Colistin and doripenem combinations against <i>Pseudomonas aeruginosa</i>: profiling the time course of synergistic killing and prevention of resistance

Ly, Neang S.; Bulitta, Jürgen B.; Rao, Gauri G.; Landersdorfer, Cornelia B.; Holden, Patricia N.; Forrest, Alan; Bergen, Phillip J.; Nation, Roger L.; Li, Jian; Tsuji, Brian T.

doi:10.1093/jac/dku567

Cited by 57 publications

(56 citation statements)

References 32 publications

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“…In a recent multicenter study, 94 of 105 (89.5%) patients who were treated with intravenous CMS were diagnosed with bacterial pneumonia (9). In these infections, the bacterial density of the total population is remarkably high and, as a consequence, results in a higher frequency of resistant mutants (19). Zaccard et al determined that a significant proportion of patients (26.1%) with Gram-negative pneumonia have been shown to have a bacterial burden higher than Ն3 ϫ 10 7 in dilution-transformed colony counts of bronchoalveolar lavage fluid (17,29).…”

Section: Discussionmentioning

confidence: 99%

“…HFIM. The HFIM was used to simulate the time course of unbound plasma concentrations observed in patients receiving polymyxin B regimens by using an approach that was previously described (19,20). Cellulosic hollow-fiber cartridges (C3008; Fiber Cell Systems, Fredrick, MD) were utilized in all experiments, and samples were serially collected for 336 h. Total population counts were quantified by depositing appropriately diluted bacterial samples on Mueller-Hinton agar (MHA) plates.…”

Section: Methodsmentioning

confidence: 99%

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Paradoxical Effect of Polymyxin B: High Drug Exposure Amplifies Resistance in Acinetobacter baumannii

Tsuji

Landersdorfer

Lenhard

et al. 2016

Antimicrob Agents Chemother

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f Administering polymyxin antibiotics in a traditional fashion may be ineffective against Gram-negative ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. Here, we explored increasing the dose intensity of polymyxin B against two strains of Acinetobacter baumannii in the hollow-fiber infection model. The following dosage regimens were simulated for polymyxin B (t 1/2 ‫؍‬ 8 h): nonloading dose (1.43 mg/kg of body weight every 12 h [q12h]), loading dose (2.22 mg/kg q12h for 1 dose and then 1.43 mg/kg q12h), front-loading dose (3.33 mg/kg q12h for 1 dose followed by 1.43 mg/kg q12h), burst (5.53 mg/kg for 1 dose), and supraburst (18.4 mg/kg for 1 dose). Against both A. baumannii isolates, a rapid initial decline in the total population was observed within the first 6 h of polymyxin exposure, whereby greater polymyxin B exposure resulted in greater maximal killing of ؊1.25, ؊1.43, ؊2.84, ؊2.84, and ؊3.40 log 10 CFU/ml within the first 6 h. Unexpectedly, we observed a paradoxical effect whereby higher polymyxin B exposures dramatically increased resistant subpopulations that grew on agar containing up to 10 mg/liter of polymyxin B over 336 h. High drug exposure also proliferated polymyxin-dependent growth. A cost-benefit pharmacokinetic/pharmacodynamic relationship between 24-h killing and 336-h resistance was explored. The intersecting point, where the benefit of bacterial killing was equal to the cost of resistance, was an fAUC 0 -24 (area under the concentration-time curve from 0 to 24 h for the free, unbound fraction of drug) of 38.5 mg · h/liter for polymyxin B. Increasing the dose intensity of polymyxin B resulted in amplification of resistance, highlighting the need to utilize polymyxins as part of a combination against high-bacterial-density A. baumannii infections.T he polymyxin antibiotics have emerged as a last line of defense for the treatment of Gram-negative strains resistant to all other currently available antibiotics (1-3). Polymyxin B and colistin are often the only available agents with activity against these Gram-negative superbugs (4, 5). Even more worrisome is the first report of plasmid-mediated polymyxin resistance in Escherichia coli, which could be transferred to other Gram-negative strains (6). Furthermore, current dosage regimens for both polymyxin B and colistin result in polymyxin plasma concentrations that are suboptimal in a significant proportion of patients (7-10). In vitro and animal studies clearly demonstrate that antibiotic resistance is amplified during exposure to suboptimal polymyxin concentrations, especially against polymyxin-heteroresistant strains that are frequently isolated in Acinetobacter baumannii (11)(12)(13)(14).Administering nontraditional, high-intensity polymyxin regimens may be a strategy to maximize bacterial killing while minimizing resistance and potential toxicity. We have previously determined that front-loading colistin resulted in greater bacteri...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Paradoxical Effect of Polymyxin B: High Drug Exposure Amplifies Resistance in Acinetobacter baumannii

Tsuji

Landersdorfer

Lenhard

et al. 2016

Antimicrob Agents Chemother

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“…In regards to the mechanistic advantages of polymyxin combinations, we further refined a previously developed mechanism-based mathematical model for colistin monotherapy 31 and colistin combinations 32 based on the known mechanism of the antibacterial activity of polymyxins and doripenem. The proposed population PD model well characterized the timecourse of bacterial growth and killing due to monotherapy and combination regimens against both A. baumannii isolates.…”

Section: Discussionmentioning

confidence: 99%

Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii : pharmacodynamics of new dosing strategies

Rao

Bulitta

et al. 2016

J. Antimicrob. Chemother.

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Objectives: Polymyxin B is being increasingly utilized as a last resort against resistant Gram-negative bacteria. We examined the pharmacodynamics of novel dosing strategies for polymyxin B combinations to maximize efficacy and minimize the emergence of resistance and drug exposure against Acinetobacter baumannii. Methods:The pharmacodynamics of polymyxin B together with doripenem were evaluated in time -kill experiments over 48 h against 10 8 cfu/mL of two polymyxin-heteroresistant A. baumannii isolates (ATCC 19606 and N16870). Pharmacokinetic/pharmacodynamic relationships were mathematically modelled using S-ADAPT. A hollow-fibre infection model (HFIM) was also used to simulate clinically relevant polymyxin B dosing strategies (traditional, augmented 'front-loaded' and 'burst' regimens), together with doripenem, against an initial inoculum of 10 9 cfu/mL of ATCC 19606.Results: In static time -kill studies, polymyxin B concentrations .4 mg/L in combination with doripenem 25 mg/L resulted in rapid bactericidal activity against both strains with undetectable bacterial counts by 24 h. The mathematical model described the rapid, concentration-dependent killing as subpopulation and mechanistic synergy. In the HFIM, the traditional polymyxin B combination regimen was synergistic, with a .7.5 log 10 reduction by 48 h. The polymyxin B 'front-loaded' combination resulted in more rapid and extensive initial killing (.8 log 10 ) within 24 h, which was sustained over 10 days. With only 25% of the cumulative drug exposure, the polymyxin B 'burst' combination demonstrated antibacterial activity similar to traditional and 'front-loaded' combination strategies. The polymyxin B 'front-loaded' and 'burst' combination regimens suppressed the emergence of resistance.Conclusions: Early aggressive dosing regimens for polymyxin combinations demonstrate promise for treatment of heteroresistant A. baumannii infections.

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“…This fraction was previously defined as the subpopulation fraction by Ly et al (17). The extended MBM suggested inducible aminoglycoside resistance for the aminoglycoside-resistant population (i.e., IR) ( Fig.…”

Section: Yadav Et Almentioning

confidence: 93%

Optimization of Synergistic Combination Regimens against Carbapenem- and Aminoglycoside-Resistant Clinical Pseudomonas aeruginosa Isolates via Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling

Yadav

Bulitta

Nation

et al. 2017

Antimicrob Agents Chemother

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Optimizing antibiotic combinations is promising to combat multidrugresistant Pseudomonas aeruginosa. This study aimed to systematically evaluate synergistic bacterial killing and prevention of resistance by carbapenem and aminoglycoside combinations and to rationally optimize combination dosage regimens via a mechanism-based mathematical model (MBM). We studied monotherapies and combinations of imipenem with tobramycin or amikacin against three difficult-to-treat double-resistant clinical P. aeruginosa isolates. Viable-count profiles of total and resistant populations were quantified in 48-h static-concentration time-kill studies (inoculum, 10 7.5 CFU/ml). We rationally optimized combination dosage regimens via MBM and Monte Carlo simulations against isolate FADDI-PA088 (MIC of imipenem [MIC imipenem ] of 16 mg/liter and MIC tobramycin of 32 mg/liter, i.e., both 98th percentiles according to the EUCAST database). Against this isolate, imipenem (1.5ϫ MIC) combined with 1 to 2 mg/liter tobramycin (MIC, 32 mg/liter) or amikacin (MIC, 4 mg/liter) yielded Ն2-log 10 more killing than the most active monotherapy at 48 h and prevented resistance. For all three strains, synergistic killing without resistance was achieved by Ն0.88ϫ MIC imipenem in combination with a median of 0.75ϫ MIC tobramycin (range, 0.032ϫ to 2.0ϫ MIC tobramycin ) or 0.50ϫ MIC amikacin (range, 0.25ϫ to 0.50ϫ MIC amikacin ). The MBM indicated that aminoglycosides significantly enhanced the imipenem target site concentration up to 3-fold; achieving 50% of this synergistic effect required aminoglycoside concentrations of 1.34 mg/liter (if the aminoglycoside MIC was 4 mg/liter) and 4.88 mg/liter (for MICs of 8 to 32 mg/liter). An optimized combination regimen (continuous infusion of imipenem at 5 g/day plus a 0.5-h infusion with 7 mg/kg of body weight tobramycin) was predicted to achieve Ͼ2.0-log 10 killing and prevent regrowth at 48 h in 90.3% of patients (median bacterial killing, Ͼ4.0 log 10 CFU/ml) against double-resistant isolate FADDI-PA088 and therefore was highly promising.

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Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance

Abstract: Our findings provide insight into optimal antibiotic treatment and may serve as a framework for new drug combinations and combination modelling.

Cited by 57 publications

References 32 publications

Paradoxical Effect of Polymyxin B: High Drug Exposure Amplifies Resistance in Acinetobacter baumannii

Paradoxical Effect of Polymyxin B: High Drug Exposure Amplifies Resistance in Acinetobacter baumannii

Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii : pharmacodynamics of new dosing strategies

Optimization of Synergistic Combination Regimens against Carbapenem- and Aminoglycoside-Resistant Clinical Pseudomonas aeruginosa Isolates via Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling

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