Increased amoxicillin-clavulanic acid resistance in Escherichia coli blood isolates, Spain.To determine the evolution and trends of amoxicillin-clavulanic acid resistance among Escherichia coli Escherichia coli (ĕsh'ərĭk`ēə kō`lī), common bacterium that normally inhabits the intestinal tracts of humans and animals, but can cause infection in other parts of the body, especially the urinary tract. isolates in Spain, we tested 9,090 blood isolates from 42 Spanish hospitals and compared resistance with trends in outpatient consumption. These isolates were collected by Spanish hospitals that participated in the European Antimicrobial Resistance Surveillance System network from April 2003 through December 2006. ********** In addition to being an essential component of the gut lora, Escherichia coli is an etiologic agent for both hospital- and community-acquired infections in humans (1-3). As with other bacterial pathogens, this bacterium can develop resistance and multidrug resistance multidrug resistance, n the adaptation of tumor cells or infectious agents to resist chemotherapeutic agents. to several antimicrobial families; consequently, antimicrobial treatment of invasive E. coli E. coli: see Escherichia coli. E. coli in full Escherichia coli Species of bacterium that inhabits the stomach and intestines. E. coli can be transmitted by water, milk, food, or flies and other insects. infections can be challenging (1). Amoxicillin-clavulanic acid (AMC (Advanced Mezzanine Card) See AdvancedTCA. ) is one of the most consumed antimicrobial agents Antimicrobial agents Chemical compounds biosynthetically or synthetically produced which either destroy or usefully suppress the growth or metabolism of a variety of microscopic or submicroscopic forms of life. in many countries (4-6), principally for respiratory and urinary tract infections urinary tract infection (UTI), n infection in one or more of the structures that make up the urinary system. Occurs more often in women and is most commonly caused by bacteria. . However, little is known about its impact on antimicrobial drug resistance, particularly in E. coli. E. coli is one of the indicator organisms of the European Antimicrobial Resistance Surveillance System (EARSS EARSS European Antimicrobial Resistance Surveillance System ) (7), an international network of surveillance systems that attempt to collect reliable and comparable antimicrobial resistance data on invasive pathogens (1). The Study The 42 participating Spanish hospitals were selected according to according to prep. 1. As stated or indicated by; on the authority of: according to historians. 2. In keeping with: according to instructions. 3. EARSS criteria (1,7). The total catchment population was [approximately equal to] 9 million people, or [approximately equal to] 22.5% of the Spanish population. The first blood E. coli isolates obtained from each patient between 2003 and 2006 were included. Each laboratory identified the strains and tested their susceptibilities according to standard microbiologic procedures; all used commercial microdilution systems. Susceptibility data were interpreted according to Clinical Laboratory Standards Institute criteria (8). For epidemiologic purposes, intermediate susceptibility to AMC was considered as resistance. Multidrug resistance was defined as resistance to [greater than or equal to] 3 of the following antimicrobial agents: ciprofloxacin ciprofloxacin /cip·ro·flox·a·cin/ (sip?ro-flok´sah-sin) a synthetic antibacterial effective against many gram-positive and gram-negative bacteria; used as the hydrochloride salt. cip·ro·flox·a·cin n. , gentamicin gentamicin /gen·ta·mi·cin/ (jen?tah-mi´sin) an aminoglycoside antibiotic complex isolated from bacteria of the genus Micromonospora, , cotrimoxazole, and cefotaxime. To assess the comparability of susceptibility test susceptibility test Antimicrobial susceptibility test, see there results, an external quality assurance exercise (UK National External Quality Assessment Scheme) was performed yearly. Hospital-acquired infections Hospital-Acquired Infections Definition A hospital-acquired infection is usually one that first appears three days after a patient is admitted to a hospital or other health care facility. were defined as infections acquired at least 48 hours after hospital admission. Community-acquired infections were those in which E. coli-positive cultures were identified at or within 48 hours of hospital admission. Outpatient consumption of penicillin/[beta]-lactamase inhibitors (World Health Organization code J01CR02) for the period 2002-2006 was assessed from the Especialidades Consumo de Medicamentos database, which showed retail pharmacy sales of all medicines acquired with National Health System prescriptions and covered nearly 100% of the Spanish population (5). The information was tabulated, and the number of units was converted into defined daily doses Defined daily doses (DDDs) are a WHO statistical measure of drug consumption. DDDs are used to standardise the comparative usage of various drugs between themselves or between different healthcare environments. (DDD DDD Direct Distance Dialing DDD Digital/Digital/Digital (audio CD format, recording/mixing/mastering) DDD Degenerative Disc Disease DDD Domain Driven Design DDD Data Display Debugger (GNU Project) ) of active drug ingredients according to WHO methodology (9). The number of DDD per 1,000 inhabitants
The game is based loosely on the concepts from SameGame. per day (DIDs) was calculated for each active drug ingredient. Differences in the antimicrobial resistance prevalence between different groups were assessed by Fisher exact test. Association was determined by calculation of the odds ratio (OR) with 95% confidence intervals (CI). The significance of the antimicrobial resistance trends was calculated by [chi square chi square (kī), n a nonparametric statistic used with discrete data in the form of frequency count (nominal data) or percentages or proportions that can be reduced to frequencies. ] test for trend. The null hypothesis null hypothesis, n theoretical assumption that a given therapy will have results not statistically different from another treatment. null hypothesis, n was rejected for values of (jargon) for values of - A common rhetorical maneuver at MIT is to use any of the canonical random numbers as placeholders for variables. "The max function takes 42 arguments, for arbitrary values of 42". "There are 69 ways to leave your lover, for 69 = 50". p<0.05. Statistical analyses were performed by using GraphPad Prism version 3.02 software (GraphPad Software, Inc., San Diego, CA, USA). Participating hospitals reported data on 9,090 cases of E. coli bacteremia bacteremia: see septicemia. bacteremia Presence of bacteria in the blood. Short-term bacteremia follows dental or surgical procedures, especially if local infection or very high-risk surgery releases bacteria from isolated sites. during the study period, corresponding to the same number of patients; 4,526 (49.8%) were male patients and 4,564 (50.2%) were female patients. A total of 1,531 cases (16.8%) were diagnosed in 2003; 2,526 (27.8%) in 2004; 2,438 (26.8%) in 2005; and 2,597 (28.6%) in 2006. Of the total number of isolates, 328 (3.6%) were obtained from children [less than or equal to] 14 years of age; 2,857 (31.4%) were obtained from patients [greater than or equal to] 15 and [less than or equal to] 64 years of age; and 5,909 (65%) were obtained from patients >64 years of age. There were 3,384 (37.9%) isolates implicated im·pli·cate tr.v. im·pli·cat·ed, im·pli·cat·ing, im·pli·cates 1. To involve or connect intimately or incriminatingly: evidence that implicates others in the plot. 2. in hospital-acquired infections and 5,540 (62.1%) in community-acquired infections; information was missing for 166 cases. Of the 9,090 E. coli isolates tested, 1,136 (12.5%) were nonsusceptible to AMC, 5.1% were resistant, and 7.4% were intermediate. The prevalence of amoxicillin/clavulanic acid nonsusceptibility in relation to gender, age, infection origin, and resistance to other antibimicrobial drugs is detailed in the Table. Multidrug resistance was present in 198 (17.4%) of the nonsusceptible AMC isolates. The most prevalent phenotypes included multidrug resistance to ciprofloxacin, cotrimoxazole, and gentamicin, which was detected in 73 nonsusceptible AMC isolates (36.9% of multiresistant isolates and 6.4% of isolates overall), and resistance to ciprofloxacin, cotrimoxazole, and cefotaxime was detected in 55 isolates (27.8% of multiresistant isolates; 4.9% of isolates overall). Multidrug resistance was more prevalent in nosocomial nosocomial /noso·co·mi·al/ (nos?o-ko´me-il) pertaining to or originating in a hospital. nos·o·co·mi·al adj. 1. Of or relating to a hospital. 2. (23.5%) than in community-acquired isolates (15.1%; OR 1.99, 95% CI 1.46-2.72; p<0.0001). Among nonsusceptible AMC isolates, susceptibility to other antimicrobial drugs, including ciprofloxacin, gentamicin, cefotaxime, and cotrimoxazole, was more frequent in community- (28.7%) than in hospital-acquired isolates (13.3%; OR 1.68, 95% CI 1.27-2.22; p = 0.0003). This suggests that more therapeutic options were available for community-acquired isolates. The overall rate of invasive E. coli nonsusceptibility to AMC increased from 9.3% (2003) to 15.4% (2006) ([chi square] test for trend 36.51; p<0.0001) (Figure 1); this increase was observed in 64.3% of the participant hospitals. This increase was also detected in both intermediate and resistant isolates, with annual distributions of 5.6% and 3.8%, respectively, in 2003; 6.8% and 4.8% in 2004; 7.5% and 5.4% in 2005; and 9.4% and 6% in 2006. AMC nonsusceptibility according to age groups increased over the study period as follows: children [less than or equal to] 14 years of age (10.6% in 2003, 14.6% in 2004, 14.3% in 2005, and 16.3% in 2006); patients [greater than or equal to] 15 and [less than or equal to] 64 years 9.6% in 2003, 11.2% in 2004, 11.7% in 2005, and 13.3% in 2006); patients >64 years (8.8% in 2002, 11.3% in 2004, 15.9% in 2005, and 16.3% in 2006). The prevalence of AMC nonsusceptibility in community-acquired infections increased from 8.9% (2003) to 15.6% (2006) ([chi square] test for trend 29.43; p<0.0001). AMC nonsusceptibility in nosocomial infections Nosocomial infections Infections that were not present before the patient came to a hospital, but were acquired by a patient while in the hospital. Mentioned in: Enterobacterial Infections, Staphylococcal Infections increased from 9.2% (2003) to 15.2% (2006) ([chi square] test for trend 11.94; p = 0.0006). In the final 2 years of the study period (2005-2006), the proportion of AMC-nonsusceptible isolates increased from 12.9% to 15.9%. This increase was due to community-acquired E. coli isolates only; the nonsusceptible proportion varied from 11.5% (2005) to 15.6% (2006) (OR 1.42, 95% CI 1.16-1.74; p = 0.0009) in community-acquired isolates compared with 15.4% (2005) to 15.2% (2006) in hospital-acquired isolates (Figure 1). Community-acquired infection probably included healthcare-associated infections, a recently described epidemiologic category distinct from both community-acquired and nosocomial status. [FIGURE 1 OMITTED] In this study, the number of blood isolates of E. coli producing extended-spectrum [beta]-lactamase (ESBL ESBL Extended Spectrum Beta Lactamase ESBL East Staffordshire Badminton League (UK) ) was 614 (6.7%); 188 of them (30.6%) were nonsusceptible to AMC. When ESBL-producing E. coli isolates were excluded from analysis, AMC nonsusceptibility increased from 8.4% (2003) to 14.3% (2006) ([chi square] test for trend 34.39; p<0.0001) in total isolates; from 8.2% (2003) to 14.5% (2006) ([chi square] test or trend 25.23; p<0.0001) in community-acquired isolates; and from 8.9% (2003) to 13.3% (2006) ([chi square] test for trend 6.35; p = 0.012) in hospital-acquired isolates (Figure 1). The proportion of isolates highly susceptible to AMC (MIC [less than or equal to] 4 mg/L) steadily decreased over the study period as follows: 70.2% (2003), 70% (2004), 64.8% (2005), and 57.4% (2006) ([chi square] test for trend 99.36; p<0.0001). [FIGURE 2 OMITTED] Community consumption of penicillin/[beta]-lactamase inhibitors, predominantly AMC, increased 34.7% from 2000 to 2006 (Figure 2), whereas total antimicrobial drug consumption remained relatively constant (19.6 DIDs in 2000 compared with 19.1 DIDs in 2006). After AMC, the most used [beta]-lactam antimicrobial agents in the community in Spain were amoxicillin amoxicillin /amox·i·cil·lin/ (ah-mok?si-sil´in) a semisynthetic derivative of ampicillin effective against a broad spectrum of gram-positive and gram-negative bacteria. a·mox·i·cil·lin n. , cefuroxime, and cefixime; their consumption did not vary or slightly decreased from 2002 through 2005 (6). Conclusions The increased AMC resistance of E. coli isolates from blood observed in this study is of serious concern from clinical and epidemiologic standpoints because AMC is the first-choice antimicrobial treatment for many invasive E. coli infections. Increased AMC resistance coincided with growing AMC consumption at the community level. In urinary infections, previous treatment with AMC is a risk factor for the development of AMC resistance (10). AMC resistance mechanisms ([beta]-lactamase overproduction o·ver·pro·duce tr.v. o·ver·pro·duced, o·ver·pro·duc·ing, o·ver·pro·duc·es To produce in excess of need or demand. o , AmpC cephalosporinase hyperproduction, and inhibitor-resistant penicillinases) (11) might be favored by strong AMC consumption. EARSS is funded by the European Commission, DG Sanco (Agreement SI2.123794). This study was supported by Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III; Spanish Network for the Research in Infectious Diseases (REIPI C03/14), and Spanish Network for the Research in Infectious Diseases (REIPI RD06/0008); and by research grants from Fondo de Investigaciones Sanitarias (FIS FIS n abbr (BRIT) (= Family Income Supplement) → ayuda estatal familiar P1040837) and the Direccion General de Salud Publica, Ministry of Health, Spain (reference 1429/05-11). DOI (Digital Object Identifier) A method of applying a persistent name to documents, publications and other resources on the Internet rather than using a URL, which can change over time. : 10.3201/eid1408.071059 References (1.) Oteo J, Lazaro E, de Abajo FJ, Baquero F, Campos J; Spanish members of EARSS. Antimicrobial-resistant invasive Escherichia coli, Spain. Emerg Infect Dis. 2005;11:546-53. (2.) Fluit AC, Jones ME, Schmitz FJ, Acar J, Gupta R, Verhoef J. Antimicrobial susceptibility and frequency of occurrence of clinical blood isolates in Europe from the SENTRY antimicrobial surveillance program, 1997-1998. Clin Infect Dis. 2000;30:454-60. DOI: 10.1086/313710 (3.) Lark RL, Saint S, Chenoweth C, Zemencuk JK, Lipsky BA, Plorde JJ. Four-year prospective evaluation of community-acquired bacteremia: epidemiology, microbiology and patient outcome. Diagn Microbiol Infect Dis. 2001;41:15-22. DOI: 10.1016/S0732-8893-(01)00284-X (4.) Goossens H, Ferech M, Vander Stichele R, Elseviers M; ESAC ESAC European Space Astronomy Centre (Madrid, Spain) ESAC Employer Services Assurance Corporation ESAC Electronic Shock Absorber Control ESAC European Study Abroad Center ESAC Energy Systems Analysis Consortium Project Group. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet. 2005;365:579-87. (5.) Lazaro BE, Madurga SM, de Abajo FJ. Evolucion del consumo de antibioticos en Espana, 1985-2000. Med Clin (Barc). 2002;118:561-8. (6.) Campos J, Ferech M, Lazaro E, de Abajo F, Oteo J, Stephens P, et al. Surveillance of outpatient antibiotic consumption in Spain according to sales data and reimbursement data. J Antimicrob Chemother. 2007;60:698-701. DOI: 10.1093/jac/dkm248 (7.) European Antimicrobial Resistance Surveillance System [cited 2007 Jan 8]. Available from http://www.rivm.nl/earss (8.) Clinical and Laboratory Standards Institute (CLSI CLSI Clinical and Laboratory Standards Institute (Wayne, PA) CLSI Cisco Link Services Interface ). Performance standards for antimicrobial susceptibility testing--17th informational supplement. M100-S17. Vol 27, No. 1. Wayne (PA): The Institute; 2007 [cited 2008 Jun 27]. Available from http://www.clsi.org (9.) World Health Organization Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC ATC Air Traffic Control ATC Average Total Cost ATC Certified Athletic Trainer ATC At the Center (Hartford, Maine retreat center) ATC Applied Technology Council ATC All Things Considered classification and DDD assignment. Oslo (Norway): The Organization; 2005. (10.) Leflon-Guibout V, Ternat G, Heym B, Nicolas-Chanoine MH. Exposure to co-amoxiclav as a risk factor for co-amoxiclav-resistant Escherichia coli urinary tract infection. J Antimicrob Chemother. 2002;49:367-71. DOI: 10.1093/jac/49.2.367 (11.) Miro E, Navarro F, Mirelis B, Sabate M, Rivera A, Coll P, et al. Prevalence of clinical isolates of Escherichia coli producing inhibitor-resistant period. Antimicrob Agents Chemother. 2002;46:3991-4. DOI: 10.1128/AAC.46.12.3991-3994.2002 Jesus Oteo, * Jose Campos, * ([dagger]) Edurne Lazaro, ([double dagger]) Oscar Cuevas, * Silvia Garcia-Cobos, * Maria Perez-Vazquez,* F. J. de Abajo, ([double dagger]) and Spanish Members of EARSS (1) * Institute de Salud Carlos III, Madrid, Spain; ([dagger]) Consejo Superior de Investigaciones Cientificas, Madrid; and ([double dagger]) Agencia Espanola del Medicamento y Productus Sanitarios, Madrid DOI: 10.3201/eid1408.071059 (1) Spanish Members of EARSS (European Antimicrobial Resistance Surveillance System: E. Loza, F. Baquero (Hospital Ramon y Cajal Ra·mòn y Ca·jal , Santiago 1852-1934. Spanish histologist. He shared a 1906 Nobel Prize for research on the nervous system. ), D. Fontanals (Corporacio Sanitaria Parc Tauli), P. Berdonces (Hospital Galdakao), R. Moreno (Hospital General de Castellon), P. Lopez and G. Royo (Hospital General Universitario de Elche), J. Lite and J. Garau (Hospital Mutua de Terrassa), G. Megias-Lobon and E. Ojeda (Hospital General Yague), C. Miranda and M.D. Rojo (Hospital Universitario Virgen de la Nieves), A. Fleites (Hospital Central de Asturias), C. Amores (Hospital San Agustin), P. Teno (Hospital San Pedro de Alcantara), M. Menendez-Rivas (Hospital Infantil del Nino Jesus), M.M. Perez-Moreno and I. Buj (Hospital Verge de la Cinta), F. Merino Merino Breed of medium-sized sheep originating in Spain that has become prominent worldwide. It has a white face, white legs, and crimped fine-wool fleece. Known as early as the 12th century, it may have been a Moorish importation. and A. Campos (Hospital de Soria), M.T. Perez-Pomata and A. Gonzalez (Hospital General Universitario de Guadalajara), B. Fernandez and A. Tinajas (Complexo Hospitalario de Ourense), E. Garduno and R. Jimenez (Hospital Infanta Infanta laughs at the death of the little Dwarf who can no longer dance for her. [Br. Lit.: Oscar Wilde “The Birthday of the Infanta”] See : Heartlessness Cristina), C. Raya Raya may refer to:
concha of auricle ), M.T. Cabezas (Hospital de Poniente), P. Alvarez, V. Pulian and M. Garcia-Campello (Complejo Hospitalario de Pontevedra), I. Wilhemi (Hospital Severe Ochoa), F.J. Vasallo-Vidal (Hospital do Meixoeiro), A. Delgado-Iribarren (Fundacion Hospital de Alcorcon), P. Pena (Hospital La Paz), M. Jose Gastanares (Hospital San Millan), A. Yague and N. Gonzalo (Hospital Vega Baja), M.D. Crespo and J.J. Palomar (Complejo Hospitalario de Albacete), L. Marco and M.J. Revillo (Hospital Miguel Servet), N. Montiel (Hospital Costa del Sol Costa del Sol (kō`stä thĕl sōl`), a strip of coastline, S. Spain, in Andalusia, extending from Motril to Estepona The area has become famous as a Mediterranean coastal resort, and its tourist industry continues to expand. ), A. Pinedo (Hospital Virgen de la Victoria), J. A. Lepe (Hospital Rio Tinto), J.C. Alados (Hospital de Jerez), M. Rodriguez (Hospital Puerto Real), E. Martin (Hospital Valme), I. Cuesta cuesta (kwĕs`tə), asymmetric ridge characterized by a short, steep escarpment on one side, and a long, gentle slope on the other. The steep side exposes the edge of erosion-resistant rock layers that form the cuestas. (Hospital Ciudad de Jaen), V. Gallardo (Consejeria de Salud de la Junta de Andalucia), J. Calvo and L. Martinez (Hospital Marques Marques may refer to:
Dr Oteo is a specialist in medical microbiology. He works in the Centro Nacional de Microbiologia of the Ministry of Health, Madrid, Spain. His primary research interest is the molecular basis and surveillance of bacterial resistance to antimicrobial agents. Address for correspondence: Jose Campos, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Carretera Pozuelo a Majadahonda 28220, Majadahonda, Madrid, Spain; email: jcampos@isciii.es The opinions expressed by authors contributing to this journal do not necessarily reflect the opinions of the Centers for Disease Control and Prevention Centers for Disease Control and Prevention (CDC), agency of the U.S. Public Health Service since 1973, with headquarters in Atlanta; it was established in 1946 as the Communicable Disease Center. or the institutions with which the authors are affiliated.
Table. Association of AMC nonsusceptibility of Escherichia coli from
blood with gender, age, infection origin, and resistance to other
antimicrobial agents, Spain, 2003-2006 *
AMC
nonsusceptibility,
Variable % Odds ratio
Gender
Male 13.6 1.23
Female 11.4
Age
[less than or equal to] 14 y 14.2 1.12
>14 y 12.8
Infection origin
Nosocomial 13.8 1.18
Community 12.0
Antimicrobial susceptibility
Ciprofloxacin susceptible 9.0 2.93
Ciprofloxacin resistant 22.5
Gentamicin susceptible 11.5 2.64
Gentamicin resistant 25.6
ESBL-negative 11.5 3.40
ESBL-positive 30.7
95%
Confidence
Variable interval p value
Gender
Male 1.08-1.39 0.001
Female
Age
[less than or equal to] 14 y 0.83-1.52 0.51
>14 y
Infection origin
Nosocomial 1.04-1.34 0.012
Community
Antimicrobial susceptibility
Ciprofloxacin susceptible 2.59-3.32 <0.0001
Ciprofloxacin resistant
Gentamicin susceptible 2.22-3.14 <0.0001
Gentamicin resistant
ESBL-negative 2.84-4.08 <0.0001
ESBL-positive
* AMC, amoxicillin-clavulanic acid; ESBL, extended-spectrum R-lactamase.
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