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

Expert Commentary

To date combination therapy for infections by CR GNB is not supported by evidence from a series of adequately sized RCTs. However, pre-clinical data and emerging clinical evidence from observational studies have suggested that antibiotic combinations may be better than monotherapy against CR GNB. Although the preliminary clinical evidence is mainly based on studies involving CR K. pneumoniae, this practice has been extrapolated and applied to the management of other important CR GNB such as P. aeruginosa, A. baumannii and other Enterobacteriaceae.

There are some data available indicating that combination therapy containing a carbapenem drug is associated with improved outcomes in the treatment of CR K. pneumoniae. However, there is still no definitive evidence of which is the most appropriate combination scheme, and it is likely that the best antibiotic combination should be individualized, depending on the organism, its susceptibility profile, the site of the infection and the patient to be treated. In order to help clinicians decide which would be the best combination therapy, we propose an algorithm for the choice of the antimicrobial drugs (Figure 2). The primary aim of the therapy is to optimize the use of the cornerstone therapy. Second, physicians should look for an adjuvant agent that is active or most likely active against the pathogen and further optimize its PK/PD target attainment. The activity of the drug is not necessarily based on the breakpoints defined by CLSI or EUCAST, but on the probability of PK/PD target attainment when dosage regimens are optimized based on the known PK proprieties. The proposed flowchart for selecting the main and adjuvant drug considered the published data and the authors' clinical experience with antibiotics against CR GNB infections. Additionally, we considered the probability of achieving anti-bacterial activity by attaining PK/PD targets through the optimization of dosage regimens, the toxicity profile and the potential for synergism based on preclinical studies. When using the fluxogram, it should be kept in mind that an adjuvant compound may be completely inactive in monotherapy and still be highly beneficial in a rationally designed combination regimen.

Figure 2.

Flowchart for selecting mainstream and adjuvant therapy against Gram-negative bacteria. (a) Colistin methanesulfonate sodium (CMS) – Loading dose: 150,000 IU (corresponding to 5 mg colistin base activity) × weight in kg; caution should be taken in using any dose above the current maximum approved daily dose of 10 million IU (300 mg of colistin base activity); maintenance dose started 12 or 24 h later: 9–12 million IU/day split into 2 or 3 doses (every 8 or 12 h) for patients with creatinine clearance ≥60 ml/min. Adjust for renal dysfunction.102 Polymyxin B – Loading dose recommended: 20,000–25,000 IU/kg (2–2.5 mg/kg) followed 12 h later by 25,000 IU/kg/day (MIC<1 mg/l) to 30,000 IU/kg/day (MIC = 1 or 2 mg/l) split into two daily doses (every 12 h). For polymyxin B, no need for dose adjustment in renal dysfunction or continuous venous–venous hemodialysis.36 CMS may be preferred for urinary tract infections owing to high urinary concentrations. (b) If the pathogen is suspected to be a metallo-β-lactamase-producing GNB, the aztreonam MIC may be evaluated at the same time as the MIC of the carbapenems. For aztreonam MICs ≤8 mg/l, consider aztreonam as the preferred combination drug at a dose of 6–8 g/day split into 3–4 doses that are given as 3–4 h infusion. (c) Some authors suggest that if the MIC ≤4 mg/l for carbapenems (maybe ≤2 mg/l for doripenem), a carbapenem should be the cornerstone drug in the combination scheme. (d) Doripenem: 2 g every 8 h infused over 3–4 h. Meropenem: 2 g every 8 h over 3–4 h. Imipenem may be used 1 g every 6 h, but there is few data concerning its stability in extended infusion and it poses a higher risk of convulsion at higher doses. Many carbapenemases possess a higher hydrolytic activity against imipenem. (f) Go to step (4) if the organism is a Pseudomonas aeruginosa. (e) 9–12 g/day of the sulbactam component every 6–8 h infused over 3–4 h. High-dose extended infusion sulbactam may also be considered against organisms with MIC = 16 mg/l. (g) 200 mg as loading dose followed by 100 mg every 12 h for MIC = 0.5 or 1 mg/l, or 100 mg as loading dose followed by 50 mg every 12 h may be appropriate for MIC ≤0.25 mg. Higher doses may be considered for severe urinary tract infections. (h) Since the pharmacokinetic/pharmacodynamic (PK/PD) parameters of fosfomycin are not well defined, high doses (20–24 g/day divided in 3 or 4 doses) are recommended for fosfomycin MIC = 16–32 mg/l. Lower doses (12–16 g/day) may be appropriate for MIC<16 mg/l. Further studies are required to confirm these suggestions. (i) Gentamicin and tobramycin should be chosen on the basis of the lower MIC; MIC ≤0.5: 5 mg/kg once daily. MIC 1 or 2 mg/l: 7 mg/kg once daily (for MIC = 4 mg/l even higher doses may be more appropriate); a loading dose must be administered in critically ill patients. Amikacin: 15 mg/kg once daily is more likely appropriate for MIC ≤4; for MIC = 8 or 16 mg/l higher doses may be necessary; a loading dose ≥25 mg/kg must be administered in critically ill patients. Increased doses and shorter duration of therapy (preferably <7 days) may be necessary, since toxicity depends on aminoglycoside therapy duration and dose. If drug level monitoring is available, consider to apply target concentration intervention software or to follow a nomogram, for example, the Hartford algorithm.217 (j) Few PK/PD data for GNB; IV is preferable if available; 10 mg/kg every 12 h. Higher doses have been used but toxicity must be further evaluated.196 (k) Doripenem or meropenem at doses indicated above + ertapenem 1 g daily. Addition of a third non-carbapenem drug should also be considered. (l) If tigecycline is the cornerstone drug, high doses should always be considered regardless of the MIC. (m) There are very few or no data for fosfomycin, aminoglycosides and rifampicin as the mainstream drug. If the use of any of these drugs is supported by the MIC, the use of two other drugs is strongly recommended. Emergence of resistance to fosfomycin, rifampicin and aminoglycoside monotherapy is very common, both in vitro and in patients.