Carbapenem resistance in Pseudomonas aeruginosa and Acinetobacter baumannii in the nosocomial setting in Latin America.

Critical Reviews in Microbiology

ISSN: 1040-841X (Print) 1549-7828 (Online) Journal homepage: http://www.tandfonline.com/loi/imby20

Carbapenem resistance in Pseudomonas aeruginosa and Acinetobacter baumannii in the nosocomial setting in Latin America Jaime A Labarca, Mauro José Costa Salles, Carlos Seas & Manuel GuzmánBlanco To cite this article: Jaime A Labarca, Mauro José Costa Salles, Carlos Seas & Manuel GuzmánBlanco (2016) Carbapenem resistance in Pseudomonas aeruginosa and Acinetobacter baumannii in the nosocomial setting in Latin America, Critical Reviews in Microbiology, 42:2, 276-292, DOI: 10.3109/1040841X.2014.940494 To link to this article: http://dx.doi.org/10.3109/1040841X.2014.940494

Published online: 27 Aug 2014.

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Date: 09 October 2017, At: 11:53

http://informahealthcare.com/mby ISSN: 1040-841X (print), 1549-7828 (electronic) Crit Rev Microbiol, 2016; 42(2): 276–292 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/1040841X.2014.940494

REVIEW ARTICLE

Carbapenem resistance in Pseudomonas aeruginosa and Acinetobacter baumannii in the nosocomial setting in Latin America Jaime A Labarca1, Mauro Jose´ Costa Salles2, Carlos Seas3, and Manuel Guzmań-Blanco4 Department of Infectious Diseases, School of Medicine, Pontificia Universidad Cato´lica de Chile, Lira, Santiago, Chile, 2Hospital Irmandade da Santa Casa de Miserico´rdia de Saõ Paulo, Saõ Paulo, Brazil, 3Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru´, and 4Hospital Privado Centro Me´dico de Caracas and Hospital Vargas de Caracas, Caracas, Venezuela

Downloaded by [Southern Cross University] at 11:53 09 October 2017

1

Abstract

Keywords

Increasing prevalence of carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter baumannii strains in the nosocomial setting in Latin America represents an emerging challenge to public health, as the range of therapeutic agents active against these pathogens becomes increasingly constrained. We review published reports from 2002 to 2013, compiling data from throughout the region on prevalence, mechanisms of resistance and molecular epidemiology of carbapenem-resistant strains of P. aeruginosa and A. baumannii. We find rates of carbapenem resistance up to 66% for P. aeruginosa and as high as 90% for A. baumannii isolates across the different countries of Latin America, with the resistance rate of A. baumannii isolates greater than 50% in many countries. An outbreak of the SPM-1 carbapenemase is a chief cause of resistance in P. aeruginosa strains in Brazil. Elsewhere in Latin America, members of the VIM family are the most important carbapenemases among P. aeruginosa strains. Carbapenem resistance in A. baumannii in Latin America is predominantly due to the oxacillinases OXA-23, OXA-58 and (in Brazil) OXA-143. Susceptibility of P. aeruginosa and A. baumannii to colistin remains high, however, development of resistance has already been detected in some countries. Better epidemiological data are needed to design effective infection control interventions.

Carbapenem, infection, Latin America, nosocomial, resistance

Introduction Pseudomonas aeruginosa and Acinetobacter baumannii are important causes of hospital-acquired infections, especially in intensive care units (ICUs) (Gaynes et al., 2005; Rodriguez-Bano et al., 2004; Vincent et al., 2009). The prevalence of these pathogens is of particular concern in Latin America, as evidenced by results of the Extended Prevalence of Infection in Intensive Care (EPIC II) study (Vincent et al., 2009). Of 719 culture-positive patients who participated in the Latin America arm, the point prevalences of P. aeruginosa and A. baumannii infections were 26% and 14%, respectively, rates that were far higher than the point prevalences in Western Europe (17% and 6%) and North America (13% and 4%) (Vincent et al., 2009). Carbapenems are first-line therapy for ventilator-associated pneumonia and other prominent infections caused by P. aeruginosa and A. baumannii (Hospital-Acquired Pneumonia Guideline Committee of the American Thoracic Society and Infectious Diseases Society of America, 2005).

Address for correspondence: Dr Jaime A Labarca, MD, School of Medicine, Pontificia Universidad Cato´lica de Chile, Department of Infectious Diseases, Lira 63, Santiago, Chile. E-mail: jlabarca@ med.puc.cl

History Received 12 November 2013 Revised 16 June 2014 Accepted 28 June 2014 Published online 26 August 2014

Until a few years ago, carbapenems had excellent clinical utility for the treatment of infections by P. aeruginosa and A. baumannii because of their potent activity against these organisms. Both P. aeruginosa and A. baumannii developed resistance mechanisms after relentless exposure to carbapenems and other classes of antimicrobial agents, and resistance of these pathogens to carbapenems consequently increased (Centers for Disease Control and Prevention, 2004; Curcio, 2011; Jones et al., 2004; Streit et al., 2004). The substantial morbidity and mortality associated with infections by P. aeruginosa or A. baumannii are exacerbated by development of resistance and lack of therapeutic options (Vincent et al., 2009; Zavascki et al., 2006). For example, the mortality rate among patients with nosocomial infections caused by metallo-b-lactamase (MBL)–carrying P. aeruginosa has been reported as greater than 50% (Zavascki et al., 2006). As more strains of P. aeruginosa and A. baumannii have acquired extensive carbapenem resistance, clinicians have considered the use of alternative agents, including the polymyxins B and E (colistin) and tigecycline. However, use of colistin is limited by its toxicity profile, and tigecycline has limited efficacy in clinical use (Bergen et al., 2012; Freire et al., 2010; Vila et al., 2012). In addition, tigecycline is inactive against P. aeruginosa.

DOI: 10.3109/1040841X.2014.940494

The recent epidemiology of P. aeruginosa and A. baumannii in Latin America has not been reviewed extensively, possibly because available data come from different network programs with varying degrees of participation from each country’s hospitals. Therefore, the objectives of this review are to summarize the most recent data derived from Latin American countries regarding the epidemiology of carbapenem resistance in the region for the two most important non-fermenting Gram-negative rods, providing information about prevalence, mechanisms of resistance and molecular epidemiology in both outbreak and endemic situations.


Methods To review the published clinical data on the epidemiology of carbapenem resistance in P. aeruginosa and A. baumannii in Latin America, a systematic search of the biomedical literature was conducted. Medline (via PubMed) was searched, limited by the dates 1 January 2002 to 29 April 2013, for articles using the following terms: [(carbapenem OR imipenem OR meropenem OR doripenem OR ertapenem) AND (resistance OR resistant OR susceptible OR susceptibility)] OR (carbapenemase). The result of this search was combined with two separate searches for ‘‘Pseudomonas aeruginosa’’ and ‘‘Acinetobacter baumannii’’, both of which were then merged with a search for the following terms: (‘‘Latin America’’ OR ‘‘South America’’ OR ‘‘Central America’’ OR Mexico OR Guatemala OR Honduras OR Nicaragua OR ‘‘Costa Rica’’ OR Cuba OR ‘‘Dominican Republic’’ OR Panama OR Colombia OR Venezuela OR Guyana OR Suriname OR ‘‘French Guiana’’ OR Brazil OR Ecuador OR Peru OR Bolivia OR Paraguay OR Uruguay OR Chile OR Argentina). In addition, the Latin American medical database Scientific Electronic Library Online (SciELO) was searched for the terms (Pseudomonas aeruginosa OR Acinetobacter baumannii) AND carbapenemases. Data from the Pan American Health Organization (PAHO) were also used to assess the frequency of carbapenem resistance in Latin American countries. Separate searches were conducted on PubMed regarding the in vitro activity of colistin and tigecycline in Latin America. Only studies reporting data for 450 P. aeruginosa isolates and 430 A. baumannii isolates collected within the past 10 years were selected for assessing drug resistance. Only studies reporting data collected in 2005 or later were included in the tables. Pseudomonas aeruginosa Incidence in Latin America Surveillance studies provide excellent epidemiological data on nosocomial P. aeruginosa infections at the regional level in Latin America. As a reference point for the early 2000s, the global Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) study (n ¼ 1159 isolates in South America) reported the minimum concentration required to inhibit growth of 90% of strains (MIC90) for meropenem and imipenem as 64 mg/mL (Unal et al., 2005). The percentages of P. aeruginosa isolates susceptible to meropenem and imipenem were 57% and 52%, respectively, which compared

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unfavorably with P. aeruginosa isolates collected in Europe (76% and 70%, respectively) and North America (89% and 85%, respectively) during the same period (Unal et al., 2005). More recent regional surveillance data are shown in Table 1 (Bertrand et al., 2012; Cereda et al., 2011; Fernandez-Canigia et al., 2012; Gales et al., 2011, 2012; Garza-Gonzalez et al., 2010; Jones et al., 2009; Llaca-Diaz et al., 2012; Marra et al., 2011; Morfin-Otero et al., 2012b; Reinert et al., 2007; Rossi et al., 2008; Silva et al., 2011b; Toledo et al., 2012; Villalobos Rodriguez et al., 2011; Xavier et al., 2010; Zavascki et al., 2007a). In Tigecycline Evaluation and Surveillance Trial (TEST) surveillance data (2004–2009), the susceptibility rate of P. aeruginosa isolates to meropenem in Latin America (59%) was lower than that in North America (79%) and Europe (68%), but similar to that found in the Asia Pacific Rim (58%) (Bertrand et al., 2012). In data from the SENTRY Antimicrobial Surveillance Program for 2006–2009, 24% of Latin American P. aeruginosa isolates had reduced susceptibility (MIC 8 mg/mL) to imipenem, a rate that was lower than that found in the Asian-Pacific region (31%) and Europe (28%), but higher than the corresponding rate in the USA (18%) (Gales et al., 2011). At the country level, the PAHO surveillance system annually ascertains the phenotypes of P. aeruginosa strains obtained from nosocomial infections by susceptibility testing against commonly used antimicrobial drug classes (Figure 1) (Pan American Health Organization, 2009, 2010). In Central America, rates of carbapenem resistance among isolates collected in 2009 ranged from 20% (in Honduras) to 40% (in Nicaragua) (Pan American Health Organization, 2009, 2010). Findings from studies conducted in Mexico from 2005 until 2012 documented imipenem and meropenem MIC90 of 48 mg/mL and a range of susceptibility rates from 67 to 76% (Table 1). PAHO data from 2009 revealed that the incidence of carbapenem-resistant P. aeruginosa varied widely across South American countries (Figure 1) (Pan American Health Organization, 2009, 2010). Bolivia had the lowest resistance rates to imipenem (20%) and meropenem (14%), whereas its neighbor Peru had the highest resistance rates (66% and 57%, respectively) (Pan American Health Organization, 2009, 2010). It is not prudent to directly compare PAHO data with those derived from cohort studies (Table 1) due to temporal and methodological variabilities. However, results of a recent study conducted in public and private hospitals throughout Colombia corroborated recent PAHO data and suggested stable carbapenem resistance, as evidenced by rates of 15% in 2007, 16% in 2008 and 14% in 2009 (Villalobos Rodriguez et al., 2011). In Chile, susceptibility data for 1935 P. aeruginosa isolates were collected by a network associated with the Chilean Society of Infectious Diseases (Table 1) (Silva et al., 2011b). In 2007, the percentage of isolates susceptible to imipenem and meropenem was 68% and 70%, respectively (Silva et al., 2011b). Lower levels of susceptibility were observed for both antimicrobials in ICUs (54% for imipenem; 58% for meropenem) compared with other patient-care areas (78% and

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Crit Rev Microbiol, 2016; 42(2): 276–292

Table 1. In vitro activities of carbapenems against hospital-acquired Pseudomonas aeruginosa isolates: regional surveillance and cohort studies (450 isolates) reporting data collected in Latin America since 2005.

Study period

Isolates (N)

Latin America (regional surveillance) SENTRY* (Jones et al., 2009)

1999–2007

4277

SENTRY* (Gales et al., 2011) SENTRYy,z (Gales et al., 2012)

2006–2009 2008–2010

1462 1099

TESTy (Reinert et al., 2007) TESTô (Rossi et al., 2008) TESTx (Bertrand et al., 2012)

2004–2006 2004–2007 2004–2009

TESTk (Fernandez-Canigia et al., 2012)

2004–2010

250 446 180 676 461 2273


Country (region)

Central America Mexico (Monterrey) (Garza-Gonzalez et al., 2010) Mexico (Monterrey) (Llaca-Diaz et al., 2012)

2006–2009 2011–2012

250 242

Mexico (Guadalajara) (Morfin-Otero et al., 2012b)

2005–2010

404

Mexico (SENTRY) (Gales et al., 2012)

2008–2010

198

South America Argentina (SENTRY) (Gales et al., 2012)

2008–2010

234

2004–2005

245

Brazil (Saõ Paulo) (Xavier et al., 2010)

2005

59

Brazil (nationwide) (Marra et al., 2011)

2007–2010

Brazil (nationwide) (Cereda et al., 2011)

2008–2009

212 201 94

Brazil (Curitiba) (Toledo et al., 2012) Brazil (SENTRY) (Gales et al., 2012)

2010–2011 2008–2010

NS 490

Chile (nationwide) (Silva et al., 2011b)

2009

Chile (SENTRY) (Gales et al., 2012)

2008–2010

Colombia (nationwide) (Villalobos Rodriguez et al., 2011)

2007 2008 2009

Brazil (Porto Alegre) (Zavascki et al., 2007a)

1935 177 2963 3266 2670

Carbapenem Imipenem Meropenem Imipenem Imipenem Meropenem Imipenem Imipenem Imipenem Meropenem Imipenem Meropenem Meropenem Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem NS Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem Imipenem

MIC90 (mg/mL)

Susceptible (%)

48 48 16 16 16 32 16 32

69 72 62 58 57 66 66 56 59 67 64

16 48 48 48 48

Resistant (%)

28 35 19 18 26

67 75 76 70 71

29 20 18 13

51 46 32 32

57 52 48 48

48 48

44 43

37 36 47 44 8–18#

55 53 68 70 60 67 15 16 14

MIC90 ¼ minimum concentration required to inhibit growth of 90% of strains; TEST ¼ Tigecycline Evaluation and Surveillance Trial. *Participating countries not specified. Argentina, Brazil, Chile, Mexico. z Susceptibility rates reported for individual countries are also shown in this table. ô Argentina, Brazil, Chile, Colombia, Guatemala, Honduras, Jamaica, Mexico, Panama, Puerto Rico, Venezuela. x Argentina, Brazil, Chile, Colombia, El Salvador, Guatemala, Honduras, Jamaica, Mexico, Nicaragua, Panama, Puerto Rico, Venezuela. k Argentina, Brazil, Chile, Colombia, El Salvador, Guatemala, Honduras, Jamaica, Mexico, Nicaragua, Panama, Venezuela. # Depending on infection type. y

77%, respectively) (Silva et al., 2011b). Similarly, though country-specific PAHO data are not available for Brazil, several cohort studies found that 43–55% of P. aeruginosa isolates were susceptible to carbapenems (Table 1). The International Nosocomial Infection Control Consortium (INICC) has reported rates of imipenem resistance in P. aeruginosa isolates associated with deviceassociated infections of 19% in Colombia between 2002 and 2005 (10 ICUs in nine hospitals) (Moreno et al., 2006), 26% in Peru between 2003 and 2007 (four ICUs in four hospitals) (Cuellar et al., 2008), and 28% in Brazil between 2003 and 2006 (five ICUs in three hospitals) (Salomao et al., 2008). These findings are similar to those of the National Healthcare Safety Network (2006–2007), which reported the rate of

carbapenem resistance in P. aeruginosa associated with device-associated healthcare-associated infections in ICUs in the USA as 25% (Hidron et al., 2008). Mechanisms of resistance Resistance to carbapenems is usually the result of one or a convergence of multiple resistance mechanisms. The three most important mechanisms of carbapenem resistance in P. aeruginosa are production of acquired Ambler class B b-lactamases (also referred to as MBLs), mutational loss of one of the intrinsic 48 k-Da outer membrane porin OprD homologues and overexpression of efflux pumps (Bonomo et al., 2006; Moore et al., 2011; Pseudomonas Genome


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279

Figure 1. Prevalence of imipenema and meropenemb resistance among Pseudomonas aeruginosa nosocomial isolates reported in the 2010 Pan American Health Organization surveillance study (Pan American Health Organization, 2010), and range of resistance rates to imipenemc and meropenemd reported in surveillance and cohort studies* (data collected in Latin America since 2005). *For surveillance and cohort studies, refer to Table 1 for related data and references. yFor this country, data from the 2009 PAHO report are given because data were not provided in the 2010 report. zFor this country, the rate of reduced susceptibility (inverse of susceptibility rate) is given because resistance data were not available.

Database; Sykes, 2010; Tamber et al., 2006). MBL genes usually occur within class I integrons that also harbor other antimicrobial resistance genes (Bonomo et al., 2006). While occurrence of MBLs is a commonly studied and reported mechanism of resistance in P. aeruginosa, porin loss is the most common cause of imipenem resistance among P. aeruginosa isolates in the absence of local MBL outbreaks (Bonomo et al., 2006). In 1999 in Saõ Paulo, Brazil, a fatal infection was caused by the first known P. aeruginosa strain (48-1997A) to produce an MBL (SPM-1) in Latin America (Toleman et al., 2002). Subsequently, the first report of dissemination of an SPM1-like, MBL-producing epidemic strain of P. aeruginosa in Latin America occurred among unrelated Brazilian hospitals in 2003 (Gales et al., 2003), and the first nosocomial outbreak in southern Brazil occurred in a teaching hospital in Porto Alegre, 2004 (Zavascki et al., 2005). Carbapenem-susceptible P. aeruginosa isolates harboring non-expressive blaSPM may act as reservoirs of this gene (Pellegrino et al., 2008). The first isolation of blaVIM-2 in Latin America was reported in Chile and Venezuela (both in 2002) (Mendes et al., 2004). Among recent studies reporting on mechanisms of resistance in carbapenem-resistant P. aeruginosa strains in South America, most have detected the presence of MBL genes and/or MBL production, primarily SPM, VIM, and IMP variants (Table 2) (Cavalcanti et al., 2012; Cejas et al., 2008; Cezario et al., 2009; Crespo et al., 2004; Doi et al., 2007; Fehlberg et al., 2012; Franco et al., 2010; Goncalves et al., 2009; Marra et al., 2006, 2011; Martins et al., 2007; Pagniez et al., 2006; Pe´rez et al., 2008; Polotto et al., 2012; Quinones-Falconi et al., 2010; Sader et al., 2005b;

Zavascki et al., 2006). Excellent regional reference data were published by the SENTRY Antimicrobial Surveillance Program, which analyzed 54 P. aeruginosa strains resistant to imipenem and meropenem (both MICs 16 mg/L) collected between 2001 and 2003 in 10 medical centers (Buenos Aires, Brasilia, Floriano´polis, Porto Alegre, Saô Paulo, Santiago, Mexico City and Caracas) (Sader et al., 2005a). Among those, MBL production was identified in 25 P. aeruginosa strains to give a continent-wide prevalence of 46%. In this study, the greatest density of MBL strains occurred in Brazil, where 21 (54%) of 39 isolates harbored SPM-1. Other genes coding for MBLs were IMP-16, detected in one isolate from Brazil, and VIM-2, detected in three isolates from Venezuela (Sader et al., 2005a). Separately, VIM-2 was produced by 100% of 17 strains demonstrating resistance to imipenem in Venezuela between 2007 and 2010 (Guevara et al., 2012). In Buenos Aires, until 2006 a relatively small proportion of carbapenem-resistant P. aeruginosa strains produced VIM-2 and VIM-11 (11%) and IMP-13 (14%) (Cejas et al., 2008; Pagniez et al., 2006). SPM-1 was commonly detected among carbapenem-resistant isolates in Brazil (Table 2). Detection of carbapenemresistant P. aeruginosa strains harboring IMP-1, IMP-16 and VIM-2 has also been reported in Brazil (Fehlberg et al., 2012; Franco et al., 2010; Marra et al., 2006, 2011; Martins et al., 2007; Picaõ et al., 2009; Polotto et al., 2012; Sader et al., 2005a; Scheffer et al., 2010). In contrast, VIM was the only MBL detected in carbapenem-resistant P. aeruginosa strains collected in Chile and Colombia (Crespo et al., 2004; Pe´rez et al., 2008). Of note, the presence of MBLs was detected in only 19% of imipenem-resistant strains in the Chilean study (Pe´rez et al., 2008), highlighting that other mechanisms such

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Table 2. Occurrence of metallo-b-lactamases in Pseudomonas aeruginosa throughout Latin America (studies analyzing 450 isolates).

Study period

Isolates (N)

Occurrence of MBLs, % (n/N)

Mexico (Mexico City) (Quinones-Falconi et al., 2010)

2004–2005

86*

3 (3/86)

Argentina (Buenos Aires) (Pagniez et al., 2006)

2002–2004

91*

11 (10/91)

Argentina (Buenos Aires) (Cejas et al., 2008) Brazil (Saõ Paulo) (Fehlberg et al., 2012)

2006 2000–2002

129 82

14 (18/129) 10 (8/82)

Brazil (Minas Gerais) (Cezario et al., 2009) Brazil (Porto Alegre, Saõ Lucas) (Zavascki et al., 2006) Brazil (Porto Alegre) (Martins et al., 2007)

2003–2005 2004–2005 2003–2004

47* 298 92y

77 (33/43) 29 (86/298) 36 (33/92)

Brazil (Saõ Paulo) (Doi et al., 2007) Brazil (Saõ Paulo) (Franco et al., 2010)

2005–2006 2006

51* 69*

57 (29/51) 30 (21/69)

Brazil (Saõ Paulo) (Marra et al., 2006)

2000–2002

76

30 (23/76)

Brazil (Saõ Paulo) (Sader et al., 2005b)

2000–2001

82*

44 (36/82)

Brazil (Saõ Paulo) (Polotto et al., 2012)

2009

56y

30 (17/56)

Brazil (Goiaˆnia) (Goncalves et al., 2009) Brazil (Recife) (Cavalcanti et al., 2012) Brazil (nationwide) (Marra et al., 2011)

2005–2007 2002–2003 2008–2009 2007–2010

62z 61z 12z 59*

56 98 25 51

Chile (Santiago) (Pe´rez et al., 2008) Colombia (Cali) (Crespo et al., 2004)

2004–2005 1999–2003

59* 54*


Country (region)

(35/62) (60/61) (3/12) (30/59)

19 (11/59) Not reported

Genetic determinant or expression (n/N of tested isolates) VIM-2 (2/3) IMP-15 (1/3) VIM-2 (3/10) VIM-11 (7/10) IMP-13 (18/18) SPM-1 (5/8) IMP-1 (1/8) IMP-16 (1/8) GES-5 (1/8) SPM-1 (4/15) SPM-1 (14/14) SPM-1–like (18/33) IMP-1–like (5/33) SPM-1 (29/29) SPM-1 (17/21) VIM-2 (4/21) SPM-1 (4/23) IMP-1 (2/23) IMP-16 (1/23) SPM-1 (20/36) VIM-2 (11/36) IMP-1 (3/36) SPM-1 (10/17) IMP-1 (7/17) SPM-1 (26/35) SPM-1 (58/60) SPM-1 (3/3) IMP (6/30) SPM (24/30) VIM (11/11) VIM-8 (42/54) VIM (2/54)

MBL ¼ metallo-b-lactamase. *Carbapenem-resistant isolates. y Carbapenem- or ceftazidime-resistant isolates. z Carbapenem- and ceftazidime-resistant isolates.

as porin loss caused much of the carbapenem resistance of P. aeruginosa isolates in this study. Similarly, in Brazil the high prevalence of P aeruginosa strains harboring MBL genes is exacerbated by the presence of simultaneous multiple resistance mechanisms. For instance, while only 10% of carbapenem-resistant isolates from the Hospital Saõ Paulo in 2000–2002 harbored MBL genes, the prevalence of oprD downregulation and efflux pump overexpression was 93% and 71%, respectively (Fehlberg et al., 2012). In addition to other mechanisms of resistance, KPC carbapenemases have been found in P. aeruginosa strains in countries where KPC is endemic in Enterobacteriaceae. A KPC-producing strain of P. aeruginosa was identified in Colombia in 2006 (Villegas et al., 2007b), and an international multidrug-resistant clone belonging to sequence type (ST) 654 involved in the dissemination of KPCproducing P. aeruginosa was detected in Argentina in the same year (Pasteran et al., 2012). A strain of P. aeruginosa producing KPC-2 was also detected in 2010 in Brazil (Jacome et al., 2012). The presence of MBL-encoding genes in conjunction with overexpressed efflux systems, porin downregulation and AmpC overproduction was also a feature of multidrugresistant P. aeruginosa isolates causing bloodstream infections in the same Brazilian hospital during 2005 (Xavier et al., 2010). The prevalences of the MBL-encoding genes

SPM-1 and IMP-1 were 24% and 2%, respectively (Xavier et al., 2010). Of note, the MexXY-OprM and MexAB-OprM efflux systems were overexpressed in 51% and 27% of isolates studied, respectively, whereas AmpC b-lactamase was overexpressed in 12% of P. aeruginosa isolates. Furthermore, decreased oprD expression was observed in 87% of the imipenem non-susceptible P. aeruginosa isolates (Xavier et al., 2010). There is a paucity of quality data pertaining to carbapenem resistance of P. aeruginosa due to efflux mechanisms in Latin American countries other than Brazil. In a 10-year observational study that phenotypically evaluated overexpression of efflux systems in 372 P. aeruginosa strains at a hospital in Argentina, carbapenem resistance due to efflux mechanisms fluctuated between 50% (in 2000) and 2.5% (in 2008) (Orecchini et al., 2010). Molecular epidemiology More than 50% of multidrug-resistant P. aeruginosa isolates belong to a few clonal types, with ST235 responsible for outbreaks throughout Europe, Asia and South America (Agodi et al., 2007; Cholley et al., 2010; Maatallah et al., 2011). Several clonal outbreaks have been associated with hospital staff, patients and medical devices serving as reservoirs for cross-transmission (Agodi et al., 2007; Cholley et al., 2011; Kayabas et al., 2008; Srinivasan et al., 2003).



DOI: 10.3109/1040841X.2014.940494

Pseudomonas aeruginosa strains producing IMP-15 and VIM-2 emerged in Mexico City during 2004–2005 (Table 2), although only the VIM-2 isolates were clonally related in that study (Quinones-Falconi et al., 2010). In a separate report, 12 IMP-15–producing P. aeruginosa isolates recovered in Mexico in 2003 were clonally related (Garza-Ramos et al., 2008a). blaIMP-15 was encoded in class 1 integron ln95 in this study (Garza-Ramos et al., 2008a), while in another study conducted at the same time in Mexico, blaIMP-18 was identified in In96 (Garza-Ramos et al., 2008b). The first report of two genetically related carbapenem-resistant P. aeruginosa isolates from two different institutions in Mexico occurred in 2004 (Sanchez-Martinez et al., 2010). The strains harbored blaIMP-18 housed within In169, which also contained two copies of aminoglycoside adenyltransferase aadA2 and OXA-2 (Sanchez-Martinez et al., 2010). In Buenos Aires, IMP-13–producing P. aeruginosa isolates belonged to 5 different clonal types (Cejas et al., 2008), whereas VIM-2– and VIM-1–producing P. aeruginosa isolates did not correspond to a unique clonal type (Pagniez et al., 2006). In a study of 59 imipenem-resistant P. aeruginosa strains isolated in Santiago, Chile, 11 strains (19%) were VIM-producing and none of the isolates were clonally related in this single-center study (Pe´rez et al., 2008). A study reporting the first detection of VIM-2 in P. aeruginosa isolates in the Colombian nationwide network identified clonally related imipenem-resistant isolates in five centers (Villegas et al., 2006). In Brazil, there has been a dynamic epidemiology of carbapenem-resistant P. aeruginosa isolates, which at one time was closely related to the Brazilian SPM clone (Cavalcanti et al., 2012; Sader et al., 2005a). There was high prevalence of a clone related to the SPM Brazilian clone in 2002–2003, but in 2008–2009, most P. aeruginosa isolates were MBL negative, of a higher genomic variety and unrelated to those that had been detected previously (Cavalcanti et al., 2012). Further biochemical analysis of 50 SPM-1–producing P. aeruginosa isolates exhibiting 11 distinct ribotyping genotypes collected from 11 different

281

Brazilian cities revealed that these isolates (as well as three IMP-1–producing P. aeruginosa isolates) descended from a common ancestor (Silva et al., 2011a). Five distinct STs were identified among a total of 55 P. aeruginosa isolates studied. Forty-nine of the 50 SPM-1–producing P. aeruginosa isolates presented an identical allelic profile (ST277); the three IMP-1–producing P. aeruginosa strains were classified as ST593; and three additional STs were also identified (Silva et al., 2011a). Case-control data collected from an adult ICU in Minas Gerais, Brazil (2003–2005) indicated that poor infection control practices led to clonal dissemination of MBL-producing P. aeruginosa strains (Cezario et al., 2009). Most isolates (95%) were resistant to imipenem as well as to other antimicrobial drug classes with the exception of polymyxin. MBL production occurred in 77% of strains, of which only SPM-1 was identified in the 15 specimens analyzed. Four clones were identified, with a predominance of clone A (62%) and B (23%) (Cezario et al., 2009). Colistin (polymyxins B and E) activity Colistin has demonstrated excellent in vitro activity against P. aeruginosa isolates, including carbapenem-resistant phenotypes, although it must be borne in mind that reported antimicrobial susceptibility to polymyxins is influenced by many factors including the Mueller–Hinton media employed for testing (Girardello et al., 2012; Hogardt et al., 2004; van der Heijden et al., 2007). In the global SENTRY study conducted between 2001 and 2004, 99% of 1626 P. aeruginosa isolates from Latin America were susceptible to polymyxin B, whereas only 66% of these isolates were susceptible to imipenem and 68% to meropenem (Gales et al., 2006). Table 3 shows that, in surveillance and cohort studies, at least 95% of P. aeruginosa isolates were susceptible to colistin in recent reports from Latin America as a whole and Chile, Mexico, Argentina and Brazil individually (Cereda et al., 2011; Gales et al., 2011, 2012; Kvitko et al., 2011; Morfin-Otero et al., 2012b; Silva et al., 2011b; Zavascki et al., 2007a).

Table 3. In vitro activity of colistin against Pseudomonas aeruginosa in Latin America (studies conducted since 2005; 450 isolates).

Country (region) Latin America (SENTRY)* (Gales et al., 2011) Latin America (SENTRY)z (Gales et al., 2012) Mexico (Guadalajara) (Morfin-Otero et al., 2012b) Mexico (SENTRY) (Gales et al., 2012) Argentina (SENTRY) (Gales et al., 2012) Brazil (nationwide) (Cereda et al., 2011) Brazil (Porto Alegre) (Zavascki et al., 2007a) Brazil (Porto Alegre) (Kvitko et al., 2011) Brazil (SENTRY) (Gales et al., 2012) Chile (nationwide) (Silva et al., 2011b) Chile (SENTRY) (Gales et al., 2012)

Study period

Type of isolate

Isolates (N)

2006–2009 2008–2010 2005–2010 2008–2010 2008–2010 2008–2009 2004–2005 2004–2009 2008–2010 2009 2008–2010

General nosocomial Hospital and community General nosocomial Hospital and community Hospital and community General and ICU General nosocomial General nosocomial Hospital and community General and ICU Hospital and community

1057 1099 404 198 234 94 245 133 490 1935 177

MIC90 (mg/mL) 2 2ô 2x

MIC90 ¼ minimum concentration required to inhibit growth of 90% of strains; ICU ¼ intensive care unit. * Participating countries not specified. y Susceptibility rates were 99.7% for colistin and 99.9% for polymyxin B. z Argentina, Brazil, Chile, Mexico. Susceptibility rates reported for individual countries are also shown in this table. ô MIC90 to polymyxin B was 1; susceptibility and resistance rates were the same as colistin. x Drug was polymyxin B.

Susceptible (%) 100y 100 100 100 100 99 100x 100x 99 95 100

Resistant (%) 0.1 0 1

282



Activity of colistin against carbapenem-resistant pathogens is of particular interest. Isolated reports from the past decade demonstrate the strong activity of colistin and the polymyxins against carbapenem-resistant P. aeruginosa strains in Brazil (Cavalcanti et al., 2012; Furtado et al., 2011; Gales et al., 2003; Picaõ et al., 2009; Polotto et al., 2012; Sader et al., 2005b; Scheffer et al., 2010). However, carbapenem-resistant P. aeruginosa isolates resistant to colistin (MICs 4 mg/mL) were detected in Brazil and Chile in 2005–2006 (Doi et al., 2007; Fica et al., 2007; Franco et al., 2010), posing a challenge for treatment. Acinetobacter spp. (baumannii)


Incidence in Latin America More than half (55%) of A. baumannii isolates in developed and developing countries are carbapenem resistant (Mera et al., 2010; Rosenthal et al., 2012). Recent surveillance in Latin America reveals that Acinetobacter spp. strains have low-to-moderate levels of susceptibility to carbapenems (range, 8–63%), and MICs of imipenem and meropenem (MIC90 range, 48 to 128 mg/mL) to carbapenems are elevated (Table 4) (Bantar et al., 2009; Bertrand et al., 2012; Coelho-Souza et al., 2013; dos Santos Saalfeld et al., 2009; Fernandez-Canigia et al., 2012; Ferreira et al., 2011; Gales et al., 2011, 2012; Garza-Gonzalez et al., 2010; Hart Casares et al., 2008, 2010; Llaca-Diaz et al., 2012; Marra et al., 2011; Morfin-Otero et al., 2012a, 2012b; Reinert et al., 2007; Rossi et al., 2008; Sevillano et al., 2012; Silva et al., 2011b; Toledo et al., 2012; Viana et al., 2011; Villalobos Rodriguez et al., 2011; Villegas et al., 2007a; Zavascki et al., 2007b). In TEST 2004–2009 surveillance, the susceptibility rate of A. baumannii isolates to meropenem was lower in Latin America (27%) than in North America (60%), Europe (53%) and the Asia Pacific Rim (31%) (Bertrand et al., 2012). In SENTRY 2006–2009 surveillance, 26% of Acinetobacter

isolates from Latin America had reduced susceptibility (MIC 8 mg/mL) to imipenem; this rate was 41% in the Asia-Pacific region, 21% in Europe and 12% in the USA (Gales et al., 2011). The proportion of Acinetobacter isolates susceptible to imipenem in Latin America declined markedly during this time period, from 73% in 2006 to 58% in 2007, 40% in 2008 and 24% in 2009 (Gales et al., 2011). In Central America, PAHO data collected in 2009 showed that rates of carbapenem resistance were highest in Panama (77% of isolates resistant to imipenem; 72%, meropenem), followed by Guatemala (64%, imipenem; 62%, meropenem), and approximately 20% elsewhere (Figure 2) (Pan American Health Organization, 2009, 2010). Results of three cohort studies conducted in Mexico from 2005 until 2012 documented imipenem and meropenem MIC90 of 48 mg/mL and a range of resistance rates from 36 to 76% (Table 4). Similar to findings of susceptibility testing in P. aeruginosa, the incidence of carbapenem-resistant A. baumannii varies widely across South American countries, according to data from PAHO and cohort studies (Figure 2) (Pan American Health Organization, 2009, 2010). Again, Bolivia had the lowest resistance rates to imipenem (19%) and meropenem (7%) in the PAHO report, whereas its southern neighbor Argentina had the highest resistance rates (78% and 81%, respectively) (Pan American Health Organization, 2009, 2010). Multiple studies indicate that 15–49% of A. baumannii isolates in Argentina are susceptible to carbapenems (Table 4). Rates of carbapenem resistance in Acinetobacter spp. in Argentina appear to have almost tripled over the past 15 years, with reported rates of 25% in 1997–2000, 48% in 2001–2003, 39% in 2004–2007 and 460% in 2005–2006 (Bantar et al., 2008, 2009; Rossi et al., 2008). In Bolivia, one study reported that 35% of A. baumannii isolates were resistant to imipenem (Sevillano et al., 2012). Table 4 summarizes several cohort studies reporting on variable A. baumannii carbapenem resistance rates in Brazil.

Table 4. In vitro activities of carbapenems against hospital-acquired Acinetobacter spp. isolates: regional surveillance and cohort studies (430 isolates) reporting data collected in Latin America since 2005. Study period

Isolates (N)

2005–2006

735

2006–2009 2008–2010

1057 845

TEST (Reinert et al., 2007) TESTz,x (Rossi et al., 2008) TESTk (Bertrand et al., 2012)

2004–2006 2004–2007 2004–2009

TESTy (Morfin-Otero et al., 2012a)

188 313 163 651

2004–2009

Country (region) Latin America (regional surveillance) Bantar et al* (Bantar et al., 2009) y,z

SENTRY (Gales et al., 2011) SENTRYô (Gales et al., 2012) ô

TESTz,# (Fernandez-Canigia et al., 2012)

2004–2010

Cuba (Hart Casares et al., 2008)

2006

307 1499 72

Cuba (Hart Casares et al., 2010)

2010

40

Central America Guatemala (TEST) (Fernandez-Canigia et al., 2012)

2004–2010

141

Carbapenem Imipenem Meropenem Imipenem Imipenem Meropenem Imipenem Imipenem Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem Meropenem

MIC90 (mg/mL)

48 48 32 32 128 32 32 32 32 32

Susceptible (%) 48 47 48 31 30 61 63 8 27

63 34

Resistant (%) 50 56 68 66 33

56–63 (2006–2009) 34 61 53 55 82 90

30 (continued )


DOI: 10.3109/1040841X.2014.940494

Study period

Isolates (N)

Honduras (TEST) (Fernandez-Canigia et al., 2012) Mexico (Guadalajara) (Morfin-Otero et al., 2012b)

2004–2010 2005–2010

51 362

Mexico (Monterrey) (Garza-Gonzalez et al., 2010) Mexico (Monterrey) (Llaca-Diaz et al., 2012)

2006–2010 2011–2012

550 268

Mexico (SENTRY) (Gales et al., 2012)

2008–2010

239

Mexico (TEST) (Fernandez-Canigia et al., 2012) Mexico (TEST) (Rossi et al., 2008) Panama (TEST) (Fernandez-Canigia et al., 2012)

2004–2010 2004–2007 2004–2010

333 95 48

South America Argentina (nationwide) (Bantar et al., 2009)

2005–2006

355

Argentina (SENTRY) (Gales et al., 2012)

2008–2010

172

Argentina (TEST) (Fernandez-Canigia et al., 2012)

2004–2010

Argentina (TEST) (Rossi et al., 2008) Bolivia (Cochabamba) (Sevillano et al., 2012) Brazil (Rio Grande do Sul) (Zavascki et al., 2007b)

2004–2007 2008–2009 2002–2006

Brazil (Parana´) (Viana et al., 2011)

2004–2007

148 321 178 46** 844 174 102

Brazil (nationwide) (Marra et al., 2011)

2007–2010

Brazil (Porto Alegre) (Ferreira et al., 2011)

2006–2007

290 289 274

Brazil (Salvador) (Coelho-Souza et al., 2013)

2002–2008

31

Brazil (Maringa´ ICU study) (dos Santos Saalfeld et al., 2009) Brazil (Curitiba) (Toledo et al., 2012)

2008

66yy

Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem Imipenem Imipenem Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem Imipenem/ meropenem Imipenem/ meropenem NS

NS

NS

Brazil (SENTRY) (Gales et al., 2012)

2010 2011 2008–2010

355

Brazil (TEST) (Fernandez-Canigia et al., 2012) Brazil (TEST) (Rossi et al., 2008) Chile (nationwide) (Bantar et al., 2009)

2004–2010 2004–2007 2005–2006

118 45 208

27 27 25

Chile (nationwide) (Silva et al., 2011b)

2009

840

Chile (SENTRY) (Gales et al., 2012)

2008–2010

79

Chile (TEST) (Fernandez-Canigia et al., 2012)

2004–2010

Chile (TEST) (Rossi et al., 2008) Colombia (nationwide) (Villegas et al., 2007a) Colombia nationwide) (Bantar et al., 2009)

2004–2007 2005 2005–2006

39 139 46 542 156

Colombia (nationwide) (Villalobos Rodriguez et al., 2011) Colombia (TEST) (Fernandez-Canigia et al., 2012)

2007 2008 2009 2004–2010 2004–2007 2005–2006

Venezuela (TEST) (Fernandez-Canigia et al., 2012)

2004–2010

96

Imipenem Meropenem Imipenem Imipenem Meropenem Meropenem

60 43

Colombia (TEST) (Rossi et al., 2008) Venezuela (nationwide) (Bantar et al., 2009)

754 543 404 35 220 39 119

Imipenem Meropenem Meropenem Imipenem Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem Imipenem Meropenem Imipenem NS Imipenem Meropenem Imipenem


Country (region)

Carbapenem Meropenem Imipenem Meropenem Meropenem Imipenem Meropenem Imipenem Meropenem Meropenem Imipenem Meropenem

MIC90 (mg/mL) 48 48 416 48 48

Susceptible (%) 28 52 52 30

283

Resistant (%) 36 37 59 76 75

41 40 61 1 17 31 36 15 15 49 15

67 63

39 35 99.9 99 64 32

73 73 56 56 69

432

52

Range, 16–64

100 8–36zz 8–34zz

74 74 70 68 47 47 90 27 33 31

53 46 22

31 24 25

7 34 (range, 11–62) 67 68 48 47 46 31 41 50

MIC90 ¼ minimum concentration required to inhibit growth of 90% of strains; NS ¼ not specified; TEST, Tigecycline Evaluation and Surveillance Trial. *Latin American Tigecycline Surveillance Group; participating countries: Argentina, Colombia, Chile, Venezuela. y Participating countries not specified. z Susceptibility rates reported for individual countries are also shown in this table. ô Argentina, Brazil, Chile, Mexico. x Argentina, Brazil, Chile, Colombia, Guatemala, Honduras, Jamaica, Mexico, Panama, Puerto Rico, Venezuela. k Argentina, Brazil, Chile, Colombia, El Salvador, Guatemala, Honduras, Jamaica, Mexico, Nicaragua, Panama, Puerto Rico, Venezuela. # Argentina, Brazil, Chile, Colombia, El Salvador, Guatemala, Honduras, Jamaica, Mexico, Nicaragua, Panama, Venezuela. **Three isolates were Acinetobacter genomic species 13TU. yy 18 were environmental isolates. zz Depending on infection type.


284



Figure 2. Prevalence of imipenema and meropenemb resistance among Acinetobacter baumannii nosocomial isolates reported in the 2010 Pan American Health Organization surveillance study (Pan American Health Organization, 2010), and range of resistance rates to imipenemc and meropenemd reported in surveillance and cohort studies* (data collected in Latin America since 2005). *For surveillance and cohort studies, refer to Table 4 for related data and references. yFor this country, data from the 2009 PAHO report are given because data were not provided in the 2010 report.

In two of the largest nationwide studies, the average rate of carbapenem resistance increased from 3% in 2003 to 56% in 2007–2010 (Kiffer et al., 2005; Marra et al., 2011). Very low rates of carbapenem resistance were observed in A. baumannii between 2002 and 2006 at Hospital Sao Lucas, Rio Grande do Sul despite extremely high levels of carbapenem-resistant P. aeruginosa, suggesting that factors other than antimicrobial drug usage contribute to the epidemiology of A. baumannii in the hospital environment (Zavascki et al., 2007b). There was substantial variability in susceptibility rates of A. baumannii isolates recovered in Chile, as shown in Table 4. Similar to the finding for P. aeruginosa, one study in Chile reported far lower levels of A. baumannii susceptibility to imipenem and meropenem among isolates recovered from ICUs (62% and 57%, respectively) relative to other patientcare areas (83% and 84%) (Silva et al., 2011b). A steep trendwise increase in carbapenem resistance in Acinetobacter spp. was observed in Colombia, where cohort data revealed resistance rates increasing from 11% in 2001 to 460% in Latin American Tigecycline Surveillance Group data from 2005 to 2006 and PAHO data from 2009 (Bantar et al., 2009; Leal et al., 2006; Pan American Health Organization, 2010; Villalobos Rodriguez et al., 2011; Villegas et al., 2007a). Finally, data from Venezuela indicated carbapenem susceptibility rates of 22–53% among A. baumannii isolates (Table 4). Mechanisms of resistance Acinetobacter baumannii is endowed with several intrinsic mechanisms of antimicrobial resistance (Lee et al., 2011; Mussi et al., 2005, 2011). The single most

important mechanism responsible for A. baumannii resistance to carbapenems is the expression of Ambler class D b-lactamases (i.e. oxacillinases) and, to a much lesser extent, MBLs including IMP and VIM (Bonomo et al., 2006; Opazo et al., 2012; Poirel et al., 2006). The carbapenemases OXA23 and OXA-58-like were first detected in Europe and have since appeared in Latin America (Dalla-Costa et al., 2003; Donald et al., 2000; Figueiredo et al., 2011; Higgins et al., 2009; Opazo et al., 2012; Paton et al., 1993; Poirel et al., 2005; Rodriguez et al., 2010). The carbapenem-hydrolyzing Ambler class D b-lactamase OXA-143 was recovered from A. baumannii blood isolates during a 2004 Brazilian ICU outbreak (Higgins et al., 2009). Extremely high prevalence of acquired OXA-23 genes was detected in carbapenem-resistant A. baumannii isolates recovered from the nosocomial settings of Argentina (63% of carbapenem-resistant isolates), Brazil (42–100%) and Colombia (98%) during the past decade (Table 5) (Antonio et al., 2011; Carvalho et al., 2009; Coelho-Souza et al., 2013; Dalla-Costa et al., 2003; Ferreira et al., 2011; Grosso et al., 2011; Higgins et al., 2010; Marra et al., 2011; Martins et al., 2009, 2013; Merkier et al., 2008; Schimith Bier et al., 2010; Villegas et al., 2007a). In addition, the OXA-58 gene has been identified in Argentina, Bolivia, Brazil, Chile, Colombia and Venezuela (Coelho et al., 2006; Figueiredo et al., 2011; Higgins et al., 2010; Lopes et al., 2013; Martins et al., 2009; Opazo et al., 2012). In Brazil, the prevalence of OXA-143 (58%) and OXA-23 (42%) was reported to be much higher than that of OXA-58 (3%) among carbapenem-resistant A. baumannii isolates recovered in eight medical centers (2004–2008) (Antonio et al., 2011). OXA-72-producing A. baumannii isolates have also been reported in Brazil (Antonio et al., 2011;


DOI: 10.3109/1040841X.2014.940494

285

Table 5. Occurrence of carbapenemases in carbapenem-resistant Acinetobacter baumannii in South America (studies analyzing 430 isolates).

Country (region)

Study period

Isolates* (N)

Occurrence of carbapenemases, % (n/N)

Argentina (Buenos Aires) (Merkier et al., 2008)

1995–2006

41y

Not reported

Brazil (Curtiba) (Schimith Bier et al., 2010) Brazil (nationwide) (Antonio et al., 2011)

2002–2005 2004–2008

172 36

100 (172/172) Not reported

Brazil (Porto Alegre) (Ferreira et al., 2011) Brazil (Rio de Janeiro) (Carvalho et al., 2009) Brazil (nationwide) (Marra et al., 2011) Brazil (Porto Alegre) (Martins et al., 2013) Colombia (nationwide) (Villegas et al., 2007a)

2006–2007 2006–2007 2007–2010 2007 2005

274z 110 112 53 66

84 88 76 100 98

(230/274) (97/110) (85/112) (53/53) (65/66)

Genetic determinant or expression (n/N of tested isolates) OXA-23 (26/41) OXA-58 (13/41) OXA-23–like (172/172) OXA-143 (21/36) OXA-23 (15/36) OXA-58 (1/36) OXA-72 (2/36) OXA-23 (131/214ô) OXA-23 (96/110) OXA-23 (85/112) OXA-23–like (53/53) OXA-23–like (65/66)

*Isolates were carbapenem-resistant unless otherwise noted. Isolates had diminished susceptibility to imipenem (MIC90, 32 mg/mL) and meropenem (MIC90, 16 mg/mL). z 69% of isolates were carbapenem-resistant. ô 214 isolates tested were carbapenem-resistant.


y

Werneck et al., 2011), and an A. baumannii isolate producing the novel oxacillinase OXA-235 was recovered in Mexico in 2007 (Higgins et al., 2013). The occurrence of MBLs among 50 phenotypically diverse A. baumannii clinical isolates from a tertiary hospital in Rio Grande do Sul, Brazil, during 2008 was 6% (Machado et al., 2011). Molecular epidemiology A large body of evidence indicates that A. baumannii is clonal in nature (Higgins et al., 2012, 2010; Villegas et al., 2003; Young et al., 2007). Clonal lineages appear to have originated in at least eight different geographical locations worldwide and then spread to new locations, possibly via transfer of patients (Higgins et al., 2010). Clones of A. baumannii can persist for several years in the nosocomial setting, enabling outbreaks and acquiring additional mechanisms of resistance in response to environmental changes (Barbolla et al., 2008; Ferreira et al., 2011; Viana et al., 2011). Epidemic A. baumannii strains can be readily identified (and their clonality assessed) by their tendency to have an antibiogram reflective of multidrug resistance. International clones I–III predominate and their detection at various distinct geographical locations at different points have not yet been explained. Countless outbreaks have occurred worldwide (Marais et al., 2004; Mezzatesta et al., 2012; Wang et al., 2007), including Latin America (Barbolla et al., 2008; Dalla-Costa et al., 2003; Mendes et al., 2007). In Buenos Aires since 2001, identification and spread of the epidemic carbapenem-resistant A. baumannii clone IV was readily identified at several hospitals, possibly caused by colonization of transferred patients, staff and environment (Arduino et al., 2012; Barbolla et al., 2003; Barbolla et al., 2008; Rodriguez et al., 2009). The OXA-23 gene has disseminated throughout South America via several novel A. baumannii clones and nonclonal strains. The fact that this carbapenem-resistance determinant can recirculate after years of dormancy within clones as well as in partially related and unrelated clusters underscores

the mobility of OXA-23 (Schimith Bier et al., 2010). There is also evidence of clonal expansion and diversification during persistence and, again, an ease of transmission within and between hospitals located in different cities (Stietz et al., 2013). In Argentina, novel STs were detected in Buenos Aires (1983–2012) and Rosario (2006–2009) hospitals along with international clone I (international clones II and III were not detected) (Stietz et al., 2013). All but one A. baumannii multidrug-resistant isolate collected from 2007 to 2012 in Buenos Aires and Rosario hospitals in this study harbored blaOXA-23-like (Stietz et al., 2013). Also in Buenos Aires, there was polyclonal spread (clones I and IV) of OXA-23 and OXA-58 in A. baumannii isolates during 1995–2006, highlighting the need for continuous molecular surveillance and infection control to mitigate further mobilization of epidemic carbapenem-resistant clones (Merkier et al., 2008). In Brazil, spread of OXA-23 is not attributed to any one predominant clone (Viana et al., 2011). For instance, in Rio de Janeiro, A. baumannii OXA-23 producers included both nonclonal and clonal isolates (Carneiro et al., 2010; Carvalho et al., 2009). The reasons for such a complex dissemination of these strains are multifactorial but may involve horizontal transmission of the genetic element containing the OXA-23 gene in addition to person-to-person transfer of the same strain (Martins et al., 2009). Seventy percent of OXA-23-producing A. baumannii clinical isolates collected from eight hospitals in Rio de Janeiro between 2006 and 2007 were assigned to international clone II; however, as in Argentina, local diversity was observed as evidenced by detection of new STs which presented the genes blaOXA-66, blaOXA-69, blaOXA-95 and blaOXA-132 (Grosso et al., 2011). In Bolivia, the first report of carbapenem-resistant A. baumannii isolates due to the presence of OXA-58 was associated with multidrug-resistant, inter-related clones, which were grouped via molecular typing by pulsed field gel electrophoresis into four genotypes (A–D) (Sevillano et al., 2012). These clones were not related to European A. baumannii clones I, II or III. Isolates from clone A were

286



resistant to all antibiotics tested with the exception of colistin, whereas most isolates belonging to groups B, C and D were susceptible only to carbapenems and colistin (Sevillano et al., 2012). Analysis of 66 carbapenem-resistant isolates of A. baumannii collected from tertiary care hospitals participating in a nationwide surveillance network in Colombia revealed that production of OXA-23 was by four clones (n ¼ 45 isolates) and 21 unique pulsotypes (Villegas et al., 2007a). One clone was detected in two hospitals within one city, whereas another clone had disseminated between two hospitals in different cities. In three of the four clones examined, OXA-23 was chromosomally encoded, and in the fourth clone, it was plasmid encoded (Villegas et al., 2007a).

Colistin (polymyxins B and E) and tigecycline activity Surveillance and cohort data have shown that both colistin and tigecycline have excellent in vitro activity against Acinetobacter spp. nosocomial isolates (both MIC90 values, 2 mg/mL; Table 6) (Bantar et al., 2009; Bertrand et al., 2012; Coelho-Souza et al., 2013; dos Santos Saalfeld et al., 2009; Fernandez-Canigia et al., 2012; Gales et al., 2011, 2012; Hart Casares et al., 2010; Herrera et al., 2011; Medell et al., 2012; Mendes et al., 2010; Morfin-Otero et al., 2012a; Morfin-Otero et al., 2012b; Reinert et al., 2007; Rossi et al., 2008; Sevillano et al., 2012; Silva et al., 2011b). In general, 98–100% of A. baumannii isolates recovered from hospital settings in Cuba, Mexico, Argentina, Bolivia, Brazil and Chile were susceptible to


Table 6. In vitro activity of colistin and tigecycline against Acinetobacter spp. in Latin America (studies conducted since 2005; 430 isolates).

Country (region)

Study period

Colistin Latin America (SENTRY)* (Gales et al., 2011) Latin America (SENTRY)z,ô (Gales et al., 2012) Cuba (Medell et al., 2012)

2006–2009 2008–2010 2007–2010

Cuba (Hart Casares et al., 2010) Mexico (Guadalajara) (Morfin-Otero et al., 2012b) Mexico (SENTRY) (Gales et al., 2012) Argentina (Entre Rıós) (Herrera et al., 2011) Argentina (SENTRY) (Gales et al., 2012) Bolivia (Cochabamba) (Sevillano et al., 2012) Brazil (Parana´) (dos Santos Saalfeld et al., 2009) Brazil (Salvador) (Coelho-Souza et al., 2013) Brazil (SENTRY) (Gales et al., 2012) Chile (nationwide) (Silva et al., 2011b) Chile (SENTRY) (Gales et al., 2012) Tigecycline Latin America (TEST)z (Reinert et al., 2007) Latin America (TEST)** (Rossi et al., 2008) Latin Americaô,z (Bantar et al., 2009) Latin America (TEST)ôô (Bertrand et al., 2012) Latin America (TEST)* (Morfin-Otero et al., 2012a) Latin America (TEST)xx (Fernandez-Canigia et al., 2012) Cuba (Hart Casares et al., 2010) Mexico (nationwide) (Mendes et al., 2010) Argentina (nationwide) (Mendes et al., 2010) Argentina (nationwide) (Bantar et al., 2009) Brazil (Parana´) (dos Santos Saalfeld et al., 2009) Brazil (Salvador) (Coelho-Souza et al., 2013) Brazil (nationwide) (Mendes et al., 2010) Chile (nationwide) (Silva et al., 2011b) Chile (nationwide) (Mendes et al., 2010) Chile (nationwide) (Bantar et al., 2009) Colombia (nationwide) (Bantar et al., 2009) Venezuela (nationwide) (Bantar et al., 2009)

Type of isolates

Isolates MIC90 Susceptible Resistant (mg/mL) (%) (%) (N)

2008–2010 2008–2009 2008 2002–2008 2008–2010 2009 2008–2010

General nosocomial 1057 Hospital and community 845 Lower respiratory tract NR of ICU MV patients General nosocomial 40 General nosocomial 362 Hospital and community 239 Clinically significant 75 Hospital and community 172 General nosocomial 46k Carbapenem-resistant ICU 66# Meningitis 31 Hospital and community 355 General and ICU 840 Hospital and community 79

2004–2006 2004–2007 2005–2006 2004–2009 2004–2009 2004–2010 2010 2005–2009 2005–2009 2005–2006 2008 2002–2008 2005–2009 2009 2005–2009 2005–2006 2005–2006 2005–2006

Hospital and community 188 Hospital and community 486 General nosocomial 735 ICU 814 Hospital and community General nosocomial 1806 General nosocomial 40 General nosocomial 277 General nosocomial 260 General nosocomial 355 Carbapenem-resistant ICU 66# Meningitis 31 General nosocomial 611 General and ICU 840 General nosocomial 143 General nosocomial 208 General nosocomial 156 General nosocomial 119

2010 2005–2010 2008–2010

1

1x 2

99y 98

99 98 100 100 100 100

1

1 2 0 1.5

3 98 100 100

1 2 2 2 2 1 2

n/a 97 91zz n/a n/a 100 93zz 100

1 2

0.4 2

0 1 0

95 1

100zz 89zz 84zz

0 0 8

MIC90 ¼ minimum concentration required to inhibit growth of 90% of strains; ICU ¼ intensive care unit; MV ¼ mechanically ventilated; n/a ¼ susceptibility data not available; TEST ¼ Tigecycline Evaluation and Surveillance Trial. *Participating countries not specified. y Susceptibility rates were 98.9% for colistin and 99.1% for polymyxin B. z Argentina, Brazil, Chile, Mexico. ô Susceptibility rates reported for individual countries are also shown in this table. x For polymyxin B, MIC90 was 0.5, susceptibility was 99% and resistance was 1.4%. k Three were Acinetobacter genomic species 13TU. # Including 18 environmental isolates. **Argentina, Brazil, Chile, Colombia, Guatemala, Honduras, Jamaica, Mexico, Panama, Puerto Rico, Venezuela. yy Latin American Tigecycline Surveillance Group; participating countries: Argentina, Colombia, Chile, Venezuela. zz Applying breakpoints proposed by Jones et al. (Jones et al., 2007) ôô Argentina, Brazil, Chile, Colombia, El Salvador, Guatemala, Honduras, Jamaica, Mexico, Nicaragua, Panama, Puerto Rico, Venezuela. xx Argentina, Brazil, Chile, Colombia, El Salvador, Guatemala, Honduras, Jamaica, Mexico, Nicaragua, Panama, Venezuela.


DOI: 10.3109/1040841X.2014.940494

colistin (Table 6). However, a colistin-resistant A. baumannii isolate was recovered in Salvador, Brazil in 2008 (CoelhoSouza et al., 2013), and phenotypic analysis of A. baumannii isolates collected from the lower respiratory tract of ICU patients in Cuba undergoing mechanical ventilation revealed that some (2%) were resistant to colistin (Medell et al., 2012). Further studies are required to determine whether resistance can develop during colistin exposure (Zavascki et al., 2009). To date, there are no recommendations from the Clinical and Laboratory Standards Institute (CLSI) or the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for susceptibility testing of A. baumannii to tigecycline, and most centers use breakpoints for Enterobacteriaceae despite concerns about this approach (Peleg et al., 2008). In addition, other factors, such as cation concentration, could influence susceptibility results. From the available data, tigecycline MIC distributions among A. baumannii isolates were consistent throughout the region, with MIC90 values of 1–2 mg/mL, and susceptibility rates of A. baumannii isolates to tigecycline ranged 84–100% (Table 6). According to TEST surveillance data, the in vitro activity of tigecycline has remained substantially constant between 2004 and 2009 in Latin America (Morfin-Otero et al., 2012a). Among 104 imipenem-resistant Acinetobacter isolates collected in Latin America in 2004–2007, the tigecycline MIC90 was 2 mg/mL, and 97% of the isolates were susceptible to tigecycline using breakpoints pertaining to Enterobacteriaceae (Rossi et al., 2008). Of the 93 multidrug-resistant lineages of A. baumannii collected in Buenos Aires (1983–2012) and Rosario (2006–2009) hospitals, all isolates were susceptible to colistin, and the tigecycline MIC90 was 1 mg/mL (Stietz et al., 2013).

Conclusions Our review of the literature identified abundant data demonstrating the emergence of carbapenemases in P. aeruginosa and A. baumannii in the Latin American region and in individual countries. Information from the region is found in surveillance from PAHO, SENTRY and TEST, and there are many additional reports from individual cities and countries (most notably from Brazil). PAHO, in particular, is an important regional effort providing data from a large number of Latin American countries; although individual laboratories utilize different methods, quality control is enforced and data are standardized for presentation. The PAHO system is part of a larger program of the World Health Organization, the value of which has been established in many publications. The current prevalence of carbapenem resistance in the region is very high, up to 66% for P. aeruginosa (Figure 1) and even higher for A. baumannii, with rates of resistance as high as 90% (Figure 2). The data indicate that in every country where a trend is available, the rate of resistance to carbapenems is increasing. To our knowledge, information from local unpublished reports also indicates that rates of carbapenem resistance are increasing in Latin America, especially in A. baumannii. At the regional and local levels, the prevalence of P. aeruginosa and A. baumannii and resistance rates to carbapenems among these pathogens


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are much higher than those reported in the developed countries of North America and Europe. Emergence of resistance to carbapenems among P. aeruginosa and A. baumannii strains creates difficult choices for clinicians because of the lack of antimicrobials retaining activity against these pathogens. As shown in our review, colistin retains good in vitro activity against P. aeruginosa and A. baumannii and tigecycline against A. baumannii. However, colistin has well-known doselimiting toxicity issues (Bergen et al., 2012; Vila et al., 2012), and tigecycline has some pharmacological limitations and has been found less effective in some clinical trials for specific infections (Freire et al., 2010; Ramirez et al., 2013). Tigecycline is associated with higher all-cause mortality than other agents and should be used only when alternative agents are not suitable (Wyeth Pharmaceuticals Inc, 2013). Importantly, there are few agents under development with promise to treat these highly drug-resistant pathogens. The main reason for increasing prevalence of carbapenemresistant P. aeruginosa and A. baumannii in Latin America is probably transmission from patient to patient, which not only causes local outbreaks but also insidious dissemination within hospitals. Continued circulation of more epidemic and endemic strains drives use of last-line antibiotics, especially carbapenems, and more selection pressure for carbapenem resistance ensues. Emergence of A. baumannii strains with acquired resistance to carbapenems has coincided with increasing use of this antimicrobial class (Gaynes et al., 2005; Lee et al., 2011; Mera et al., 2010). Although there is no consensus, antibiotic use may be an independent risk factor for development of P. aeruginosa and A. baumannii resistance to carbapenems (Castelo Branco Fortaleza et al., 2013; Furtado et al., 2010; Tuon et al., 2012). Meta-analysis data indicate that an additional 39% of patients may develop carbapenem resistance on treatment (Zilberberg et al., 2010). Further, carbapenem use was a risk factor for emergence of carbapenem-resistant, multidrug-resistant Acinetobacter isolates (Paterson, 2006). One specific issue in the Latin American region is the origin and spread of the SPM-encoding gene among P. aeruginosa from Brazil. During the first part of the past decade, there was a great increase in carbapenem resistance in P. aeruginosa mainly due to the predominance of one or few clones with the SPM-encoding gene. Later, other mechanisms of carbapenem resistance came to the fore. While SPM-producing isolates showed diversity, phylogenetic studies confirmed a unique ancestor. An important factor that facilitates the spread of these resistant bacteria is poor infection-control practices, mainly in hospitals, as was demonstrated in several outbreak studies in Brazil. Our review highlights areas in which research is lacking. Most studies on carbapenem resistance in P. aeruginosa and Acinetobacter spp., including those meeting the search criteria of this article, are based on description of the presence of carbapenemases. However, porin loss and efflux mechanisms (Villagra et al., 2012) are described less or not at all in Latin American isolates. The prevalence of these mechanisms of resistance in isolates with and without carbapenemase production is not known. Given this lack of information, it is more appropriate to describe the presence of carbapenemases


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in these isolates than to attribute carbapenem resistance to the carbapenemases themselves. There are carbapenemases, especially in OXA group, that have weak activity to hydrolyze carbapenems, and it is possible that resistance appears when these carbapenemases combine with other mechanisms of resistance in the same isolate. Further studies should not only investigate the presence of carbapenemases, but should also seek to detect porin deficiencies and efflux mechanisms, in order to better describe and infer the mechanism of resistance. This is especially critical for P. aeruginosa, where carbapenemases are found in a smaller proportion of isolates in nonepidemic scenarios. Additionally, despite the impact of drug-resistant pathogens on public health, only a few reports have been released on the modes of transmission, epidemiology of risk factors and interventions to control the problem of carbapenemresistant P. aeruginosa and A. baumannii in Latin America. Reports of infection-control interventions to ameliorate this problem are almost absent, and most studies evaluating infection-control issues are related to investigations of outbreaks. Limitations of this review include the lack of data available for some countries in Latin America as well as the possible bias in data reported from different networks. For example, data from SENTRY and surveillance studies sponsored by pharmaceutical companies are obtained from only a few centers in each country. Methodology of data reporting, collection and analysis may also differ among laboratories, countries and surveillance networks. Data derived from single-center studies (e.g., teaching hospitals) likely report elevated resistance rates. Additionally, there is a delay in reporting of data in peer-reviewed publications. Much information is reported only at local conferences or in local databases and is therefore not available in the journal articles we reviewed. Despite these limitations, the review of available published data we have presented provides a comprehensive, organized and balanced account of the prevalence of resistance to A. baumannii and P. aeruginosa in nosocomial settings in Latin America. In conclusion, carbapenem resistance is increasing in the Latin American region in P. aeruginosa, and especially in A. baumannii, with a resistance rate of more than 50% of isolates in many countries. Carbapenem resistance in P. aeruginosa is due mainly to mechanisms other than carbapenemases, especially porin defects. The most important carbapenemases in non-outbreak situations outside of Brazil are those in the VIM group. In Brazil the epidemiology has been different due to the presence and clonal spread of SPM-1-producing P. aeruginosa. In the case of A. baumannii, carbapenem resistance is due mainly to oxacillinases, the most important being OXA-23, OXA-58 and OXA-143. Colistin susceptibility remains high with more than 95% of isolates susceptible in most countries for P. aeruginosa and A. baumannii, although there are reports of elevated MICs against colistin among P. aeruginosa strains in Brazil and Chile. Regionally, the rate of tigecycline susceptibility should be analyzed carefully. Among A. baumannii isolates, this rate is generally greater than 90%. Updated microbiological information is needed, and it is critical to have more epidemiological information in the region to implement


infection control strategies to reduce the public-health impact of this problem.

Declaration of interest This publication was funded by Pfizer Inc. Medical writing support was provided by Malcolm Darkes and Lisa Baker of Engage Scientific Solutions and was funded by Pfizer Inc.

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[Carbapenem-resistance in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii].

Carbapenem resistant Pseudomonas aeruginosa and Acinetobacter baumannii at Mulago Hospital in Kampala, Uganda (2007-2009).

Quantitative proteomics to study carbapenem resistance in Acinetobacter baumannii.

Mobile genetic elements related to carbapenem resistance in Acinetobacter baumannii.

Nosocomial Acinetobacter baumannii Infections and Changing Antibiotic Resistance.

Nosocomial transmission of carbapenem-resistant Pseudomonas aeruginosa among burn patients.

Bulgecin A as a β-lactam enhancer for carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii clinical isolates containing various resistance mechanisms.

Effect of carbapenem consumption patterns on the molecular epidemiology and carbapenem resistance of Acinetobacter baumannii.

Increasing resistance rate to carbapenem among blood culture isolates of Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa in a university-affiliated hospital in China, 2004-2011.

Emergence of plasmid-mediated quinolone resistance genes in clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa in Henan, China.

sulbactam.

Carbapenem resistance and acquired class D beta-lactamases in Acinetobacter baumannii from Croatia 2009-2010.

Evaluation of Ciprofloxacin (gyrA, parC Genes) and Tetracycline (tetB Gene) Resistance in Nosocomial Acinetobacter baumannii Infections.

Resistance markers and genetic diversity in Acinetobacter baumannii strains recovered from nosocomial bloodstream infections.

Molecular characterization of carbapenem-insensitive Acinetobacter baumannii in Egypt.

Molecular epidemiology of carbapenem non-susceptible Acinetobacter baumannii in France.

The comparison of genotyping, antibiogram, and antimicrobial resistance genes between carbapenem-susceptible and -resistant Acinetobacter baumannii.

Prediction of Putative Resistance Islands in a Carbapenem-Resistant Acinetobacter baumannii Global Clone 2 Clinical Isolate.

Types and prevalence of carbapenem-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii complex in Northern Taiwan.

Phenotypic characterization and colistin susceptibilities of carbapenem-resistant of Pseudomonas aeruginosa and Acinetobacter spp.

Association of biofilm production with multidrug resistance among clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa from intensive care unit.

Carbapenem Susceptibility and Multidrug-Resistance in Pseudomonas aeruginosa Isolates in Egypt.

Response to letter to the editor: Acinetobacter baumannii using several mechanisms for carbapenem resistance.

Mutant prevention concentrations of imipenem and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii.