Combination Therapy for Carbapenem-resistant Gram-negative Bacteria

Alexandre P Zavascki; Jurgen B Bulitta; Cornelia B Landersdorfer


Expert Rev Anti Infect Ther. 2013;11(12):1333-1353. 

In This Article


Aminoglycosides have been used for more than 50 years against a large variety of infections. They act at the 30S subunit of the ribosome, interfering with bacterial protein synthesis.[170] This effect likely contributes to prevention of emergence of resistance in combination regimens, as inhibition of protein synthesis will prevent the over-expression of resistance mechanisms that depend on protein synthesis (Figure 1). The main aminoglycosides prescribed for GNB infections are gentamicin, tobramycin and amikacin, and the PK properties of these drugs are quite similar.[170,171] Aminoglycosides cause concentration-dependent bacterial killing and have a prolonged post-antibiotic effect.[170,171] Whereas a Cmax/MIC ratio of 8–10 for aminoglycosides has been associated with maximal bacterial killing and clinical efficacy,[170–172] it has also been suggested that the AUC/MIC may be more closely associated with bactericidal activity, especially in Enterobacteriaceae.[173]

A gentamicin or tobramycin dose of 7 mg/kg infused over 30 min leads to peak concentrations from approximately 15–30 mg/l.[174,175] After 15 mg/kg of amikacin over 30 min, the maximum concentration was on average 40.9 mg/l.[176] Considering the protein binding of aminoglycosides (usually <10%), these doses would be optimal against pathogens with MICs <2 mg/l for gentamicin and tobramycin, and ≤4 mg/l for amikacin. It should be noted that the susceptibility breakpoints for these drugs are 2 or 4 mg/l for gentamicin and tobramycin, and 8 or 16 mg/l for amikacin depending on the organism or if established by European Committee on Antimicrobial Susceptibility Testing or Clinical and Laboratory Standards Institute.[301,302] However, there are some data associating AUC/MIC with surrogate clinical outcomes, such as the probability of afebrility by day 7 of aminoglycoside therapy as well as nephrotoxicity.[177–180] For gentamicin and tobramycin, the highest probabilities of clinical success with lower probabilities of renal toxicities were seen when 5 mg/kg once daily was administered for organisms with MIC ≤0.5 mg/l.[180] When using 7 mg/kg once daily against organisms with MIC = 4 mg/l (CLSI susceptibility breakpoint), the probability of afebrility by day 7 drops to 58% and the probability of nephrotoxicity increases to 51%.[180] According to these latter studies, the current breakpoints may be too high if a high probability of successful treatment with acceptable toxicity is expected.[177] In addition, it is well demonstrated that critically ill patients have a larger volume of distribution and therefore require higher aminoglycoside loading doses to achieve therapeutic concentrations.[181] A first dose of ≥25 mg/kg amikacin should be administered to achieve therapeutic concentrations in these patients.[181] It is likely that these higher doses would be still required along the entire therapy, but clinical data on this are lacking.[181]

The administration of a single daily dose of aminoglycosides has been widely used in order to achieve higher peak serum concentrations and decrease the risk for nephrotoxicity and ototoxicity.[177] However, it should be noted that this benefit on nephrotoxicity depends on the cumulative dose and there is virtually no difference between once- or multiple-daily dosage regimens after 5 or 6 days of therapy using currently recommended doses.[179] Once daily dosing has also been associated with a lower propensity for adaptive resistance in P. aeruginosa owing to the adaptive over-expression of the MexY transporter component of the MexXY-OprM efflux pump.[182] Additionally, the post-antibiotic effect of aminoglycosides had a longer duration for higher peak concentrations.[177]

Nonetheless, even potentiating activity and lowering toxicity with once-daily regimens, it is difficult to achieve optimal activity of aminoglycosides in monotherapy when the MICs of CR GNB for these organisms are above the susceptibility breakpoint, considering the narrow therapeutic window of aminoglycosides. Fortunately, there are some CR GNB isolates, especially some KPC-producing Enterobacteriaceae that still remain susceptible to at least one of these agents. It is also likely that aminoglycosides can achieve synergistic killing in combination with another antibiotic at sub-MIC concentrations.[183] However, determination of the MIC of the drug may be useful to adjust dosage regimens to maximize therapeutic effect and decrease toxicity. Except for synergistic combinations, aminoglycoside monotherapy has a limited role when the isolate presents with in vitro resistance.

Another point is that it may be useful to assess the susceptibility profiles of the different aminoglycosides, since they may present some differences in potency against distinct species and in resistance profiles, depending on the molecular mechanism implied in aminoglycoside resistance.[184] Some data indicated that tobramycin was the most active agent against P. aeruginosa and A. baumannii, with MICs that were 2- to 4-fold lower than those for gentamicin.[171] Thus, considering the similar PK of the latter drugs, tobramycin might be preferred against non-fermenters. Against Enterobacteriaceae, amikacin usually presents lower resistance rates than gentamicin and tobramycin.[185]

Aminoglycosides are generally administered as once-daily doses. Due to a narrow therapeutic index, individualizing dosage regimens is important to attain PK/PD targets and decrease toxicity.[170] Various nomograms have been developed to guide dosing by therapeutic drug monitoring. Furthermore, advanced clinical software that incorporate the aminoglycoside concentrations observed in a patient with Bayesian population PK models and the effect of specific patient characteristics on the PK to provide optimized individualized dosage regimens are available and recommended.[186,303] It is beyond the scope of this review to discuss each nomogram or algorithm, but these can be found elsewhere.[170,187] Finally, plazomicin (formerly ACHN-490), a new aminoglycoside with increased resistance to some aminoglycoside-modifying enzymes, has been clinically evaluated and it may be potentially useful in the near future against isolates with resistance to other drugs in this class.[184]