Treatment and diagnosis of severe KPC-producing Klebsiella pneumoniae infections: a perspective on what has changed over last decades

Figures & data

Figure 1. Combination therapies frequently employed before availability of novel β-lactam/β-lactam inhibitor (BL/BLI) combinations and β-lactams (BL) for the treatment of severe infections caused by KPC-producing Klebsiella pneumoniae. CNS: central nervous system; KPC-Kp: Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae; MIC: minimum inhibitory concentration; PK/PD: pharmacokinetic/pharmacodynamic. Information included in the table is from Refs. [9,15,19–34].

Table 1. Current IDSA and ESCMID recommendations for the treatment of severe infections caused by KPC-producing Klebsiella pneumoniae.

Guidelines/Guidance document	Recommended treatment for severe KPC-Kp infections	Comments
ESCMID guidelines [36]	For patients with severe infections due to CRE, including KPC-Kp, the guidelines suggest meropenem/vaborbactam or ceftazidime/avibactam if active in vitro (Conditional recommendation with low/moderate level of evidence) In patients with CRE infections resistant to meropenem/vaborbactam and ceftazidime/avibactam, the guidelines conditionally recommend cefiderocol (Conditional recommendation with low level of evidence) The guidelines state that there is currently no evidence to recommend for or against the use of imipenem/relebactam for severe CRE infections (No recommendation) For patients with CRE infections susceptible to and treated with ceftazidime-avibactam, meropenem-vaborbactam, or cefiderocol, the guidelines do not recommend combination therapy (Strong recommendation with low level of evidence) For the targeted treatment of severe infections caused by CRE resistant to novel agents and susceptible in vitro only to polymyxins, aminoglycosides, tigecycline and/or fosfomycin, the guidelines suggest treatment with more than one drug active in vitro, with no recommendation for or against specific combinations (Conditional recommendation with moderate level of evidence)	The ESCMID recommendations refer to targeted treatment (i.e. after susceptibility test results, whereas the optimal place in therapy of novel agents for the empirical treatment (i.e. before the identification of the causative agent and susceptibility test) of severe infections in patients at risk of KPC-Kp etiology remains to be provided in official documents of major infectious diseases scientific societies Recommendations of ESCMID are mostly similar to those of IDSA, although a difference, likely relying on the different development methods, is the lack of recommendations on the role of imipenem/relebactam in the ESCMID guidelines, while this agent is among first-line choices recommended by IDSA. This possibly relied on the fact that the in IDSA guidance document (the first version was released before the ESCMID guidelines) was conceived to delineate the way to correctly use novel agents that had become available and were (are) less toxic than previously used approaches. In turn, this prioritized urgency toward extensive and comprehensive methodological adherence to GRADE methodology and guidelines development. On the other hand, ESCMID guidelines are methodologically in line with standard requirements for guidelines development. This nonetheless does not allow to provide recommendations for those areas (e.g. use of imipenem/relebactam) for which clinical evidence for the treatment of CRE infections is still preliminary or absent despite well supported by preclinical evidence. In this regard, it has been suggested that ESCMID and IDSA approaches should be considered as complementary, with a joint approach being required for future refinement of current recommendations with the availability of novel evidence [48]
IDSA guidance document [37] (No strength of recommendation and level of evidence provided)	Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem/relebactam are preferred treatment options for severe infections caused by KPC-Kp resistant to both ertapenem and meropenem. Cefiderocol is a further alternative in the case of pyelonephritis and complicated urinary tract infections Polymyxin B and colistin should be avoided for the treatment of severe infections caused by CRE Combination of a novel β-lactam agent with an aminoglycoside, fluoroquinolone, or polymyxin is not routinely recommended for the treatment of infections caused by CRE	The IDSA recommendations refer to targeted treatment (i.e. after susceptibility test results, whereas the optimal place in therapy of novel agents for the empirical treatment (i.e. before the identification of the causative agent and susceptibility test) of severe infections in patients at risk of CRE etiology remains to be provided in official documents of major infectious diseases scientific societies

CRE: carbapenem-resistant Enterobacterales; ESCMID: European Society of Clinical Microbiology and Infectious Diseases; GRADE: Grading of Recommendations Assessment, Development, and Evaluation; IDSA: Infectious Diseases Society of America; KPC-Kp: Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae.

Table 2. Overview of established laboratory methods for detection of KPC-type carbapenemases in patients with severe infections caused by KPC-producing Klebsiella pneumoniae.

		Time to results	Specimen	Information provided	Limitation(s)	Note	Commercial assay(s)	Ref.
Phenotypic tests	Modified Hodge test (MHT)	18–24 h	Pure culture	Carbapenemase activity	• False-positive results for high-level AmpC producers or CTX-M-type ESBL producers • Weak detection of NDM producers	Early CLSI-endorsed method	–	[64,65,69]
	Modified carbapenemase inactivation method (mCIM)	18–24 h	Pure culture	Carbapenemase activity	–	Laboratory developed test	–	[64,65,68]
	Gradient MIC strip	18–24 h	Pure culture	Production of KPC or MBL	• Poor specificity with AmpC	–	ETEST^® KPC	[66–68]
	(Multidisc) combined-disk tests (CDT)	18–24 h	Pure culture	Production of KPC, MBL or OXA-48	• Identification of carbapenemase Producers among AmpC-positive species (e.g. Enterobacter spp.)	Laboratory developed test	–	[64,65,68]
	Carba NP test II	30 min–2 h	Pure culture	Production of class A, B or D β-lactamases	• Weak detection of OXA-48 producers	CLSI-endorsed method	RAPIDEC^® CARBA NP	[64,68,69]
Genotypic tests	MALDI-TOF MS	30 min	Pure culture	Identification of a gene product (often) accompanying KPC	• Alternate MALDI-TOF instrument Settings (on the usual instrument) • Identification limited by the presence of blaKPC aboard of pKpQIL-like plasmids	–	–	[68,70]
	Lateral flow immunoassay (LFIA)	20 min	Pure culture, positive blood culture, rectal swab	Production of KPC, MBL (VIM, IMP, NDM), OXA-48-like	• Possible false-negative results with new enzyme variants • Non high throughput • False-negative results may occur with some KPC variants (e.g. KPC-31) • Unable to detect novel carbapenemases	–	NG Test Carba 5^® RESIST-4 O.K.N.V.^® KPC K-SeT	[68,71]
	PCR, real time-PCR	50 min–4 h	Pure culture rectal swab	Detection of specific carbapenemase genes (e.g. blaKPC, blaNDM, blaIMP, blaVIM, blaOXA 48-like)	• Unable to detect novel carbapenemases	Include laboratory developed test	Hyperplex SuperBug ID Check-Direct CPE assay CRE ELITe MGB^® kit Revogene^® Carba C Novodiag^® CarbaR+ AllPlex^TM Entero-DR assay Xpert Carba-R test CARBAPLEX^®	[72,73]
	Loop-mediated isothermal amplification (LAMP)	25 min	Pure culture	Detection of specific carbapenemase genes (e.g. blaKPC, blaNDM, blaIMP, blaVIM, blaOXA 48-like)	• Unable to detect novel carbapenemases	–	eazyplex^® superBug	[72]
	Syndromic assay	40 min–6 h	Positive blood culture, whole blood, respiratory sample, synovial fluid	Detection of specific carbapenemase genes (e.g. blaKPC, blaNDM, blaIMP, blaVIM, blaOXA 48-like) and pathogens	• Limited spectrum of target carbapenemases • Unable to detect novel carbapenemases • Multiple positive results or targets may complicate test interpretation • Higher cost than confirmatory molecular tests based on PCR\RT-PCR • False-positive results may occur • No detection of off-target pathogens	Minimal hands-on time, highly automated	Biofire^® FilmArray panels (Blood Culture Identification 2, Pneumonia Panel plus, Bone and Joint Infection) Unyvero^® ePlex^® BCID-GN panel Verigene^® (BC-GN) T2Resistance Panel \ T2Bacteria Panel	[74,75]
	Whole-genome sequencing (WGS)	2 h–3 days	Pure culture	Detection of all resistance genes	• Need of trained microbiologists • Need of dedicated instrumentation, infrastructures • Longer time to results than other molecular assays	Not yet FDA- / CE- IVD cleared	–	[76]

CE: Conformite Europeenne; CLSI: Clinical and Laboratory Standards Institute; CTX-M: active on cefotaxime, first isolated in Munich; ESBL: extended-spectrum β-lactamases; FDA: Food and Drug Administration; IMP: active on imipenem; IVD: in vitro diagnostic; KPC: Klebsiella pneumoniae carbapenemase; MALDI-TOF: matrix assisted laser desorption/ionization - time of flight; MBL: metallo-β-lactamases; MIC: minimum inhibitory concentration; NDM: New Delhi MBL; OXA: oxacillinase; PCR: polymerase chain reaction; TAT: turnaround time from pure culture of isolate; VIM: Verona integron-encoded.

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Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.