Susceptibility of Gram-Negative Pathogens Isolated from Patients with Complicated Intra-Abdominal Infections in the United States, 2007-2008: Results of the Study for Monitoring Antimicrobial Resistance Trends (SMART)

Abstract

During 2007-2008, 1,036 Gram-negative bacilli were isolated from patients with complicated intra-abdominal infections in the United States. Against members of the family Enterobacteriaceae, the most active agents in vitro were ertapenem, imipenem, and amikacin, while the least active agent was ampicillin-sulbactam. Ertapenem and imipenem were active against all extended-spectrum-beta-lactamase (ESBL)-positive Escherichia coli. Antimicrobial resistance in Gram-negative bacilli isolated from patients with complicated intra-abdominal infections in the United States continues to increase.

In 2003, the Infectious Diseases Society of America published guidelines on the appropriate selection of antimicrobials for the management of patients with complicated intra-abdominal infections (IAIs) (14). These guidelines addressed the choice of antimicrobials for both empirical and directed antimicrobial therapy for both community-associated and hospital-associated infections/pathogens. Several surveillance studies and reports have documented the increased levels of antimicrobial resistance to many of the recommended agents with significant awareness of the incidence of extended-spectrum-beta-lactamase (ESBL)-positive Escherichia coli and Klebsiella pneumoniae/oxytoca (2, 5, 7, 8, 10). In 2002, the Study for Monitoring Antimicrobial Resistance Trends (SMART) was initiated to monitor yearly the antimicrobial susceptibility of Gram-negative bacilli associated with both community- and hospital-associated IAIs. This report documents the in vitro susceptibility of the most common pathogens associated with IAI in the United States in 2007-2008 to ertapenem, imipenem, and 10 comparator antimicrobial agents.

(This work was presented in part as a poster [poster 814] at the 47th Annual Meeting of the Infectious Diseases Society of America, Philadelphia, PA, 29 October to 1 November 2009.)

Up to 100 consecutive aerobic or facultative anaerobic Gram-negative bacilli were collected from patients with complicated IAIs from 18 hospital sites in the United States representing all 9 CDC regions in 2007-2008. Antimicrobial susceptibility testing and ESBL detection/confirmation were performed using broth microdilution as previously described (5). Reference strains recommended by the Clinical and Laboratory Standards Institute (CLSI) for quality control were utilized, and MICs were interpreted according to CLSI guidelines (3). A total of 1,036 isolates were collected in 2007-2008 (Table 1). The most commonly isolated pathogens were as follows (percentage of total is shown in parentheses): E. coli (43.1), K. pneumoniae (17.7), Pseudomonas aeruginosa (13.3), Enterobacter cloacae (8.4), Proteus mirabilis (3.0), Klebsiella oxytoca (2.7), Enterobacter aerogenes (2.3), Citrobacter freundii (1.7), and Serratia marcescens (1.5). Overall, members of the family Enterobacteriaceae accounted for 84.7% of all pathogens and 80.4% of the group of pathogens containing only species with greater than 10 isolates represented. Bacteria that were not members of the family Enterobacteriaceae, including P. aeruginosa and Acinetobacter spp., accounted for most of the remaining pathogens.

TABLE 1.

Susceptibility of IAI pathogens in the United States, 2007-2008

Organism	No. of isolates (% of total) (n = 1,036)	% of isolates susceptible to the following antimicrobiala:
		ETP	IMP	AK	CPE	CFT	CFX	CAZ	CAX	CP	LVX	P/T	A/S
C. freundii	18 (1.7)	94	100	100	94	67	17	72	67	72	78	72	61
E. aerogenes	24 (2.3)	100	100	100	100	79	8	63	79	96	96	88	21
E. cloacae	87 (8.4)	92	100	99	85	62	1	66	64	85	88	69	17
E. coli isolates
All	447 (43.1)	99	100	98	97	96	93	96	96	80	81	96	62
ESBL-positive	21 (2.0)	100	100	71	48*	38*	71*	52*	38*	33	33	62	24
ESBL-negative	426 (41.1)	99	100	100	100	99	94	98	98	82	83	98	64
K. oxytocab	28 (2.7)	100	100	100	96	96	96	96	89	96	100	89	57
K. pneumoniae isolates
All	183 (17.7)	96	99	95	91	85	84	86	85	80	84	85	69
ESBL-positive	32 (3.1)	78	94	69	47*	19*	66*	19*	19*	19	28	28	3
ESBL-negative	151 (14.6)	100	100	100	100	99	87	100	99	93	96	97	83
P. mirabilisb	31 (3.0)	100	93	100	100	100	100	94	100	97	100	100	97
P. aeruginosa	138 (13.3)	NA	78	96	72	9	NA	76	17	72	72	83	NA
S. marcescens	15 (1.5)	100	100	100	100	100	26	100	100	93	93	100	13
All Enterobacteriaceae with >10 isolatesc	833 (80.4)	98	99	98	95	89	76	89	89	82	84	90	58
All Enterobacteriaceaed	878 (84.7)	98	99	98	95	89	76	89	89	83	85	90	58
Other non-Enterobacteriaceaee	20 (1.9)	NA	69	31	23	8	NA	32	15	15	47	23	46

^aAntimicrobial abbreviations: ETP, ertapenem; IMP, imipenem; AK, amikacin; CPE, cefepime; CFT, cefotaxime; CFX, cefoxitin; CAZ, ceftazidime; CAX, ceftriaxone; CP, ciprofloxacin; LVX, levofloxacin; P/T, piperacillin-tazobactam; A/S, ampicillin-sulbactam. CLSI standard M100-S19 recommends interpreting all cephalosporin results as resistant for ESBL-positive strains (3), and these values are indicated with an asterisk. NA, not available because no CLSI breakpoint defined. Numbers in boldface type are susceptibilities that were ≥90%.

^bIncludes two ESBL-positive strains.

^cAll members of the family Enterobacteriaceae with more than 10 isolates.

^dSpecies with <10 isolates are not shown.

^eOther non-Enterobacteriaceae includes Pasteurella spp. (1 isolate), P. fluorescens (2 isolates), S. maltophilia (6 isolates), and Acinetobacter spp. (11 isolates).

Against all members of the family Enterobacteriaceae or members of the Enterobacteriaceae with more than 10 isolates per species in this study, the most active agents (percent susceptible ≥ 90%) included the carbapenems (ertapenem and imipenem), amikacin, cefepime, and piperacillin-tazobactam. Ampicillin-sulbactam was the least active agent, with only 58% of all members of the Enterobacteriaceae susceptible (Table 1). E. coli, the most commonly isolated pathogen, was susceptible to most antimicrobials, with only ciprofloxacin, levofloxacin, and ampicillin-sulbactam displaying susceptibilities of <82%. E. coli with an ESBL phenotype exhibited a distinctly higher level of resistance to most antimicrobials overall. The carbapenems (ertapenem and imipenem) retained their activity against ESBL-positive E. coli, while the activity of amikacin, ciprofloxacin, levofloxacin, piperacillin-tazobactam, and ampicillin-sulbactam was considerably diminished. Table 1 shows the percent susceptibility of cephalosporins to ESBL-positive E. coli. However, despite the reported percent susceptibilities, CLSI recommends that for clinical purposes, all cephalosporins should be reported as resistant (3). However, in 2010, the CLSI lowered the breakpoints for several extended-spectrum cephalosporins (ceftazidime, ceftriaxone, and cefotaxime) to more accurately reflect the pharmacokinetics/pharmacodynamics of these agents and to better ensure that ESBL-positive E. coli isolates and K. pneumoniae/oxytoca isolates are currently reported as resistant (4). Applying the new breakpoints to a global collection of ESBL-positive Enterobacteriaceae resulted in 7%, 31%, and 6% of these isolates susceptible to ceftriaxone, ceftazidime, and cefotaxime, respectively (1). Continued confirmation testing of ESBL status may still be required for epidemiologic purposes. K. pneumoniae, the second most commonly isolated pathogen, displayed overall susceptibility of ≥90% for the carbapenems, cefepime, and amikacin. ESBL-positive K. pneumoniae, in comparison to ESBL-positive E. coli, was less susceptible to ertapenem (78% versus 100%), imipenem (94% versus 100%), and ampicillin-sulbactam (3% versus 24%). ESBL production was detected in 4.7% and 17.5% of E. coli and K. pneumoniae isolates, respectively. E. coli and K. pneumoniae/K. oxytoca accounted for 63.5% of all members of the Enterobacteriaceae isolated, indicative of their prevalence in IAI. Of the remaining Enterobacteriaceae isolates, susceptibilities were very similar for C. freundii, E. aerogenes/cloacae, P. mirabilis, and S. marcescens. Each of these species was >90% susceptible to ertapenem, imipenem, and amikacin (Table 1). The in vitro activity of ciprofloxacin and levofloxacin varied among the IAI pathogens. Among all members of the Enterobacteriaceae, susceptibility of ≥90% was noted only for E. aerogenes, K. oxytoca, ESBL-negative K. pneumoniae, P. mirabilis, and S. marcescens. Piperacillin-tazobactam activity varied with ESBL phenotype but was consistently lower than ertapenem or imipenem. Amikacin was the only antimicrobial with >90% activity against P. aeruginosa, while 83%, 78%, 76%, and 72% of isolates were susceptible to piperacillin-tazobactam, imipenem, ceftazidime, and ciprofloxacin, respectively.

Surveillance studies investigating the susceptibility of pathogens to frequently used IAI antimicrobials have documented the decreased activity of recommended antimicrobials over the past 10 years. However, specific data for the United States describing susceptibility patterns for IAI pathogens from the United States remains limited. In this study, percent susceptibility of recommended IAI antimicrobials, such as imipenem and ciprofloxacin, varied by year (Fig. 1). Comparing Enterobacteriaceae and non-Enterobacteriaceae isolates each year from 2002 to 2008 in the United States from the SMART study, the susceptibility to both imipenem and ciprofloxacin vary. Only the decreased in vitro activity of ciprofloxacin versus Enterobacteriaceae reached statistical significance (P < 0.001) when comparing 2002 to 2008. One focus of global surveillance studies has been to document the increasing incidence of ESBL-producing E. coli and K. pneumoniae/oxytoca (6, 11-13). The global increase in ESBL-positive and fluoroquinolone-resistant Enterobacteriaceae has challenged standard therapeutic treatment regimens. The identification of CTX-M-type ESBLs as predominant in certain areas of the United States from 2000 to 2006 has altered antimicrobial treatment algorithms with decreased susceptibility to fluoroquinolones among CTX-M phenotypes (16%) compared to 36% among SHV or TEM phenotype (9). The specific examination of antimicrobial susceptibility among IAI pathogens has been under way since 2002 in the SMART study with the primary goal of monitoring changes in resistance for commonly prescribed antimicrobials used for empirical and directed therapy of Gram-negative bacilli in IAIs. Between 2004 and 2007, studies of global isolates from IAIs in the SMART program demonstrated that the susceptibilities of Gram-negative isolates to the carbapenems have remained stable (2, 6, 13), with E. coli and K. pneumoniae isolates, including ESBL-positive isolates, remaining between 98 and 100% susceptible to ertapenem and imipenem. Susceptibility to amikacin has remained high with the percent susceptible continuously over 90 in almost all countries examined (6). The emergence of ESBL-positive E. coli and K. pneumoniae, however, has brought with it the reduced activity of fluoroquinolones (ciprofloxacin and levofloxacin) against these phenotypes (5). In 2004, >77% of E. coli and >84% of K. pneumoniae of mixed phenotypes were susceptible to both ciprofloxacin and levofloxacin. By 2007, only 17% of ESBL-positive E. coli and 70% of ESBL-negative E. coli remained susceptible to ciprofloxacin (5, 13). Similar declines in susceptibility were observed for K. pneumoniae and other species of Enterobacteriaceae (5). In the United States, the levels of resistance to recommended antimicrobials for the treatment of IAI infections has not been examined in depth. In 2003, among 378 E. coli isolates collected from patients with IAI in 23 countries, all ESBL-negative isolates were susceptible to both ertapenem and imipenem and >80% of isolates were susceptible to ciprofloxacin. However, in ESBL-positive isolates, 96.2% remained susceptible to ertapenem and 99.1% remained susceptible to imipenem, while only 31% of isolates were susceptible to ciprofloxacin (12). Clearly, as the incidence of ESBL-positive E. coli and K. pneumoniae/oxytoca phenotypes increases, surveillance studies continue to document the decreasing activity of recommended IAI antimicrobials with the exception of the carbapenems. Although P. aeruginosa accounts for <10% of all Gram-negative pathogens isolated in IAIs in other studies (6), increasing carbapenem, ceftazidime, and fluoroquinolone resistance in this pathogen will continue to complicate empirical antimicrobial therapy.

FIG. 1.

Susceptibility of members of the family Enterobacteriaceae and bacteria that were not members of the Enterobacteriaceae to imipenem and ciprofloxacin from 2002 to 2008. The percent susceptibility values from 2002 to 2008 were compared using Fisher's exact two-tailed test.