Management of KPC-producing Klebsiella pneumoniae infections

Bassetti, Matteo; Giacobbe, Daniele Roberto; Giamarellou, Helen; Viscoli, Claudio; Daikos, George L.; Dimοpoulos, George; Rosa, Francesco Giuseppe De; Giamarellos‐Bourboulis, Evangelos J.; Rossolini, Gian María; Righi, Elda; Karaiskos, Ilias; Tumbarello, Mario; Nicolau, David P.; Viale, P; Poulakou, Garyfallia

doi:10.1016/j.cmi.2017.08.030

Cited by 156 publications

(127 citation statements)

References 121 publications

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“…Considering its pharmacokinetic profile, the efficacy of tigecycline in patients with BSI due to KPC-Kp is debated and considering it an appropriate therapy may be questionable. However, in our study, we used a high dosage in all cases (100 mg every 12 h) and almost all published studies considered tigecycline as an evaluable and potentially effective drug [6]. Future studies should assess the exact role of tigecycline in KPC-Kp bacteremia.…”

Section: Discussionmentioning

confidence: 99%

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Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae

et al. 2020

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Background: Bloodstream infections (BSIs) by Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (Kp) are associated with high mortality. The aim of this study is to assess the relationship between time to administration of appropriate antibiotic therapy and the outcome of patients with BSI due to KPC-Kp hospitalized in intensive care unit (ICU). Methods: An observational study was conducted in the ICUs of two academic centers in Italy. Patients with KPC-Kp bacteremia hospitalized between January 2015 to December 2018 were included. The primary outcome was the relationship between time from blood cultures (BC) collection to appropriate antibiotic therapy and 30-day mortality. The secondary outcome was to evaluate the association of different treatment regimens with 30-day mortality and a composite endpoint (30-day mortality or nephrotoxicity). A Cox regression analysis to identify factors independently associated with 30-day mortality was performed. Hazard ratio (HR) and 95% confidence interval (CI) were calculated. Results: A total of 102 patients with KPC-Kp BSI were included. The most common sources of infection were intraabdominal (23.5%), urinary tract (20.6%), and skin and skin structure (17.6%). The 30-day mortality was 45%. Median time to appropriate antibiotic therapy was shorter in patients who survived (8.5 h [IQR 1-36]) versus those who died (48 h [IQR 5-108], p = 0.014). A propensity score matching showed that receipt of an in vitro active therapy within 24 h from BC collection was associated with lower 30-day mortality (HR = 0.36, 95% CI: 0.188-0.690, p = 0.0021). At Cox regression analysis, factors associated with 30-day mortality were primary bacteremia (HR 2.662 [95% CI 1.118-6.336], p = 0.027), cardiovascular disease , p = 0.029), time (24-h increments) from BC collection to appropriate therapy (HR 1.382 [95% CI 1.132-1.687], p = 0.001), SOFA score (HR 1.122 [95% CI 1.036-1.216], p = 0.005), and age (HR 1.030 [95% CI 1.006-1.054], p = 0.012). Ceftazidime-avibactam-containing regimens were associated with reduced risk of composite endpoint (30-day mortality OR nephrotoxicity) (HR 0.231 [95% CI 0.071-0.745], p = 0.014) compared to colistin-containing regimens.Conclusions: Time to appropriate antibiotic therapy is an independent predictor of 30-day mortality in patients with KPC-Kp BSI. Appropriate antibiotic therapy should begin within 24 h from the collection of BC.

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Section: Discussionmentioning

confidence: 99%

“…Treatment of patients with BSIs caused by KPC-Kp represents a challenge for clinicians, and no data from randomized clinical trials comparing different antibiotic strategies are currently available [6]. Observational studies indicate that combination therapies are more effective than monotherapies [7,8].…”

Section: Introductionmentioning

confidence: 99%

Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae

et al. 2020

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“…12 Based mostly on cohort studies, experts recommend a combination of two active agents for the management of severe CPE infections, primarily colistin combined with meropenem if the MIC is 8 mg/L and/or an aminoglycoside, tigecycline or fosfomycin, based on in vitro susceptibility tests. 13,14 Optimal treatment is poorly defined and it is critical to develop experimental models that closely reproduce human infections to provide direct comparisons of therapeutic regimens currently available for these difficult-to-treat infections with limited therapeutic options. Most models of CPE infections described in the literature are acute murine models of pneumonia, thigh infection or septicaemia.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of colistin alone and in various combinations for the treatment of experimental osteomyelitis due to carbapenemase-producing Klebsiella pneumoniae

Crémieux

Dinh

Nordmann

et al. 2019

Journal of Antimicrobial Chemotherapy

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Objectives In a new experimental model of carbapenemase-producing Klebsiella pneumoniae osteomyelitis we evaluated the efficacy of colistin alone and in various combinations and examined the emergence of colistin-resistant strains and cross-resistance to host defence peptides (HDPs). Methods KPC-99YC is a clinical strain with intermediate susceptibility to meropenem (MIC = 4 mg/L) and full susceptibility to gentamicin, colistin and tigecycline (MICs = 1 mg/L) and fosfomycin (MIC = 32 mg/L). Time–kill curves were performed at 4× MIC. Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 cfu. Treatment started 14 days later for 7 days in seven groups: (i) control; (ii) colistin; (iii) colistin + gentamicin; (iv) colistin + tigecycline; (v) colistin + meropenem; (vi) colistin + meropenem + gentamicin; and (vii) colistin + fosfomycin. Results In vitro, colistin was rapidly bactericidal, but regrowth occurred after 9 h. Combinations of colistin with meropenem or fosfomycin were synergistic, whereas combination with tigecycline was antagonistic. In vivo, colistin alone was not effective. Combinations of colistin with meropenem or fosfomycin were bactericidal (P < 0.001) and the addition of gentamicin enhanced the efficacy of colistin + meropenem (P = 0.025). Tigecycline reduced the efficacy of colistin (P = 0.007). Colistin-resistant strains emerged in all groups except colistin + fosfomycin and two strains showed cross-resistance to HDP LL-37. Conclusions In this model, combinations of colistin plus meropenem, with or without gentamicin, or colistin plus fosfomycin were the only effective therapies. The combination of colistin and tigecycline should be administered with caution, as it may be antagonistic in vitro and in vivo.

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“…Carbapenems have become last-line drugs against extensively drugresistant (XDR) strains of Enterobacteriaceae and Acinetobacter baumannii. Now, the global dissemination of strains carrying carbapenemases has resulted in limited therapeutic options [1][2][3][4][5][6]. Low serum and urine levels shadow the use tigecycline [5], whereas ceftazidime-avibactam (CZA) is confronted by emerging resistance [6] and is not effective against enzymes that belong to the metallo-β-lactamase group.…”

Section: Introductionmentioning

confidence: 99%

The polymyxin derivative NAB739 is synergistic with several antibiotics against polymyxin-resistant strains of Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii

et al. 2019

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Management of KPC-producing Klebsiella pneumoniae infections

Cited by 156 publications

References 121 publications

Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae

Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae

Efficacy of colistin alone and in various combinations for the treatment of experimental osteomyelitis due to carbapenemase-producing Klebsiella pneumoniae

The polymyxin derivative NAB739 is synergistic with several antibiotics against polymyxin-resistant strains of Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii

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