and, as the serum concentration declines between dosing intervals, the kidney cells can recover, while the postantibiotic effect of aminoglycosides ensures that bacterial killing persists (46). Prolonged directed therapy is generally reserved for specific indications, including infections due to MDR pathogens.…”

Section: Combination Therapy and Dosing Strategiesmentioning

confidence: 99%

Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation

Serio¹,

Keepers²,

Andrews³

et al. 2018

EcoSal Plus

118

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Aminoglycosides are cidal inhibitors of bacterial protein synthesis that have been utilized for the treatment of serious bacterial infections for almost 80 years. There have been approximately 15 members of this class approved worldwide for the treatment of a variety of infections, many serious and life threatening. While aminoglycoside use declined due to the introduction of other antibiotic classes such as cephalosporins, fluoroquinolones, and carbapenems, there has been a resurgence of interest in the class as multidrug-resistant pathogens have spread globally. Furthermore, aminoglycosides are recommended as part of combination therapy for empiric treatment of certain difficult-totreat infections. The development of semisynthetic aminoglycosides designed to overcome common aminoglycoside resistance mechanisms, and the shift to once-daily dosing, has spurred renewed interest in the class. Plazomicin is the first new aminoglycoside to be approved by the FDA in nearly 40 years, marking the successful start of a new campaign to rejuvenate the class. AMINOGLYCOSIDE HISTORY Aminoglycoside antimicrobials were first discovered in the 1940s and originally isolated from actinomycetes. Streptomycin, isolated from Streptomyces griseus, was the first aminoglycoside introduced into clinical practice for the treatment of tuberculosis (1, 2). Selman Waksman (the first to coin the term "antibiotic") won the Nobel Prize in 1952 for the discovery of streptomycin, along with Albert Schatz, who was eventually recognized as a codiscoverer. Since then, a number of aminoglycosides have been discovered as products from the Streptomyces group ("mycin" aminoglycosides, e.g., neomycin, kanamycin, tobramycin) or Micromonospora group ("micin" aminoglycosides, e.g., gentamicin, sisomicin) species, or developed through chemical modifications using existing aminoglycoside scaffolds (e.g., amikacin, netilmicin, arbekacin, plazomicin). Plazomicin is an aminoglycoside that was engineered to overcome aminoglycoside-modifying enzymes (AMEs), the most common aminoglycoside resistance mechanism in Enterobacteriaceae, and is the first aminoglycoside to be approved by the FDA (June 2018) since the approval of amikacin in 1981, marking the beginning of a class rejuvenation.

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“…We acknowledge that a TDM strategy for plazomicin (and all aminoglycosides) that utilizes serial plasma concentrations at exact time points from a patient during a dosing interval will allow one to better characterize the pharmacokinetic drug profile of that individual. However, while this is feasible in research studies, in the clinical setting, where resources and sampling time are limited, the availability of once-daily nomograms such as the Hartford nomogram (which requires a single blood draw) provides convenience, cost saving, and equivalent patient outcomes (6). Of note, this current study utilized CLcr values available from the various study sites enrolled in the EPIC trial, in contrast to the central study laboratory CLcr values.…”

Section: Discussionmentioning

confidence: 99%

Application of the Hartford Hospital Nomogram for Plazomicin Dosing Interval Selection in Patients with Complicated Urinary Tract Infection

Asempa

Kuti

Seroogy³

et al. 2019

Antimicrob Agents Chemother

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Plazomicin is a new FDA-approved aminoglycoside antibiotic for complicated urinary tract infections (cUTI). In the product labeling, trough-based therapeutic drug management (TDM) is recommended for cUTI patients with renal impairment to prevent elevated trough concentrations associated with serum creatinine increases of ≥0.5 mg/dl above baseline. Herein, the utility of the Hartford nomogram to prevent plazomicin trough concentrations exceeding the TDM trough of 3 μg/ml and optimize the area under the curve (AUC) was assessed. The AUC reference range was defined as the 5th to 95th percentile AUC observed in the phase 3 cUTI trial (EPIC) (121 to 368 μg · h/ml). Observed 10-h plazomicin concentrations from patients in EPIC (n = 281) were plotted on the nomogram to determine an eligible dosing interval (every 24 h [q24h], q36h, q48h). Based on creatinine clearance (CLcr), a 15- or 10-mg/kg of body weight dose was simulated with the nomogram-derived interval. The nomogram recommended an extended interval (q36h and q48h) in 31% of patients. Compared with the 15 mg/kg q24h regimen received by patients with CLcr of ≥60 ml/min in EPIC, the nomogram-derived interval reduced the proportion of patients with troughs of ≥3 μg/ml (q36h, 27% versus 0%, P = 0.021; q48h, 57% versus 0%, P = 0.002) while significantly increasing the number of patients within the AUC range. Compared with the 8 to 12 mg/kg q24h regimen (received by patients with CLcr of >30 to 59 ml/min in EPIC), the nomogram-derived interval significantly reduced the proportion of troughs of ≥3μg/ml in the q48h cohort (72% versus 0%, P < 0.001) while maintaining a similar proportion of patients in the AUC range. Simulated application of the Hartford nomogram optimized plazomicin exposures in patients with cUTI while reducing troughs to <3 μg/ml.

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Once-daily aminoglycoside dosing: An update on current literature

Abstract: Once-daily aminoglycoside dosing is an effective, well-established method to achieve therapeutic efficacy while limiting the risk of toxicity and simplifying the processes of dosing and monitoring.

Cited by 57 publications

References 49 publications

In Vitro Emergence of High Persistence upon Periodic Aminoglycoside Challenge in the ESKAPE Pathogens

In Vitro Emergence of High Persistence upon Periodic Aminoglycoside Challenge in the ESKAPE Pathogens

Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation

Application of the Hartford Hospital Nomogram for Plazomicin Dosing Interval Selection in Patients with Complicated Urinary Tract Infection

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