1. JT Kirby, DJ Biedenbach, RN Jones, SENTRY Participants Group Univ of Iowa, Iowa City, IA; The JONES Group/JMI Laboratories, North Liberty, IA Poster # 72 Extreme Variations in Susceptibility (S) of P. aeruginosa (PSA) Among Hospitals in North America (NA), Latin America (LA), Europe (EU) and the Asia-Pacific (AP): Report from the SENTRY Antimicrobial Surveillance Program, 1997-2000 A156-22 CONCLUSIONS Overall, P. aeruginosa exhibited remarkable variations in susceptibility patterns with NA and AP showing the greatest susceptibility, and LA and EU exhibiting increased resistance for all monitored antimicrobial agents. All regions showed escalating resistance to fluoroquinolones with the highest rates occurring in LA and EU. Continued global surveillance of P. aeruginosa isolates, especially quinolone-resistant strains is warranted and new drug development is essential for sustained quality therapy for Gram- negative bacilli. Pseudomonas aeruginosa (PSA) is a Gram-negative aerobic bacillus that exhibits multi- resistance to antimicrobials and consequently ranks among the top five nosocomial pathogens. This organism is isolated from all sites or infections (blood, lung, wounds, urine) based on surveillance data collected by the National Nosocomial Infection Surveillance (NNIS) system of the Centers for Disease Control and Prevention [CDC, 1998]. Ubiquitous in nature, this common human saprophyte turns to a opportunistic pathogen following the disruption of normal host defense mechanisms such as injuries to clinical barriers caused by endotracheal tubes, intravenous lines and urinary catheters. Traumatic injuries such as burns along with the increasing use of invasive surgical procedures and iatrogenic immunosuppression for oncology patients, has led to the increased involvement of P. aeruginosa in high hospital morbidity and mortality rates. Through the use of data generated from the SENTRY Antimicrobial Surveillance Program (2000), the purpose of this study was to evaluate the in vitro efficacy of eight key anti- pseudomonal agents against isolates from blood stream, respiratory tract and urinary tract infections. These results should help formulate guidelines for effective empiric therapies. Increased resistance was also monitored from participants in four regions: North America (NA), Latin America (LA), Europe (EU), and the Asia-Pacific (AP) tracking the current variations emerging in the susceptibility patterns of PSA and to elucidate inter-regional differences of the antipseudomonal drug classes. INTRODUCTION AMENDED ABSTRACT Background: Multi-resistant (R) PSA isolated from blood stream (BSI), respiratory tract (RTI), skin and soft tissue and urinary tract infections (UTI) has subsequently increased morbidity and mortality rates worldwide. The SENTRY Program has gathered global data on pseudomonal isolates for over 4 years to determine prevailing R trends for 8 key anti-PSA drugs. Methods: SENTRY participants from four regions (centers); NA (44), LA (14), EU (30) and AP (18) collected 9,109 PSA isolates that were tested by reference NCCLS methods against 28 antimicrobials including  -lactams  inhibitor, fluoroquinolones (FQ) and aminoglycosides. Results: Overall spectrum rank order against PSA was: meropenem > piperacillin/tazobactam > imipenem > cefepime (CPM) > ceftazidime (CAZ). Rank order of % S by infection site showed BSI > RTI > UTI with  -lactam R greatest among RTI strains and FQ-R greatest among UTI isolates. FQ activity ciprofloxacin (CIP; MIC 50,  0.25  g/ml) was 2- to 4-fold > levofloxacin (MIC 50, 0.5-1  g/ml) but spectrum difference was only 2.2%. PSA showed > S to CPM compared to CAZ against BSI (84% vs 82%) and RTI (77% vs. 75%) in all regions. Regional FQ % S ranked AP (84%) > NA (74%) > EU (68%) > LA (54%). A trend towards decreased S over time in LA (-13%) and NA (-6%) was demonstrated only for FQs. A decline in S over time for all monitored drugs was found for LA (-6 to -13%) and EU (-6 to -14%) with a greater drop in tested FQ activity. Conclusions: Extreme variations have emerged in the S patterns of PSA including: inter-regional differences (NA and AP most S); escalating R to FQs (all regions); and declining S to all anti-pseudomonal classes (EU and LA). Continued monitoring of R, local interventions (infection and formulary controls) and new drug development appear essential. MATERIALS AND METHODS A total of 106 medical centers submitted 9,109 isolates of P. aeruginosa to the SENTRY Antimicrobial Surveillance Program over the four year monitoring period (1997-2000). SENTRY participants were divided into four regions (no. of centers): NA (44), LA (14), EU (30) and AP (18). Asia-Pacific strains submitted were collected in 1998 and 1999 only. P. aeruginosa isolated from blood stream (BSI), respiratory tract (RTI), and urinary tract infections (UTI) were all tested in the monitoring laboratory at the University of Iowa College of Medicine (Iowa City, Iowa) or JMI Laboratories (North Liberty, Iowa). Susceptibility testing. The minimum inhibitory concentrations (MICs) were determined on each isolate using the broth microdilution methods outlined by the National Committee for Clinical Laboratory Standards (NCCLS) [NCCLS, 2000]. Quality control (QC) was achieved by regular performance testing of the following ATCC strains: Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 29213, P. aeruginosa ATCC 27853, Streptococcus pneumoniae ATCC 49619, Enterococcus faecalis ATCC 29212, and others selected by the monitors. Antimicrobials were obtained from USA manufacturers and included 28 investigational and clinical agents for Gram-negative isolates dispensed in dry-form panels (TREK Diagnostics, Inc., Westlake, OH). All interpretations of susceptibility categories were based on criteria of the NCCLS [2001]. REFERENCES Fluit AC, Verhoef J, Schmitz F-J, the European SENTRY Participants. (2000). Antimicrobial resistance in European isolates of Pseudomonas aeruginosa. Eur J Clin Microbiol Infect Dis 19:370-374. Gales AC, Jones RN, Turnidge J, Rennie R, Ramphal R. (2001). Characterization of Pseudomonas aeruginosa isolates: Susceptibility patterns and molecular typing in the global SENTRY Antimicrobial Surveillance Program, 1997-1999. Clin Infect Dis 32(Suppl 2): S146-S155. National Committee for Clinical Laboratory Standards (2000). Methods for dilution antimicrobial tests for bacteria that grow aerobically. Approved standard M7-A5. Wayne, PA:NCCLS. National Committee for Clinical Laboratory Standards (2001). Performance standards for antimicrobial susceptibility testing. Supplemental tables, M100-S11. Wayne, PA:NCCLS. Ramphal R, Hoban DJ, Pfaller MA, Jones RN. (2000). Comparison of the activity of two broad-spectrum cephalosporins tested against 2,299 strains of Pseudomonas aeruginosa isolated at 38 North American medical centers participating in the SENTRY Antimicrobial Surveillance Program, 1997-1998. Diagn Microbiol Infect Dis 36:125-129. RESULTS Against P. aeruginosa, the rank order of antimicrobial spectrums was: meropenem (MERO) > piperacillin/tazobactam (PIP/TAZ) > imipenem (IMP) > cefepime (CPM) > ceftazidime (TAZ) > gentamicin (GENT) > ciprofloxacin (CIP) > levofloxacin (LEVO) except with respiratory tract isolates where MERO and PIP/TAZ were equivalent, and urinary tract infections where TAZ > CPM. Percent susceptibility for various infection sites ranked as follows: BSI (most susceptible) > RTI > UTI for all regions with the  -lactam resistance greatest for RTI isolates and FQ resistance highest among UTI isolates. Regional percent susceptibility of FQ’s ranked highest in AP (84%) compared to NA (74%), EU (68%), and LA (54%) for these year 2000 P. aeruginosa isolates. CIP activity (MIC 50,  0.25  g/ml) was two- to four-fold greater than levofloxacin (LEVO; MIC 50, 0.5 - 1  g/ml), but an average difference of spectrum was only 2.2% in all regions for all infection sites. CPM activity was essentially equivalent to TAZ against BSI, RTI and UTI, but CPM had a slightly superior spectrum against blood (84% versus 82%) and respiratory tract (77% versus 75%) infections. A marked decrease in percent susceptibility (increased resistance) over time was evident in LA (-6% to -13%) and Europe (-6% to -14%) for all drugs. These same regions displayed the greatest decline in FQ susceptibility LA (-13%) and EU (-8%). TABLE 1. Evolving trends in antimicrobial susceptibility of Pseudomonas aeruginosa isolates indexed by monitored geographic region during 1997-2000 (SENTRY Program). Antimicrobial agent 199920001998 Piperacillin/Tazobactam Ceftazidime Cefepime Imipenem Meropenem Gentamicin Ciprofloxacin Levofloxacin 90.7 79.6 78.3 86.8 92.4 79.6 79.8 74.4 % S overall1997 North America Percent of isolates susceptible a 90.0 81.1 85.6 84.7 90.9 86.6 77.3 73.1 88.4 79.5 84.5 88.4 90.8 86.7 76.1 74.5 88.4 82.5 84.4 87.7 89.6 83.4 73.8 72.6 -2.3 NC -2.8 NC -6.0 -1.8 199920001998 Piperacillin/Tazobactam Ceftazidime Cefepime Imipenem Meropenem Gentamicin Ciprofloxacin Levofloxacin 79.4 66.6 66.2 77.0 83.0 63.6 67.2 63.6 % S overall1997 Latin America 77.1 64.4 67.9 76.7 79.7 61.8 60.8 59.0 73.3 65.8 65.2 73.6 76.0 60.1 60.6 59.3 67.5 60.6 70.9 72.0 57.1 54.0 54.2 -11.9 -6.0 -5.6 -6.1 -11.0 -6.5 -13.2 -9.4 199920001998 Piperacillin/Tazobactam Ceftazidime Cefepime Imipenem Meropenem Gentamicin Ciprofloxacin Levofloxacin 89.5 85.9 79.6 89.4 89.7 77.2 75.4 72.9 % S overall1997 Europe 85.2 78.0 83.8 79.5 85.9 70.9 72.3 71.9 80.7 71.7 72.4 71.7 73.1 62.4 66.2 66.9 82.0 72.3 71.4 75.5 76.9 68.1 67.8 67.1 -7.5 -13.6 -8.2 -13.9 -12.8 -9.1 -7.6 -5.8 199920001998 Piperacillin/Tazobactam Ceftazidime Cefepime Imipenem Meropenem Gentamicin Ciprofloxacin Levofloxacin N/A – % S overall1997 Asia-Pacific 90.2 76.1 81.6 90.0 91.5 82.3 84.8 83.8 87.5 83.7 85.8 86.2 87.8 85.8 83.7 82.6 88.2 82.5 83.5 85.2 90.1 83.7 85.2 83.7 -2.0 NC -4.8 -1.4 NC TABLE 2. Antimicrobial activity of eight antipseudomonal agents tested against 9,109 Pseudomonas aeruginosa isolates in the SENTRY Program (1997-2000). a Susceptibility categories per NCCLS criteria [2001].  -lactams Piperacillin/Tazobactam Ceftazidime Cefepime Imipenem Meropenem Aminoglycosides Gentamicin Quinolones Ciprofloxacin Levofloxacin 8/>64 (88.0)a 2/>16 (81.5) 2/16 (83.7) 1/8 (87.2) 0.5/4 (90.7) 2/16 (81.5)  0.25/>2 (80.0) 0.5/>4 (78.2) 8/>64 (85.3) 4/>16 (74.5) 4/16 (77.1) 1/>8 (80.9) 0.5/8 (85.3) 2/16 (76.0) 0.25/>2 (73.9) 1/>4 (70.8) 8/>64 (86.1) 4/>16 (76.1) 4/>16 (75.8) 2/8 (84.1) 0.5/8 (87.7) 2/>16 (69.9) 0.25/>2 (63.7) 1/>4 (62.1) MIC 50/90 in  g/ml (%susceptible) by infection site: UrineRespiratoryBlood Antimicrobial agent a Susceptibility determined using NCCLS [2001] criteria. Ronald N. Jones, M.D. The JONES Group / JMI Laboratories 345 Beaver Kreek Centre, Suite A, North Liberty, Iowa 52317 Phone: 319-665-3370 Fax: 319-665-3371 ronald-jones@jmilabs.com