Interaction of Drug- and Granulocyte-Mediated Killing of Pseudomonas aeruginosa in a Murine Pneumonia Model

dInfections caused by multidrug-resistant Acinetobacter baumannii are a major public health problem, and polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically used polymyxins, polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant polymyxin B and colistin dosage regimens against one reference and three clinical A. baumannii strains in a dynamic one-compartment in vitro model. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for polymyxin-induced bacterial killing. All polymyxin B regimens achieved peak concentrations of at least 1 mg/liter within 1 h and caused >4 log 10 killing at 1 h. In contrast, the slow rise of colistin concentrations to 3 mg/liter over 48 h resulted in markedly reduced bacterial killing. A significant (4 to 6 log 10 CFU/ ml) amplification of resistant bacterial populations was common to all dosage regimens. The developed mechanism-based model explained the observed bacterial killing, regrowth, and resistance. The model also implicated adaptive polymyxin resistance as a key driver of bacterial regrowth and predicted the amplification of preexisting, highly polymyxin-resistant bacterial populations following polymyxin treatment. Antibiotic combination therapies seem the most promising option for minimizing the emergence of polymyxin resistance.

Section: Discussionmentioning

confidence: 99%

Colistin and Polymyxin B Dosage Regimens against Acinetobacter baumannii: Differences in Activity and the Emergence of Resistance

Cheah

Tsuji

et al. 2016

“…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). Based upon this, the bacterial inocula simulated in the HFIM were approximately 10 8 CFU/ml to mimic these clinical scenarios.…”

Section: Discussionmentioning

confidence: 99%

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

Tsuji

Landersdorfer

Lenhard

et al. 2016

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...

“…The differential equations for the two resistant populations (i.e., IR and RI) contained the same terms as those for CFU SS1 and CFU SS2 but contained different estimates for K max , KC 50 , and k 12 compared to the double-susceptible population.…”

Section: Methodsmentioning

confidence: 99%

“…Mechanistic synergy was implemented by assuming that the aminoglycoside could enhance the target site penetration of imipenem due to disruption of the outer membrane (33,34). This was implemented in the model by estimating a lower KC 50 Table 3. Subpopulation synergy (i.e., imipenem killing the aminoglycoside-resistant population and vice versa) was present for all strains.…”

Section: Methodsmentioning

confidence: 99%

Novel Approach To Optimize Synergistic Carbapenem-Aminoglycoside Combinations against Carbapenem-Resistant Acinetobacter baumannii

Yadav

Landersdorfer

Nation

et al. 2015

cAcinetobacter baumannii is among the most dangerous pathogens and emergence of resistance is highly problematic. Our objective was to identify and rationally optimize ␤-lactam-plus-aminoglycoside combinations via novel mechanism-based modeling that synergistically kill and prevent resistance of carbapenem-resistant A. baumannii. We studied combinations of 10 ␤-lactams and three aminoglycosides against four A. baumannii strains, including two imipenem-intermediate (MIC, 4 mg/liter) and one imipenem-resistant (MIC, 32 mg/liter) clinical isolate, using high-inoculum static-concentration time-kill studies. We present the first application of mechanism-based modeling for killing and resistance of A. baumannii using Monte Carlo simulations of human pharmacokinetics to rationally optimize combination dosage regimens for immunocompromised, critically ill patients. All monotherapies achieved limited killing (<2.3 log 10 ) of A. baumannii ATCC 19606 followed by extensive regrowth for aminoglycosides. Against this strain, imipenem-plus-aminoglycoside combinations yielded more rapid and extensive killing than other ␤-lactam-plus-aminoglycoside combinations. Imipenem at 8 mg/ liter combined with an aminoglycoside yielded synergistic killing (>5 log 10 ) and prevented regrowth of all four strains. Modeling demonstrated that imipenem likely killed the aminoglycoside-resistant population and vice versa and that aminoglycosides enhanced the target site penetration of imipenem. Against carbapenem-resistant A. baumannii (MIC, 32 mg/ liter), optimized combination regimens (imipenem at 4 g/day as a continuous infusion plus tobramycin at 7 mg/kg of body weight every 24 h) were predicted to achieve >5 log 10 killing without regrowth in 98.2% of patients. Bacterial killing and suppression of regrowth were best achieved for combination regimens with unbound imipenem steady-state concentrations of at least 8 mg/liter. Imipenem-plus-aminoglycoside combination regimens are highly promising and warrant further evaluation.A ntimicrobial resistance in Gram-negative bacteria is one of the three greatest threats to human health (1-3). Acinetobacter baumannii is one of the three most challenging Gram-negative pathogens, especially in intensive care units. In approximately 14,000 critically ill patients, A. baumannii infections were highly associated (P Ͻ 0.001) with increased mortality (4). A. baumannii often causes bloodstream, respiratory tract (including ventilatorassociated pneumonia), and wound infections (including burns and combat wounds); these are associated with high morbidity (1, 2, 5) and up to 87% mortality (6). Multidrug-resistant A. baumannii strains have caused major outbreaks in the United States and worldwide (7,8).In the past, ␤-lactams and aminoglycosides were successfully used to treat susceptible A. baumannii (9), but unfortunately, strains have emerged that are resistant to virtually all antibiotics in monotherapy (10, 11). While carbapenems were hitherto considered the treatment of choice against severe A. baumannii infe...