Klebsiella pneumoniae: development of a mixed population of carbapenem and tigecycline resistance during antimicrobial therapy in a kidney transplant patient

Abstract

Nine isolates of Klebsiella pneumoniae were isolated from a renal transplant patient suffering from recurrent urosepsis over a period of 4 months. Imipenem resistance was detected after imipenem-ertapenem therapy. When treatment was switched to tigecycline the K. pneumoniae developed resistance to tigecycline (MIC = 8 mg/L). The nine isolates were tested by determination of agar dilution MICs, phenotypic carbapenemase, extended-spectrum beta-lactamases and metallo-beta-lactamase (MBL) testing and pulsed-field gel electrophoresis. Polymerase chain reaction and sequencing analysis were employed for identification of bla genes and mapping of the integron carrying the MBL gene. The nine isolates were clonally related and all produced the SHV-12 enzyme. Five MBL-producing isolates showed imipenem MICs ranging from 2 to 64 mg/L and all were detected by testing with imipenem and EDTA. The five isolates harboured the bla(VIM-1) gene. Three isolates showed increased tigecycline MICs (4-8 mg/L). Serial blood cultures obtained on the same day resulted in a VIM-positive/tigecycline-susceptible and a VIM-negative/tigecycline-resistant K. pneumoniae isolate. No isolate developed concurrent imipenem and tigecycline resistance. The patient had a persistent urinary tract infection and recurrent bacteraemia caused by a mixed population of Klebesiella pneumoniae isolates adapting to the selective pressure of antimicrobial therapy at the time. The present study is a worrisome example of what could happen when an immunocompromised host is subjected to the pressures of antimicrobial therapy. In addition, we report the first treatment-emergent MIC increase of tigecycline from 0.5 to 8 mg/L in K. pneumoniae.

In Vivo Emergence of Tigecycline Resistance in Multidrug-Resistant Klebsiella pneumoniae and Escherichia coli

“…The mechanisms underlying this resistance have yet to be fully explored, but DL typing seems to indicate that tigecycline-resistant strains arose from the normal-phenotype parent strains isolated before tigecycline therapy. Our report suggests that first, in the Enterobacteriaceae, as has been reported for Gram-positive bacteria, development of resistance might be strictly related to antibiotic pressure (24,31). Second, the development of resistance might be associated with unsuccessful microbiological eradication when tigecycline is administered for infections where microorganisms are exposed to subinhibitory concentrations of the drug, such as UTI, septicemia, and abdominal abscess (7,12,17,23,32).…”

“…Since then, 13 other cases have been reported, involving mostly A. baumannii and Klebsiella pneumoniae (2,3,9,12,15,20,23,24,28,30,32). Recently, Rodríguez-Avial et al reported the first detection of tigecycline resistance in SHV-12-producing K. pneumoniae during tigecycline treatment (24).…”

Carbapenemases in Klebsiella pneumoniae and Other Enterobacteriaceae: an Evolving Crisis of Global Dimensions

“…Drug effectiveness, however, differs depending on the extent of spread of resistant isolates in each setting. Indeed, a growing number of studies indicate that the activity of these drugs is decreasing rapidly (7,21,80,85,88,96,128,142,151,156,185,186,226,243,247,275,277). In addition, rates of susceptibility to fluorinated quinolones are generally low, reflecting the multidrug-resistant nature of CPE.…”

Clinical management of infections caused by multidrug-resistant Enterobacteriaceae

“…Also, its low blood levels do not makes it an attractive drug for the treatment of vascularrelated infections [Falagas et al 2011]. Development of resistance was observed in vitro and in vivo in K. pneumoniae [Rodriguez-Avial et al 2012] and E. coli [Stone et al 2011]. Tigecycline has been used frequently in association with other drugs for the treatment of infections caused by extremely drug-resistant enterobacteria [Qureshi et al 2012;Tumbarello et al 2012].…”