KPC around the world Maria Virginia Villegas, MD, MSC

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1 KPC around the world Maria Virginia Villegas, MD, MSC Scientific Director Bacterial Resistance and Nosocomial Infections Research Area International Center for Medical Research and Training, CIDEIM, Cali, Colombia

2 Carbapenamases a Global Problem Klebsiella pneumoniae carbapenemases (KPCs) are β-lactamases produced by Gram-negative bacteria. They hydrolyse penicillins, all cephalosporins and monobactams and less efficiently carbapenems. In this talk I will summarize the epidemiology of KPC enzymes in some specific countries and highlight treatment challenges. Munoz-Price S, Poirel L, Bonomo R, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 2013;13:

3 Carbapenamases Classification Enzyme Most Common Bacteria Class A (serine-b-lactamase) Class B (metallo-β-lactamase) Class D (serine-β-lactamase) KPC, SME, IMI, NMC, GES IMP, VIM, GIM, SPM OXA Enterobacteriaceae (less common in P. aeruginosa) P. aeruginosa Enterobacteriaceae Acinetobacter spp. Acinetobacter spp. ( less common in Enterobacteriaceae)

4 Epidemiology First reported in North Carolina (USA) in 1996 in a carbapenemresistant Klebsiella pneumoniae. Subsequently, KPC enzymes have spread across countries and continents, although their prevalence by geographical location is highly variable KPC has been reported in an increasing number of Enterobacteriaceae and non-fermenting Gram-negative bacilli, but reports still predominate in K. pneumoniae. K. pneumoniae of the ST258 lineage is the predominant clone worldwide. Munoz-Price S, Poirel L, Bonomo R, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 2013;13:

5 Global spread of KPC-producing bacteria Munoz-Price et al.lancet Infect Dis 2013:13:785-96

6 USA Following the first report of KPC, 1 year later KPC was found in New York city, in many other bacteria and as the cause of hospital outbreaks. Since then, 39 states and Puerto Rico ( 1 st to describe KPC in A.baumanni in the world ) have reported it. Hospitalized patients, but also, patients in long-term care facilities, play an important role in the spread of KPC (+) strains in some regions of the USA. In the case of community-onset infection, most patients have had extensive previous health-care exposure. Munoz-Price S, Poirel L, Bonomo R, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 2013;13:

7 Latin America Colombia in 2005 became the first country in Latin America to report the presence of KPC-2-producing K. pneumoniae in 2 patients with no history of foreign travel. KPC -2 was predominant until 2008 when an outbreak of KPC-3- producing K pneumoniae was reported; the index case was a patient who travelled from Israel for a liver transplant ; the isolate was indistinguishable from the KPC -3-producing clone described previously in Israel causing many outbreaks. Villegas MV, Lolans K, Correa A, et al. and the Colombian Nosocomial Resistance Study Group. First detection of the plasmid-mediated Class A carbapenemasa, KPC-2, in clinical isolates of K. pneumoniae from South America. Antimicrob. Agents Chemother.2006; 50: Villegas, K Lolans, A Correa et al and and the Colombian Nosocomial Bacterial Resistance Study Group. First detection of the plasmid-mediated carbapenemase KPC-2 in clinical strains of Pseudomonas aeruginosa. Antimicrob. Agents

8 . PCR screening has shown spread to all major metropolitan areas Mojica MF, Correa A, Vargas DA, et al. Molecular correlates of the spread of KPC-producing Enterobacteriaceae in Colombia. Int J Antimicrob Agents 2012; 40:

9 Latin America In Argentina: from sporadic cases reported until mid-2009, an abrupt dissemination in the country occurred due to an ST258 K. pneumoniae clone. KPC is endemic now In Brazil KPC-2 carrying Enterobacteriaceae are endemic according to SENTRY surveillance SYSTEM and other reports. KPC-2 carrying bacteria have been described in hospital wastewater in Brazil Chile and Venezuela have reported several Enterobacteriaceae harboring KPC but are not endemic yet. Maya J, Ruiz S, Blanco V, Gotuzzo E, Guzman-Blanco M, Labarca J,Salles M, Quinn J, Villegas MV. Current Status of Carbapenemases in Latin America. Expert Review of Anti-infective Therapy ; 2013, 11, (7 ) :

10 Latin America and P.aeruginosa The presence of KPC in isolates of Pseudomonas aeruginosa was reported for the first time in Colombia in Subsequently, reported in Trinidad and Tobago in patients with no history of foreign travel. KPC was detected in Pseudomonas putida from a blood culture obtained from a catheter in a pediatric patient in Brazil,. In Argentina, clonal dissemination of KPC-harboring P. aeruginosa has been documented. Cuzon G, Naas T, Villegas MV, Correa A, Quinn J, andnordmann. P. Wide Dissemination of Pseudomonas aeruginosa Producing B-Lactamase blakpc-2 Gene in Colombia.. Antimicrob. Agents Chemother Maya J, Ruiz S, Blanco V, Gotuzzo E, Guzman-Blanco M, Labarca J,Salles M, Quinn J, Villegas MV. Current Status of Carbapenemases in Latin America. Expert Review of Anti-infective Therapy ; 2013, 11, (7 ) :

11 Current status of carbapenemases in Latin America Maya J, Ruiz S, Blanco V, Gotuzzo E, Guzman- Blanco M, Labarca J,Salles M, Quinn J, Villegas MV. Current Status of Carbapenemases in Latin America. Expert Review of Anti-infective Therapy ; 2013, 11, (7 ) :

12 KPC in Europe UK : KPC was reported for the first time in Scotland (2003), but in contrast to other countries, other carbapenemase like VIM, NDM and OXA-48-like enzymes are predominant. In Spain : only few cases reported in Madrid and Valencia; In Portugal: no reports in clinical cases but in 2012 there was a report of KPC-2-producing E coli from river water. Woodford N, Zhang J, Warner M, et al. Arrival of Klebsiella pneumoniae producing KPC carbapenemase in the United Kingdom. J Antimicrob Chemother 2008; 62: Curiao T, Morosini MI, Ruiz-Garbajosa P, et al. Emergence of blakpc-3-tn4401a associated with a pkpn3/4-like plasmid within ST384 and ST388 Klebsiella pneumoniae clones in Spain. J Antimicrob Chemother 2010; 65: Poirel L, Barbosa-Vasconcelos A, Simoes RR, Da Costa PM, Liu W,Nordmann P. Environmental KPCproducing Escherichia coli isolates in Portugal. Antimicrob Agents Chemother 2012;56:

13 KPC in Europe In France: the first KPC-2 (+)-producing K. pneumoniae was isolated from a patient previously hospitalized in New York in Other reports in France have been linked to imported isolates from Greece, Israel, India, Italy, Kuwait, and China; none were community acquired, and most represented only colonization. In Italy: the first KPC-3-producing K. pneumoniae was isolated in 2008, and since then, KPC-carrying bacteria have extensively spread. Now is endemic. Naas T, Nordmann P, Vedel G, Poyart C. Plasmid-mediated carbapenem-hydrolyzing beta- lactamase KPC in a Klebsiella pneumoniae isolate from France. Antimicrob Agents Chemother 2005;49: Giani T, D Andrea MM, Pecile P, et al. Emergence in Italy of Klebsiella pneumoniae sequence type 258 producing KPC-3 carbapenemase. J Clin Microbiol 2009; 47:

14 KPC in Europe In Greece : the first KPC (+) K pneumoniae isolates linked to Greece were identified in 2007 ; Within 2 years of the initial reports, KPC-producing bacteria disseminated into most acute-care facilities including all tertiary-care hospitals. Most KPC (+) isolates are genetically related and belong to the ST258 strain. KPC is the most prevalent carbapenemase in Greece (over VIM). Giakkoupi P, Papagiannitsis CC, Miriagou V, et al. An update of the evolving epidemic of blakpc-2- carrying Klebsiella pneumoniae in Greece ( ). J Antimicrob Chemother 2011; 66: Giakoupi P, Maltezou H, Polemis M, Pappa O, Saroglou G,Vatopoulos A. KPC-2-producing Klebsiella pneumoniae infections in Greek hospitals are mainly due to a hyperepidemic clone.euro Surveill 2009; 14: pii:19218

15 KPC in Israel The first strain was probably imported from the USA and dissemination occurred to the hospitals in late The arrival of K pneumoniae ST258 has had a remarkable impact on the dissemination of KPC in Israel. By 2007, the monthly incidence of new cases in acute-care hospitals peaked at 41.9 per patient-days. This lead to a nationwide intervention and the outbreak was contained nationally, with a 79% relative reduction of the incidence compared with its peak the previous year. Marchaim D, Navon-Venezia S, Schwaber MJ, Carmeli Y. Isolation of imipenem-resistant Enterobacter species: emergence of KPC-2 carbapenemase, molecular characterization, epidemiology, and outcomes. Antimicrob Agents Chemother 2008; 52: Schwaber MJ, Lev B, Israeli A, et al. Containment of a country-wide outbreak of carbapenem-resistant Klebsiella pneumoniae in Israeli hospitals via a nationally implemented intervention. Clin Infect Dis 2011; 52:

16 KPC in Asia In India: The first KPC were reported in Enterobacteriaceae from patients enrolled in clinical trials (SENTRY ) ; since then, few other cases have been described in contrast to ESBLs, NDM and OXA-48-like enzymes which are highly prevalent. In China, the first KPC was described in 2004 and since then it has spread rapidly in the country becoming endemic. Hospital sewage has been found to harbor KPC (+) in C. freundii and E cloacae, raising alarming concerns about the potential contamination of water reservoirs. Jones CH, Tuckman M, Keeney D, Ruzin A, Bradford PA. Characterization and sequence analysis of extendedspectrum-{beta}-lactamase-encoding genes from Escherichia coli,klebsiella pneumoniae, and Proteus mirabilis isolates collected during tigecycline phase 3 clinical trials. Antimicrob Agents Chemother 2009;53: Qi Y, Wei Z, Ji S, Du X, Shen P, Yu Y. ST11, the dominant clone of KPC-producing Klebsiella pneumoniae in China.J Antimicrob Chemother 2011; 66: Zhang X, Lu X, Zong Z. Enterobacteriaceae producing the KPC-2 carbapenemase from hospital sewage. Diagn Microbiol Infect Dis 2012; 73:

17 Australia, New Zealand and Africa In Australia and New Zealand less than 1% of hospitalassociated Enterobacteriaceae carry KPC enzymes; This low prevalence may reflect infection control and surveillance cultures implemented in many hospitals after the transfer of large numbers of patients from the terrorist bombings in Bali in 2002 and the Indian Ocean tsunami of In 2012, KPC-2 was reported in South Africa as the first and only country in Africa so far; in contrast NDM-1 has been associated with rapid spread to other African countries including South Africa. Munoz-Price S, Poirel L, Bonomo R, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 2013;13: Brink AJ, Coetzee J, Clay C, et al. Emergence of New Delhi metallo-beta-lactamase (NDM-1) and Klebsiella pneumoniae carbapenemase (KPC-2) in South Africa. J Clin Microbiol 2012;50:

18 KPC : few treatment options and high mortality KPC is associated with few treatment options and high mortality rates. Colistin, tigecycline, fosfomycin and gentamicin/amikacin maybe among the few options remaining ; however no single drug is ideal due to toxicity, acquired resistance or limited therapeutic levels. Moreover, colistin-resistant outbreak strains of K pneumoniae with KPC enzymes are already circulating. Despite the limitations of clinical trials published, 3 retrospective studies have examined therapy and mortality in bloodstream infections due to Enterobacteriaceae harboring KPC.

19 Treatment options and mortality Tumbarello et al published in 2012 : 125 KPC (+) bloodstream infections ; the crude 30-day mortality rate was 42%. Only triple combination with colistin, tigecycline, and meropenem was associated with increased survival (odds ratio 0.27,95% CI ; p=0.009). Zarkotou et al in 2011 published 53 KPC (+) K pneumoniae bloodstream infections; 35 patients had appropriate therapy based on invitro susceptibility : 7/15 with monotherapy died vs none of the 20 patients with combination therapy (p 0.001). Any combination using tigecycline, colistin, carbapenem, genta or amikacin had a good outcome

20 Treatment options and mortality Qureshi et al publishe in 2012 : 41 KPC (+) bloodstream infections; The 28-day mortality was 13.3% in the combination therapy group compared with 57.8% in the monotherapy group (P = 0.01). The most commonly used treatments were colistin + polymyxin B or tigecycline combined with a carbapenem Based on the findings from these studies, combination treatment seems to be the best approach for bacteraemic patients. Tumbarello M, Viale P, Viscoli C, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K pneumoniae: importance of combination therapy. Clin Infect Dis 2012; 55: Zarkotou O, Pournaras S, Tselioti P, et al. Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. Clin Microbiol Infect 2011; 17: Qureshi ZA, Paterson DL, Potoski BA, et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens.antimicrob Agents Chemother 2012; 56:

21 KPC : Infection control is key Singled actions have not shown to be effective, in contrast to bundles. Findings from several studies emphasize the importance of early identification of asymptomatic carriers and their subsequent grouping ( this factor was a key part of the successful national intervention in Israel ). A recent study in New York (NY, USA) comparing infection control practices among 9 neighbouring hospitals, found that hospitals using active surveillance cultures were more successful in decreasing the acquisition rate of KPC (+) organisms. Munoz-Price S, Poirel L, Bonomo R, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 2013;13: 785 9

22 Conclusions Since their discovery 16 years ago, KPC (+) organisms have spread worldwide, with ST258 being the predominant clone. High mortality rates have been reported with KPC infections. Combination treatment may improve survival among bacteraemic patients. Early and accurate recognition of patients carrying strains with KPC enzymes is key to implement appropriate infection control bundles to prevent spread. Only efficient and proactive surveillance aligned with regional interventions will enable control and prevention of the spread of these threatening bacteria.

23 Thanks