What are the treatment options for resistant Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria?

Figures & data

Table 1. Clinical efficacy of old and new agents against KPC-Kp infections with comparison of monotherapy vs combination therapy

Reference	Study design	Enrolled patients	Infection	Microrganism	Regimen	Comparator regimen	Outcomes
Qureshi ZA et al. [9]	Retrospective observational two center cohort study	34 patients receiving definitive therapy (59% ICU patients)	BSIs	KPC-Kp	Monotherapies (n = 19: 37% colistin, 27% 21% tigecycline, 15% others)	Combination therapies (n = 15: 47% polimixins-based, 33% tigecycline based, 20% others)	28 day mortality rates were 58% and 13% with mono and combination therapies, respectively (P = 0.01) MVA: definitive therapy with combination therapies was associated with survival, P = 0.02.
Tumbarello M et al. [10]	Multicenter observational retrospective cohort study	125 patients (43% ICU patients)	BSIs	KPC-Kp	Monotherapies (n = 46: 48% colistin, 41% tigecycline or 11% gentamicin)	Combination therapies (n = 79: 79% tigecycline based, 66% colistin based. including double carbapenem based in 8 instances)	30 day mortality rates were 34% and 54% with mono and combination therapies, respectively; P =.02. MVA: postantibiogram therapy with tigecycline + colistin + meropenem was associated, P = 0.01
Daikos GL et al. [11]	Retrospective observational two center study	175 patients (58% ICU patients)	BSIs	CR-Kp (great majority KPC-Kp)	Monotherapies (n = 72: 51%, tigecycline, 30% colistin; 17% carbapenem, 12.5%aminoglycoside, 3% others)	Combination therapies (n = 103: 49% colistin based and 47% tigecycline based; 70% carbapenem-sparing regimens)	28 day mortality rates were 44% and 27% with mono and combination therapies, respectively, (P = 0.018).
Tumbarello M et al. [12]	Retrospective observational multicenter study	661 (n = 230 34.8% ICU patients)	Various (75.4% BSIs)	KPC-Kp	Monotherapies (n = 307: 39% colistin, 38% tigecycline, 23% gentamicin	Combination therapies (n = 354: 58% carbapenem based)	14 day mortality rates were 30% and 38% with mono and combination therapies, respectively, P = 0.03. MVA: Combination therapy was associated with lower mortality, P = 0.001
Falcone M et al. [4]	Retrospective observational study	111 (all ICU patients with septic shock)	Various (70% BSIs)	KPC-Kp	Monotherapies (definitive therapy with < two antibiotics displaying in vitro activity (n = 64)	Combination therapies (definitive therapy with ≥ 2 antibiotics displaying in vitro activity (n = 44)	30 day mortality rates were 85% and 15% with monotherapy and combination therapies, respectively (P < 0.001). MVA: colistin based regimen, use of ≥ 2 active agents as definite therapy and source control were associated with favorable outcome.
Souli M et al. [14]	Prospective observational study	27 (55% ICU patients)	Various (n = 12; 44% BSIs)	KPC-Kp	DC regimen (n = 27)	n/a	Clinical & microbiological success and 28 day mortality rates were 74% and 8.5%, respectively.
Cancelli F et al. [15]	Retrospective, single-center study	55 (no ICU patients)	Various (25.5% BSIs)	KPC-Kp	DC regimen: (n = 21)	BAT (mono/combination therapy with colistin, carbapenems, aminoglycosides, tigecycline or fluoroquinolones; n = 34)	60 day mortality rates were 9.5% and 11,7% with DC regimen and BAT, respectively
De Pascale G et al. Crit Care [16]	Case–control (1:2), observational two-center study	144 ICU patients)	Various (58% BSIs)	CR-Kp (n = 130; 90% KPC Kp; colistin resistant strains: 41.7% in the DC group vs 33.3%)	DC regimen (n = 48) plus colistin, and/or gentamicin and/or tigecycline in 73% of the cases.	Standard therapy with colistin or gentamicin or tigecycline (n = 96) alone (46%) or in combination (54%).	28-day mortality rates were 29% and 48% with DC and standard therapy, respectively (P = 0.04). MVA: DC regimen was associated with a reduction in 28-day mortality (P = 0.02)
Pea F et al [17]	Observational single center study	30 patients	Various (60% BSIs)	CR-Kp	Combination therapies including meropenem showing Css/MIC ratio <4 (regimen A, n = 16)	Combination therapies including meropenem showing Css/MIC ratio ≥4 (regimen B, n = 14)	Cures were 50% and 100% with regimen A and B, respectively (univariate logistic regression analysis P = 0.03)
Giannella M et al. [18]	Post hoc analysis of a multicenter observational study	595 (38% ICU patients)	BSIs	KPC-Kp	Combination therapies with HD meropenem (n = 428)	Combination therapies not including carbapenem (n = 167)	14 day mortality rates were 25% and 20% with HD meropenem and without carbapenem regimens, respectively, P = 0.18. When adjusted for the propensity score, HD meropenem-containing combination resulted protective, P = 0.03.
Shields RK et al. [20]	Retrospective, single center observational study	37 (29.7% transplant recipients)	Various	37 CRE; 28(75.7%) out of these were KPC-Kp)	CAZ-AVI alone (n = 26) or in combination with other antimicrobials (n = 11)	n/a	30-day clinical success: 59%. 30-day mortality rate: 24% 90-day recurrence: 23%. Microbiologic failure: 27% CAZ-AVI resistance: 10%
Shields RK et al [21]	Retrospective, single center observational study	109 (51.4% ICU patients)	BSIs	107 CR-Kp (97% KPC-Kp)	CAZ-AVI alone (n = 7) or in combination with gentamicin (n = 5)	Carbapenem plus aminoglycoside (n = 25), carbapenem plus colistin (n = 30), or other regimens (n = 41)	30-day clinical success and 90 day survival were higher among patients treated with CAZ-AVI than in those treated with all other regimens
Shields RK et al. [22]	Retrospective, single center observational study	77 (57.1% ICU patients)	Various	77 CRE (72.7% KPC-Kp)	CAZ-AVI alone (n = 53) or in combination other antimicrobials (n = 24)	n/a	30-day mortality rate: 19%. 90-day mortality rate: 31%. Clinical success rates were 36%, 75% and 88% for pneumonia, BSI and UTIs, respectively. At MVA, pneumonia and RRT were associated with clinical failure. Microbiologic failures: 32% (more common in pneumonia cases). RRT was an independent predictor of resistance development.
Van Duin D et al. [23]	Prospective, multicenter, observational study.	133 (59.1% ICU patients)	Various (46% BSIs)	137 CRE; (97% Kp). 52(96%) out of 54 Kp evaluated for presence or absence of carbapenemase genes were KPC-Kp.	CAZ-AVI alone (n = 24) or in combination with other antimicrobials (n = 14)	i.v. colistin (various dosing regimens) alone (n = 6) or in combination with other antimicrobials (n = 93)	All-cause 30 day mortality were 9% and 32% with CAZ-AVI and colistin based regimens, respectively (P = .001).
Guimarães T et al. [24]	Prospective multicenter observational study	29 (n = 17; 58.6% ICU patients)	Various (41.4% primary BSIs)	Enterobacteriales coresistant to carbapenems and polymyxins (100% KPC-2 producing strains)	CAZ-AVI with or without other antimicrobials	n/a	Overall clinical success: 82.7% (75% for BSIs) 14-day mortality: 31% 30-day mortality: 51.7% .
Tumbarello M et al [25]	Retrospective multicentre observational matched cohort control study (Italy)	208(32% ICU patients)	BSIs	All KPC-Kp	CAZ-AVI as salvage therapy alone (n = 22) or in combination to other antimicrobials (n = 82)	various regimems adopted as salvage therapy	30-day mortality rate were 36% and 56% with CAZ-AVI and other salvage regimens, respectively (P = 0.005) Receipt of CAZ-AVI was the sole independent predictor of survival in multivariate analysis with and without adjustment for propensity score.
Wunderink RG et al. [29]	Randomized (2:1), multicenter, multinational, open-label, active-controlled phase-3 trial	47(11% ICU patients; 25% immuno compromised patients)	Various (47% BSI)	47 confirmed/ suspected CRE (64% KPC-Kp)	MER-VAR (n = 32)	BAT (mono/combination therapy with polymyxins, carbapenems, aminoglycosides, tigecycline or CAZ-AVI alone; n = 15)	Clinical cure rates at EOT were 59% and 33% (P = 0.03) whereas 28 mortality rates were 15.6% and 33.3% (P = 0.20) with MER-VAB and BAT, respectively. Clinical failure or renal AEs rates were 28.1% and 80% with MER-VAB and BAT, respectively.
Ackley R et al et al. [30]	Retrospective multicenter observational study	130 patients (58% ICU patients)	Various (41% BSIs)	136 CRE (62% polimicrobial infections). KPC+CRE were isolated in approximately 70% of cases.	CAZ-AVI alone (n = 41) or in combination (n = 64) with other antibiotics (polimixins, n = 30)	MER-VAB alone (n = 21) or in combination (n = 4) with other antibiotics (polimixins, n = 2)	30-day mortality rates were 19% and 11.5% with CAZ-AVI and MER-VAB, respectively (P = 0.57). In the CAZ-AVI group, increase in MIC and emergence of resistance was observed 6 and 3 cases, respectively.
McKinnell JA et al. [35]	Phase 3, open-label study. Two cohorts: Cohort 1 (C1), a randomized comparison of PLZ vs. CST; Cohort 2 (C2), a single-arm study of PLZ in patients ineligible for C1 (CARE study)	39 patients (C1), 30 patients (C2)	Various (30/39, 76.9% BSIs in C1; 15/30, 50% BSIs in C2)	CRE (no attempt to define CR mechanism)	Cohort 1: PLZ (15 mg/kg q24 h) in combination with meropenem or tigecycline Cohort 2: PLZ plus investigator’s choice of adjunctive agent	CST (300-mg load [colistin base activity] then 5 mg/kg/d) plus tigecycline or meropenem.	All-cause mortality at Day 28 in patients with BSI from C1 was 7.1% (1/14) in PLZ group compared with 40% (6/15) in CST group. Higher rates of bacteremia clearance by Day 5 were observed in patients receiving PLZ as compared to CST (17/14, 85.7% versus 7/15 46.7%)

AEs, adverse events; BAT, best available therapy; BSIs bloodstream infections; CAZ-AVI, ceftazidime avibactam; CR, carbapenem resistance; CRE, Carbapenem-resistant Enterobacteriaceae; Css, steady-state concentration; DC regimen, double-carbapenem regimen; HD, high dose; ICU, Intensive Care Unit; KPC-Kp, Klebsiella pneumoniae carbapenemase–producing K. pneumoniae; LRTIs, low respiratory tract infections; MER-VAB, meropenem/vaborbactam; MIC, minimal inhibitory concentration; MVA, multivariate analysis; PDR, pandrug resistance phenotype; XDR, extensively resistance phenotype; RRT, Renal Replacement Therapy; UTIs, urinary tract infections; PLZ, plazomicin; CST, colistin.

Table 2. Summary of new agents with activity against KPC-Kp (references [31,38,39])

Agent	Class	CRE activity other than KPC	Other MDR activity	Route of administration	FDA approval	Potential uses or indications under investigation
Eravacycline	fluorocycline (tetracycline)	yes	A. baumannii, MRSA, VRE	Oral/i.v.	cIAIs	pneumonia, ABSSSIs
Apramycin	aminoglydoside	yes	A. baumannii, P. aeruginosa, MRSA	i.v.	-	-
Cefiderocol	siderophore cephalosporin	yes	A. baumannii, P. aeruginosa	i.v.	cUTIs	infections with limited treatment options
Cefepime /taniborbactam	β-lactam/β-lactamase-inhibitor	yes	P.aeruginosa	i.v	-	cUTIs, infections with limited treatment options
Cefepime /zidebactam	β-lactam/β-lactamase-inhibitor	yes	P. aeruginosa, A. baumannii	i.v	-	pneumonia infections with limited treatment options
Imipenem/ relebactam	β-lactam/β-lactamase-inhibitor	-	P. aeruginosa	i.v	cUTIs, cIAIs	infections with limited treatment options
Meropenem/ nacubactam	β-lactam/β-lactamase-inhibitor	Yes (OXA-48 producing strains only)	P. aeruginosa (hyper-AmpC-producing strains only)	i.v.	-	pneumonia. infections with limited treatment options
Meropenem/QPX7728	β-lactam/β-lactamase-inhibitor	yes	A. baumannii, P. aeruginosa	i.v.	-	-

A. baumannii, Acinetobacter baumannii; ABSSSIs, acute bacterial skin and skin structure infections; cIAIs, complicated intra-abdominal infections; CRE, carbapenem-resistant Enterobacteriaceae; cUTIs, complicated urinary tract infections; HABP/VAP, hospital-acquired/ventilator-associated bacterial pneumonia; I.v. intravenous; KPC-Kp, Klebsiella pneumoniae carbapenemase–producing K. pneumoniae; MDR, multidrug resistant; MRSA, methicillin resistant Staphylococcus aureus; P. aeruginosa, Pseudomonas aeruginosa; VRE, vancomicin resistant Enterococcus.

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