SUPPLEMETARY MATERIAL S1 - Background information for Question 4
Note: numbers ofreferences are provided as they are listed in the original paper
4a. Colistin
Colistin (polymyxin E) is considered among the most active agents against KPC-KP. In order to timely achieve the desired serum concentration, a loading dose of colistin is required, followed by adequate maintenance doses.30However, increasing resistance to colistin has been recently reported with rates exceeding 20% and 30% of isolates in some centres in Greece and Italy, respectively.31-36PK/PD studies on colistin based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) have led to the recommendation of a loading dose of 9 MIU of colistimethate sodium (CMS), the inactive prodrug.37 Maintenance dose is 4.5 MIU every 12 hours, with adjustment based on CrCL30. fAUC/MIC is the PK/PD index that mostly correlates with the antibacterial effect and a free plasma AUC of 24 corresponds to an average free colistin concentration of 2 mg/L, which is considered a reasonable target when initiating therapy for an organism with an MIC of 1 mg/L.30,37 However, patients with CrCL ≥ 80ml/min have a low probability of achieving target colistin concentration and higher dosages are under investigation, being limited however by the risk of colistin-associated nephrotoxicity.30,37,38
Nephrotoxicity associated to colistin use has shown rates between 18% and 63%.38 Risk factors for toxicity should be considered in patients receiving colistin and include hypoalbuminemia, receipt of ≥ 3 concomitant nephrotoxins (e.g., vancomycin, aminoglycosides, NSAIDs), age, diabetes mellitus, obesity, total cumulative dose, duration of therapy, and high serum concentrations.38,39
Although currently unavailable in Europe, it is worth mentioning briefly that another polymyxin, polymyxin B, has some peculiar PK/PD characteristics, such as its pharmaceutical form which allows immediate availability (no prodrug) and the non-renal elimination, that might theoretically favour or disfavour its use over colistin in bacteraemic and urinary KPC-KP infections, respectively. 40,41Consequently, PK/PD information of colistin cannot be directly applied to polymyxin B, and vice versa.
4b. Aminoglycosides
Aminoglycosides demonstrate good susceptibility profile towards KPC-KP and could serve as a backbone in the treatment of these infections, in particular if the isolate is colistin-resistant. 42,43 (Table 2). In this regard, most observational data is currently limited to gentamicin-including combinations.42,43
Once-daily administration (ODA) has become the mainstay for aminoglycosides due to a simplified dosing and monitoring, along with decreased nephrotoxicity and costs.44Among aminoglycosides, gentamicin has the greatest nephrotoxic potential.45 Risk factors for toxicity are known and include prolonged therapy (> 7days), older age, comorbidities (e.g.., diabetes), presence of sepsis, reduced effective arterial volume, concomitant nephrotoxins, elevated through levels, and frequency of dosing. Acute kidney injury (AKI) is observed in 10 to 20% of patients, is non-oliguric, and occurs after 5 to 7 days of therapy. AKI is rarely severe and kidney function usually returns to normal within 3 weeks after therapy discontinuation.45
Optimal clinical efficacy of aminoglycosides is associated with peak-serum levels 8-10 times above the MIC. The ODA dosing aims at peak serum levels of 15-20 μg/ml both for gentamicin and tobramycin and 20-40μg/ml for amikacin, with trough levels of ≤1μg/ml and 1-4μg/ml, respectively, to avoid nephrotoxicity.44,45
4c. Tigecycline
Tigecycline is approved for the treatment of cIAI and SSSI and has in vitro activity against Enterobacteriaceae with multiple resistance mechanisms, including KPC-KP. Tigecycline pharmacokinetics at the current dosage (50mg q 12 hours following a loading dose of 100mg) is inadequate for the treatment of VAP.46,47,48 In 2010 and 2013, the US Food and Drug Administration (FDA) reported an increased risk of mortality associated with tigecycline use, compared with other regimens in the treatment of serious infections. In the pooled analysis of data from randomized clinical trials, it was evident that the major driver of increased risk of mortality was inclusion of patients with hospital-acquired pneumonia (HAP) and VAP.49 On the basis of the pooled data analysis, the FDA recommended that patients with severe infections should receive alternatives to tigecycline. However, although with the important limit of low-level evidence, current literature indicate tigecycline as a possible component of combination regimens for treating KPC-KP infections, in view of a possible survival benefit suggested in observational studies.21,22
As regards PK/PD studies, higher dosages might be necessary for KPC-KP with a MIC of tigecycline of 0.5 or 1 mg/L (e.g., 75 mg or 100 mg every 12 h following a loading dose of 150 or 200 mg respectively), given the inherent low serum drug levels usually not exceeding 0.9mg/L.50 This is extremely important for BSI and VAP, whereas for MICs < 0.5 mg/L, and particularly in intraabdominal infections, the standard dosage of 50 mg every 12 h may be adequate.50,51,52
4d. Fosfomycin
Given that fosfomycindisplays good in vitro activity against carbapenem-resistant pathogens, this agent could be a valuable agent to be used in critically ill patients with KPC-KP infections, although some doubts remain in view of the lack of large clinical data.53 The potential of fosfomycin to rapidly select resistant mutants during therapy is also a possible matter of concern. In critically ill patients, fosfomycin should be administered as 6 to 8g every 8 hours, resulting in Cmax between 260-442μg/ml.54 Since the main PD parameter of fosfomycin is ≥70% of T above MIC, values of 8μg/ml, 16μg/ml and 32μg/ml may fulfil the probability of target attainment (PTA) at 98%, 92% and 61% respectively, indicating that the highest doses and at 6h infusion should be given if MIC is ≥32μg/ml.54,55
Recent data, however, suggest that AUC/MIC could be a better parameter for fosfomycin PD compared to T>MIC.56,57
Clinical experience about the use of intravenous fosfomycin has been summed up in a recent systematic review.58As regards critically ill patients with XDR and PDR isolates, in a series of 48 patients receiving fosfomycin 6g/6hourly with a successful outcome in 54.2% and an all-cause mortality of 37.5%.38
4e. Ceftazidime/avibactam
The newly approved ceftazidime/avibactam has demonstrated good in vitro activity against KPC-KP and OXA-48-producing bacteria, but not against metallo-β- lactamases such as NDM, VIM, or IMP. Clinical data on the efficacy of ceftazidime-avibactam in real-world studies and severe infections such as BSI or pneumonia are still scarce. Two case series have been recently published,59,60 including 37 cases and 38 cases, respectively, showing encouraging results using ceftazidime-avibactam against infections caused by carbapenem-resistant Enterobacteriaceae, mostly KPC-KP. In particular, a recent study suggested a possible higher efficacy and lower toxicity of ceftazidime-avibactam compared to other regimens used against carbapenem-resistant K. pneumoniae bacteremia, although due caution is needed in interpreting this result because of the heterogeneity of included infections and the observational nature of the report .61
Worrisome reports have already identified development of resistance-conferring blaKPC-3 mutations in KP within 10 to 19 days of ceftazidime-avibactam exposure.62,63
4f. Double-carbapenem combinations
Originally, Bulik and Nicolau proposed a double-carbapenem combination (DCC) including ertapenem and doripenem as a paradoxical but possibly useful treatment against KPC-KP.64 The effect of the combination was attributed to the increased affinity of ertapenem for KPCs, acting as a suicide inhibitor hindering subsequently doripenem or meropenem degradation. Time-killing studies and checkerboard studies verified DCC synergistic activity against KPCP XDR and PDR strains in 78% of the experiments.64 First in vivo experience was a successful report of three patients, two of them with bacteraemia.65 In a recent retrospective study, 27 patients (46% BSI and 26% UTIs) were treated with DCC (ertapenem plus either meropenem or doripenem).66 Overall clinical success was 70.9% and all-cause mortality 27.4%. However, 22.1% of patients received additional active in vitro antibiotics, preventing from an unbiased evaluation of the true contribution of DCC to clinical success. In patients with infections caused by pan-drug resistant (PDR) isolates, a successful response was nonetheless noted in 78.5%.66 In a study of 32 patients, an overall clinical success of 75% was recorded with DCC; 14 critically-ill patients also benefited from the addition of colistin, despite respective MIC>2mg/L. All clinical data were verified with time kill studies.67 Finally, Cprek et al. reported overall 39% clinical success in 18 patients with carbapenem-resistant K. pneumoniae.68
However, despite promising findings, larger clinical studies are still needed for confirming and quantifying the true clinical benefit of DCC, and for comparing it with that of in vitro active agents. In the meantime, in our opinion it would be prudent to consider DCC preferentially for patients with no other therapeutic options.
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