Pseudomonas aeruginosa, staphylococcus aureus, and fluoroquinolone use.
Few long-term multicenter investigations have evaluated the relationships between aggregate antimicrobial antimicrobial /an·ti·mi·cro·bi·al/ (-mi-kro´be-al)
1. killing microorganisms or suppressing their multiplication or growth.
2. an agent with such effects. drug use in hospitals and bacterial resistance. We measured fluoroquinolone fluoroquinolone /flu·o·ro·quin·o·lone/ (-kwin´o-lon) any of a subgroup of fluorine-substituted quinolones, having a broader spectrum of activity than nalidixic acid.
n. use from 1999 through 2003 in a network of US hospitals. The percentages of fluoroquinolone-resistant Pseudomonas aeruginosa Pseudomonas aeruginosa A normal soil inhabitant and human saprophyte that may contaminate various solutions in a hospital, causing opportunistic infection in weakened Pts Clinical Infective endocarditis in IVDAs, RTIs, UTIs, bacteremia, meningitis, 'malignant' and methicillin-resistant Staphylococcus aureus methicillin-resistant Staphylococcus aureus Methicillin-aminoglycoside resistant Staphylococcus aureus, MRSA An organism with multiple antibiotic resistances–eg, aminoglycosides, chloramphenicol, clindamycin, erythromycin, rifampin, tetracycline, (MRSA MRSA Methicillin-resistant Staphylococcus aureus. See MARSA. ) were obtained from yearly antibiograms at each hospital. Univariate linear regression Linear regression
A statistical technique for fitting a straight line to a set of data points. showed significant associations between a hospital's volume of fluoroquinolone use and percent resistance in most individual study years (1999-2001 for P. aeruginosa, 1999-2002 for S. aureus The aureus (pl. aurei) was a gold coin of ancient Rome valued at 25 silver denarii. The aureus was regularly issued from the 1st century BC to the beginning of the 4th century AD, when it was replaced by the solidus. ). When the method of generalized gen·er·al·ized
1. Involving an entire organ, as when an epileptic seizure involves all parts of the brain.
2. Not specifically adapted to a particular environment or function; not specialized.
3. estimating equations was used, a population-averaged longitudinal model incorporating total fluoroquinolone use and the previous year's resistance (to account for autocorrelation Autocorrelation
The correlation of a variable with itself over successive time intervals. Sometimes called serial correlation. ) did not show a significant effect of fluoroquinolone use on percent resistance for most drug-organism combinations, except for the relationship between levofloxacin use and percent MRSA. The ecologic relationship between fluoroquinolone use and resistance is complex and requires further study.
Antimicrobial drug resistance in bacterial pathogens is of national and international concern (1,2). Although use of 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. is accepted as a major driving force behind the spread of resistance, the nature of this relationship is complex (3). Two problematic nosocomial nosocomial /noso·co·mi·al/ (nos?o-ko´me-il) pertaining to or originating in a hospital.
1. Of or relating to a hospital.
2. pathogens are Pseudomonas aeruginosa and Staphylococcus aureus Staphylococcus au·re·us
A bacterium that causes furunculosis, pyemia, osteomyelitis, suppuration of wounds, and food poisoning.
Staphylococcus aureus Staphylococcus pyogenes ; both often express multidrug resistance multidrug resistance,
n the adaptation of tumor cells or infectious agents to resist chemotherapeutic agents. . A number of case-control studies case-control study,
n an investigation employing an epidemiologic approach in which previously existing incidents of a medical condition are used in lieu of gathering new information from a randomized population. at individual hospitals have identified fluoroquinolone use as a risk factor for acquisition of fluoroquinolone-resistant P. aeruginosa and methicillin-resistant S. aureus (MRSA) (4-8). While outcomes for individual patients are most important from a clinical point of view, an ecologic perspective is also useful to assess the relationship of aggregate antimicrobial drug use to aggregate measures of bacterial resistance. Ecologic investigations across multiple hospitals have reported significant correlations between fluoroquinolone use and percent resistance for MRSA (9) and P. aeruginosa (10,11). However, these studies have primarily focused on teaching institutions, used drug expenditure data rather than hospital billing records as a measure of use, or were conducted over a limited time span. We measured fluoroquinolone use as well as the percentages of MRSA and fluoroquinolone-resistant P. aeruginosa across 24 US hospitals during a 5-year period. The purpose of this observational study In statistics, the goal of an observational study is to draw inferences about the possible effect of a treatment on subjects, where the assignment of subjects into a treated group versus a control group is outside the control of the investigator. was to determine if volume of aggregate fluoroquinolone use in individual hospitals and bacterial resistance in individual years and during the entire study period are associated.
Hospitals included in this study were participants in the Surveillance and Control of Pathogens of Epidemiologic ep·i·de·mi·ol·o·gy
The branch of medicine that deals with the study of the causes, distribution, and control of disease in populations.
[Medieval Latin epid Importance (SCOPE)--MediMedia Information Technology (MMIT MMIT Microsoft Mobile Internet Toolkit (Microsoft development tool) ) Antimicrobial Surveillance Network. MMIT (http://www.mminfotech.com) is a healthcare informatics corporation (company) Informatics Corporation - Renamed to Sterling Software Corp. that extracts drug-use data from hospital billing records. Data collection for this project began in 1999 with 19 participating hospitals; that number increased to 48 hospitals in 2003. Of these, 15 hospitals in 1999, 23 hospitals in 2000 and 2001, and 24 hospitals in 2002 and 2003 provided adequate drug-use and microbiology microbiology: see biology.
Scientific study of microorganisms, a diverse group of simple life-forms including protozoans, algae, molds, bacteria, and viruses. data for inclusion in this study. Demographic data for the hospitals in the year 2002 were obtained from the MMIT database and the American Hospital Directory (http://www. ahd.com). Members of the Council of Teaching Hospitals and Health Systems (http://www.aamc.org/members/coth/ start.htm) were designated as teaching hospitals.
Measurement of Hospital Fluoroquinolone Use
Total grams for each fluoroquinolone used during each year were electronically extracted from individual patient billing records and aggregated to reflect hospitalwide usage. The total number of patient days (PD) for the corresponding time period at each hospital was determined from the sum of individual patient lengths of stay. These data were used to express normalized antimicrobial drug use in 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. per 1,000 patient days (DDD/1,000PD) as recommended by the World Health Organization (WHO) (http://www.whocc.no/atcddd/). The DDDs used were levofloxacin 500 mg, moxifloxacin 400 mg, gatifloxacin 400 mg, and 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.
n. 1,000 mg. (Because the MMIT database does not indicate the proportion of intravenous versus oral ciprofloxacin used, we used the oral 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) for ciprofloxacin of 1,000 mg for all ciprofloxacin use).
Measurement of Hospital Susceptibility susceptibility
the state of being susceptible. Refers usually to infectious disease but may be to physical factors such as wetting or to psychological factors such as harassment. for P. aeruginosa and S. aureus
Hospital antibiograms were requested from each participating hospital for each study year. To be included in the analysis, antibiograms must have reported data on organisms from all clinical sites (i.e., systemic and urinary urinary /uri·nary/ (u´ri-nar?e) pertaining to, containing, or secreting urine.
1. Relating to urine and its production, function, or excretion.
2. isolates) and all units (including intensive care units). Ciprofloxacin or levofloxacin susceptibility was used to determine the percentage of fluoroquinolone-resistant P. aeruginosa. Oxacillin oxacillin /ox·a·cil·lin/ (ok?sah-sil´in) a semisynthetic penicillinase-resistant penicillin used as the sodium salt in infections due to penicillin-resistant, gram-positive organisms. or nafcillin nafcillin /naf·cil·lin/ (naf-sil´in) a semisynthetic, acid- and penicillinase-resistant penicillin that is effective against staphylococcal infections; used as the sodium salt. susceptibility was used to determine the percentage of MRSA.
Mixed-effects repeated-measures analysis of variance was used to analyze changes in fluoroquinolone use and resistance over the study period, and the Tukey HSD HSD Human Services Department
HSD High Speed Data
HSD Hillsboro School District (Hillsboro, OR)
HSD Hybrid Synergy Drive (Toyota/Lexus)
HSD High School Diploma
HSD Historical Society of Delaware (honestly significantly difference) test was used to compare differences between individual years. Relationships between total and individual fluoroquinolone usage and resistance in target pathogens for each year were determined by univariate linear regression. To analyze the relationship between fluoroquinolone use and percent resistance over the course of the study period, the method of generalized estimating equations (GEE gee 1
The letter g.
Used to command a horse or ox to turn to the right.
intr.v. ) was used to construct a population-averaged longitudinal model (12). Unlike traditional least squares regression, GEE models do not assume that each observation is statistically independent. Instead, only observations across units are assumed to be independent (i.e., the group of observations from the first hospital are independent from the observations from the second hospital). Other methods, such as generalized least squares, can also account for this correlation of observations within a given unit; however, these methods are based on the assumption that the correlation structure among observations from the same unit is correctly specified. The GEE method provides some protection against this misspecification. This protection can be improved by using a modified sandwich variance estimator to calculate robust standard errors. The model constructed in the current study assumed a first-order autoregressive correlation structure since a 1-year lagged resistance term was used in the model to control for the prior year's resistance. GEE methods also allow data across time points to be analyzed an·a·lyze
tr.v. an·a·lyzed, an·a·lyz·ing, an·a·lyz·es
1. To examine methodically by separating into parts and studying their interrelations.
2. Chemistry To make a chemical analysis of.
3. simultaneously, rather than in a year-by-year fashion. Therefore, this GEE model represents the longitudinal change in the outcome in relation to the longitudinal change in the set of predictor variables Noun 1. predictor variable - a variable that can be used to predict the value of another variable (as in statistical regression)
variable quantity, variable - a quantity that can assume any of a set of values using all of the available data. A p value <0.05 was considered significant, and all tests were 2-tailed. Because of the exploratory nature of this analysis, p values from univariate linear regressions were not adjusted for multiple testing.
Characteristics of Study Hospitals
Table 1 shows the demographic characteristics of the study hospitals in the year 2002. Ten hospitals were designated as teaching hospitals. The location of the hospitals was predominantly from the East (12 hospitals), with 7 hospitals from the South, 3 from the Midwest, and 2 from the West. No significant relationships were seen between resistance in P. aeruginosa or percent MRSA in the year 2002 and any of the demographic characteristics by univariate linear regression (p>0.05 for all comparisons).
Figure 1 shows changes in the mean of total and individual fluoroquinolone use from 1999 through 2003. For that period, the mean of total fluoroquinolone use increased from 119.6 [+ or -] 45.6 DDD/1,000 PD in 1999 to 150.4 [+ or -] 44.4 in 2003 (p = 0.011). These changes were driven by the early increase in fluoroquinolone use, as mean values were not significantly different in later (2000-2003) study years (p>0.05, Tukey HSD). Changes in levofloxacin use during the entire study were also significant (p = 0.016), but changes in ciprofloxacin use were not (p = 0.186). Fluoroquinolone use in individual hospitals was significantly correlated with the previous year's use (r>0.75 for all years).
[FIGURE 1 OMITTED]
The diversity of use of individual fluoroquinolones in hospitals changed during the study period. Figure 1 shows the mean use of individual fluoroquinolones across all hospitals. The number of hospitals in which a particular fluoroquinolone represented most total fluoroquinolone use also changed. In 1999, levofloxacin use represented >90% of total fluoroquinolone use in 4 (27%) of 15 hospitals; 1 hospital used >90% ciprofloxacin. In 2003, 8 (33%) of 24 hospitals used >90% levofloxacin while in 7 hospitals (30%) moxifloxacin and ciprofloxacin combined to account for >90% of total fluoroquinolone use. The percentage of MRSA and fluoroquinolone-resistant P. aeruginosa in 2003 was compared between the 8 hospitals that predominantly used levofloxacin, the 7 that predominantly used moxifloxacin and ciprofloxacin, and the remaining 9 hospitals that used a mixture of fluoroquinolones. No significant differences in mean percent resistance were found between the groups (predominant levofloxacin, predominant moxifloxacin/ciprofloxacin, or neither) for either pathogen Pathogen
Any agent capable of causing disease. The term pathogen is usually restricted to living agents, which include viruses, rickettsia, bacteria, fungi, yeasts, protozoa, helminths, and certain insect larval stages. in 2003.
Antimicrobial Drug Resistance
Figure 1 shows the changes in mean percentage resistance for the studied pathogens from 1999 to 2003. Most hospitals reported the number of isolates tested; at least 100 isolates of S. aureus and 25 isolates of P. aeruginosa were tested per year. From 1999 to 2003, mean percent fluoroquinolone resistance in P. aeruginosa increased from 33.6% to 40.5% (p = 0.00l). Mean percent MRSA increased from 42.1% in 1999 to 50.9% in 2003 (p<0.0001). Correlations between percent resistance in a given year and percent resistance in the previous year were high for both pathogens (r>0.8).
Associations between Fluoroquinolone Use and Percent Resistance in Individual Years
The results of the univariate regressions between fluoroquinolone use and resistance are summarized in Table 2. For P. aeruginosa, significant relationships occurred between total fluoroquinolone use and resistance in the same year for 1999, 2000, and 2001; the relationship had borderline borderline /bor·der·line/ (-lin) of a phenomenon, straddling the dividing line between two categories.
borderline significance in 2002 (p = 0.0562) and was not significant in 2003. Total fluoroquinolone use was associated with percent MRSA in every year except 2003. Table 2 also shows the results of univariate regression with the individual fluoroquinolones levofloxacin and ciprofloxacin. Levofloxacin use was a significant predictor of fluoroquinolone-resistant P aeruginosa in 1999, 2000, and 2001. Increasing levofloxacin use was significantly associated with increased percent MRSA for all study years except 2003. For ciprofloxacin, a negative slope (increasing ciprofloxacin use associated with decreased percent resistance) was observed for most associations with percent resistant P. aeruginosa and MRSA, but none of these associations were significant.
Modeling of Relationship between Fluoroquinolone Use and Resistance
Table 3 shows the results of population-averaged GEE models using data over the study period from 2000 to 2003. The data from 1999 were not used as an outcome variable because of the lagged resistance term used in the model. After adjusting for the previous year's percent resistance, fluoroquinolone use was generally associated with a small and nonsignificant non·sig·nif·i·cant
1. Not significant.
2. Having, producing, or being a value obtained from a statistical test that lies within the limits for being of random occurrence. effect on percent resistance in a given year for either pathogen. Levofloxacin did display a significant contribution to percent resistance in MRSA; the coefficient of 0.012 suggests that an additional 100 DDD/1,000PD would lead to a 1.2% increase in percent MRSA over the previous year (p = 0.033).
Figure 2 shows the baseline-to-endpoint changes in fluoroquinolone use and resistance in P. aeruginosa and MRSA for those 9 hospitals with complete data from 1999 to 2003. Fluoroquinolone use increased in 7 hospitals (arrows pointing to the right), and the percentage of fluoroquinolone-resistant P. aeruginosa increased in 7 and decreased in 1 (Figure 2A). For the 2 hospitals that reduced total fluoroquinolone use, percent resistance increased slightly in both. The percentage of MRSA increased in 7 hospitals; 5 of these increased fluoroquinolone use and 2 decreased use. The percentage of MRSA decreased in 2 hospitals; both increased quinolone use during the same period (Figure 2B).
[FIGURE 2 OMITTED]
The results of this longitudinal, multicenter study of fluoroquinolone use and bacterial resistance suggest a complex relationship between fluoroquinolone use in hospitals and percentage of methicillin-resistant S. aureus and fluoroquinolone-resistant P. aeruginosa when viewed from an ecologic level. Fluoroquinolone use was linked to greater percent resistance in study years by univariate linear regression. This observation is consistent with the results of other studies linking fluoroquinolone use to resistance in these pathogens (4-11), although the pathways for selection of resistance differ between the 2 pathogens. Fluoroquinolone resistance in P. aeruginosa is believed to arise largely from the selection of organisms with point mutations point mutation
A mutation that involves a single nucleotide and may consist of loss of a nucleotide, substitution of one nucleotide for another, or the insertion of an additional nucleotide. in the topoisomerase topoisomerase
an enzyme involved in DNA replication that introduces a single-strand nick in the DNA enabling it to swivel and thereby relieve the accumulated winding strain generated during unwinding of the double helix. enzymes that are targets for the fluoroquinolones (13). This hypothesis is supported by studies demonstrating the emergence of resistance during therapy with fluoroquinolones (4). For methicillin-resistant S. aureus, de novo [Latin, Anew.] A second time; afresh. A trial or a hearing that is ordered by an appellate court that has reviewed the record of a hearing in a lower court and sent the matter back to the original court for a new trial, as if it had not been previously heard nor decided. emergence of resistance as seen with P. aeruginosa is not a common event (14); rather, patients are generally believed to acquire methicillin-resistant strains of S. aureus from the environment (e.g., through cross-transmission); antimicrobial drug use may increase the likelihood of colonization colonization, extension of political and economic control over an area by a state whose nationals have occupied the area and usually possess organizational or technological superiority over the native population. or amplify the resistant population after colonization (15). Fluoroquinolones are not active against most methicillin-resistant isolates (16), providing a selective pressure for MRSA. While any antimicrobial agent that is not active against MRSA should increase a patient's risk for infection, fluoroquinolones may be particularly likely to do so, since they have appear to have unique effects on the expression of MRSA resistance determinants (17) and fibronectin-binding proteins (18).
Using a model incorporating the previous year's percent resistance as well as fluoroquinolone use and time over the entire study period, we did not find an additional effect of total fluoroquinolone use on percent resistance. Many factors beyond the volume of use of an antimicrobial agent affect the emergence and spread of antimicrobial resistance to that drug in the hospital setting. Cross-transmission between patients, acquisition of organisms from the hospital environment, and the use of different antimicrobial agents with linked resistance to the agent under study are all factors that also affect the number of resistant isolates in a given hospital (19-21). These factors are difficult to control for, since quantitative measures of infection control are lacking, and examining the effects of multiple antimicrobial agents complicates analysis. We also did not account for antimicrobial drug use in the community, which we have previously reported to be associated with hospital resistance rates (22). Because of the large number of variables that may influence resistance in the hospital setting, we would expect hospital fluoroquinolone use to have at best a modest effect on resistance. The results of our model suggest that the ecologic effect size of fluoroquinolone use is such that substantial changes in fluoroquinolone use may be required to affect percent resistance. Thus, a larger sample size, which incorporates more hospitals over a greater period, may be required to demonstrate significance, if such effects exist.
Because percent antimicrobial resistance in a given period is highly correlated to previous percent resistance (i.e., the observations are not independent), we incorporated the previous year's percent resistance into our longitudinal model. Failing to account for this autocorrelation may result in spurious spu·ri·ous
Similar in appearance or symptoms but unrelated in morphology or pathology; false.
simulated; not genuine; false. associations (23). However, our use of a 1-year lag period was imposed by the nature of our data (which was aggregated on a yearly basis) rather than biologic considerations and may not be the most accurate method of modeling this relationship. We did not time-lag the effect of fluoroquinolone use. Monnet et al. used time-series analysis Time-series analysis
Assessment of relationships between two or among more variables over periods of time. with autoregressive integrative moving average (ARIMA) functions to model the changes in percent MRSA in a hospital in Scotland during a 3-year period (24). Their transfer function model for predicting percent MRSA used the previous month's percent MRSA; the effect of fluoroquinolone use had a 4-month lag in the effect of changes in fluoroquinolone use on percent MRSA. No study has specifically examined lag effects with fluoroquinolone use and fluoroquinolone-resistant P. aeruginosa, although Lopez-Lozano et al. used a lag period of 3 and 5 months in percent resistance and a 1-month lag in ceftazidime use to model the relationship between ceftazidime use and ceftazidime-resistant gram-negative bacilli bacilli /ba·cil·li/ (bah-sil´i) plural of bacillus.
see bacillus. (25). Thus, use of yearly antibiograms may not be adequate to properly model the relationships between percent resistance in a given year, previous resistance, and fluoroquinolone use. Future studies should attempt to attain more detailed data to allow for more flexibility in modeling the relationship between antimicrobial use and resistance.
The results of this study raise a number of questions for further investigation. Why did the association between fluoroquinolone use and resistance become weaker in the later study years? Does this finding represent random fluctuation Fluctuation
A price or interest rate change. or an underlying trend? Mean fluoroquinolone use, after increasing through the first 3 study years, reached a plateau in the last 2 years (Figure 1). Perhaps associations with resistance are reflected most strongly when antimicrobial drug use is increasing, as was seen in the first 3 study years. The study by Zervos et al. (11) found a significant association between changes in fluoroquinolone use and changes in resistance in P. aeruginosa in 10 teaching hospitals from 1991 to 2000. During this period, fluoroquinolone use increased by a mean of 97% in the participating hospitals; in the present study, the mean increase during the study period was 23%. Also, the percentage of resistance among MRSA and P. aeruginosa was relatively high in all hospitals from the beginning of this study. Monnet et al., in their study of the impact of antimicrobial drug use on an outbreak of MRSA in Scotland, observed that "... antimicrobial drug use was a more important ecologic risk factor at the start of the outbreak than once MRSA had become endemic endemic /en·dem·ic/ (en-dem´ik) present or usually prevalent in a population at all times.
1. in the hospital" (24). After antimicrobial use "drives" resistance to a certain point, other effects such as cross-transmission may become the dominant mode of spread. From a scientific standpoint, this finding suggests that ecologic studies may be more likely to detect a significant effect when a particular form of resistance is in its "infancy" (current examples might be linezolid-resistant S. aureus or fluoroquinolone-resistant Streptococcus pneumoniae Streptococcus pneu·mo·ni·ae
Streptococcus pneumoniae Microbiology A pathogenic streptococcus with 90 serotypes associated with pneumonia, bacteremia, meningitis Transmission Person to person Incidence ). From a clinical point of view, this finding suggests that measures to ensure proper antimicrobial drug use would have the most effect before resistance becomes widespread.
Also of interest is the effect of individual fluoroquinolones on resistance. In our univariate analyses, levofloxacin use had a much stronger association with resistance in both pathogens than did use of ciprofloxacin. Levofloxacin also showed the only significant relationship (with percent MRSA) among the longitudinal models. However, the univariate models did not control for prior resistance levels. Also, the population-averaged modeling approach results in a pooling of effects across all hospitals, resulting in some degree of effect attenuation Loss of signal power in a transmission.
The reduction in level of a transmitted quantity as a function of a parameter, usually distance. It is applied mainly to acoustic or electromagnetic waves and is expressed as the ratio of power densities. . Indeed, the estimates from a GEE analysis can sometimes be smaller than those estimates produced from a corresponding mixed-effect model (12). This apparent effect attenuation can be viewed as a trade-off for the reduced vulnerability to model misspecification, as previously discussed. Relationships between individual fluoroquinolone use and resistance should be interpreted with caution, as it is possible that our study is biased (an unknown confounder con·found
tr.v. con·found·ed, con·found·ing, con·founds
1. To cause to become confused or perplexed. See Synonyms at puzzle.
2. that is causally associated with MRSA or resistant P. aeruginosa occurs more frequently in hospitals that use more levofloxacin). However, other ecologic studies have found similar results. At a single teaching institution in an 8-year period, Mohr et al. observed an association between increasing levofloxacin use and increasing percent resistance in P. aeruginosa; this effect was not observed for total fluoroquinolone use or use of other fluoroquinolones (26). An ecologic study across 174 hospitals across 6 years by Bhavnani et al. showed that increasing use (measured as drug expenditures) of levofloxacin and ofloxacin, but not ciprofloxacin, was associated with increased percent resistance to ciprofloxacin in P. aeruginosa (10). This ecologic effect might arise from a greater in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment.
In an artificial environment outside a living organism. potential for levofloxacin to select for resistant mutants of P. aeruginosa, as Gilbert and colleagues have observed (27). For MRSA, a different relationship between fluoroquinolone use and resistance is relevant, since the emergence of methicillin methicillin /meth·i·cil·lin/ (meth?i-sil´in) a semisynthetic penicillin highly resistant to inactivation by penicillinase; used as the sodium salt.
n. resistance during therapy is not of concern. When viewed from the perspective of selecting for preexisting pre·ex·ist or pre-ex·ist
v. pre·ex·ist·ed, pre·ex·ist·ing, pre·ex·ists
To exist before (something); precede: Dinosaurs preexisted humans.
v.intr. methicillin-resistant, fluoroquinolone-resistant Staphylococcus aureus from a population that contains both resistant and susceptible isolates, levofloxacin might be more likely to select for the preexisting resistant clones because of its greater activity against the susceptible organisms. In such a scenario, the proportion of resistant isolates (percent resistance) may increase, although the incidence of infections due to resistant bacteria may be relatively stable, as argued by Schwaber et al. (28). Thus, analysis of incidence rates of isolation of resistant organisms may tell a different story from analysis of percentage of resistant organisms. We did not determine incidence rates because some of our study hospitals did not include the number of organisms isolated on their antibiograms. Although percent resistance is most likely of concern to a clinician clinician /cli·ni·cian/ (kli-nish´in) an expert clinical physician and teacher.
n. , the incidence rates determine the overall effect on impact of resistance from an ecologic perspective. Future studies should incorporate resistance rates alongside changes in percent resistance to give the complete picture of the effect of antimicrobial drug use on resistance. The differential effects of individual fluoroquinolones on antimicrobial drug resistance are an important area for future study, as hospitals manipulate their formularies with regard to use of individual fluoroquinolones, often for economic reasons.
This study has a number of limitations. The study hospitals do not represent a random sample of US hospitals; further studies are required to determine whether the results are broadly applicable. We were unable to control for differences between hospitals in their methods of antibiogram construction, including methods and reporting of duplicate isolates, which can affect reported resistance (29), as well as hospital culturing practices (such as MRSA screening). Standardization standardization
In industry, the development and application of standards that make it possible to manufacture a large volume of interchangeable parts. Standardization may focus on engineering standards, such as properties of materials, fits and tolerances, and drafting of methods to report antibiograms has been advocated by the Clinical and Laboratory Standards Institute (formerly NCCLS NCCLS National Committee for Clinical Laboratory Standards ), but adherence is poor (30). We also were not able to control for differences in infection control measures between hospitals, which are a likely source of variability in the prevalence of resistant organisms. Finally, the associations between antimicrobial drug use and resistance found in ecologic studies such as this may not always coincide with those observed on an individual patient level (31). Case-control studies are more appropriate to quantify the risk associated with antimicrobial drug exposure in individual patients.
Our results suggest that the ecologic relationship between the hospital use of fluoroquinolones and antimicrobial resistance in P. aeruginosa and S. aureus is complex. Future studies to better define this relationship would be worthwhile, in that they would help hospitals determine where to best invest their resources to reduce the overall impact of resistance in their institutions, whether through enhanced infection control measures or more active antimicrobial stewardship, although both measures are likely important. Meanwhile, judicious ju·di·cious
Having or exhibiting sound judgment; prudent.
[From French judicieux, from Latin i use of fluoroquinolones is advocated to prevent the loss of this valuable therapeutic class.
Table 1. Demographic characteristics of study hospitals, year 2002 * Characteristic Mean [+ or -] SD No. admissions 19,122 [+ or -] 12,208 No. patient-days 96,488 [+ or -] 64,719 Case mix index 1.51 [+ or -] 0.245 Length of hospital stay, d 5 [+ or -] 0.67 No. staffed beds 358 [+ or -] 203 No. intensive care unit beds 22 [+ or -] 16 No. surgical procedures/1,000 admissions 346 [+ or -] 184 Characteristic Median (range) No. admissions 14,720 (5,206-40,676) No. patient-days 76,408 (19,244-219,634) Case mix index 1.52 (1.13-2.01) Length of hospital stay, d 5 (3.6-6.6) No. staffed beds 310 (105-778) No. intensive care unit beds 18 (3-80) No. surgical procedures/1,000 admissions 281 (163-779) * SD, standard deviation. Table 2. Associations between fluoroquinolone use and resistance in individual years * FQ-R P. aeruginosa FQ use Total FQ Levofloxacin Ciprofloxacin 1999 [R.sup.2] 0.525# 0.593# 0.233 p 0.008# 12# 0.116 n 12# 0.003# 12 2000 [R.sup.2] 0.397# 0.285# 0.519 p 0.004# 0.019# 0.348 n 19# 19# 19 2001 [R.sup.2] 0.481 0.335 0.067 p 0.001 0.009 0.2821 n 19 19 19 2002 [R.sup.2] 0.178 0.112 0.09 p 0.056 0.137 0.184 n 21 21 21 2003 [R.sup.2] 0.104 0.012 0.01 p 0.16 0.641 0.66 n 20 20 20 MRSA FQ use Total FQ Levofloxacin Ciprofloxacin 1999 [R.sup.2] 0.392# 0.644# 0.255 p 0.029# 0.0017# 0.0937 n 12# 12# 12 2000 [R.sup.2] 0.617# 0.617# 0.112 p 0.0001# 0.0001# 0.175 n 18# 18# 18 2001 [R.sup.2] 0.318# 0.32# 0.159 p 0.018# 0.018# 0.1134 n 17# 17# 17 2002 [R.sup.2] 0.267# 0.28# 0.145 p 0.019# 0.017# 0.097 n 20# 20# 20 2003 [R.sup.2] 0.157 0.02 0.001 p 0.092 0.538 0.9924 n 19 19 19 * Linear regression of fluoroquinolone (FQ) use versus percent resistance for hospitals. [R.sup.2], coefficient of determination; n, number of hospitals. Bold indicates significant relationships (p<0.05). FQ-R P. aeruginosa, fluoroquinolone-resistant Pseudomonas aeruginosa; MRSA, methicillin-resistant Staphylococcus aureus. Note: Significant relationships (p<0.05) is indicated with #. Table 3. Longitudinal GEE models * FQ-R P. aeruginosa Drug Coefficient p value Total FQ Previous year's resistance 0.875 <0.001 Total FQ use 0.002 0.883 Time -0.312 0.554 Constant 6.75 0.001 Levofloxacin Previous year's resistance 0.868 <0.001 Levofloxacin use 0.005 0.548 Time -0.317 0.579 Constant 6.78 0.001 Ciprofloxacin Previous year's resistance 0.866 <0.001 Ciprofloxacin use -0.018 0.226 Time -0.393 0.475 Constant 8.185 <0.001 MRSA Drug Coefficient p value Total FQ Previous year's resistance 0.804 <0.001 Total FQ use 0.025 0.155 Time 1.04 0.040 Constant 4.61 0.058 Levofloxacin Previous year's resistance 0.818 <0.001 Levofloxacin use 0.012 0.033 Time 1.04 0.041 Constant 6.38 0.001 Ciprofloxacin Previous year's resistance 0.845 <0.001 Ciprofloxacin use -0.004 0.848 Time 0.991 0.079 Constant 6.55 0.033 Association of fluoroquinolone and pathogen resistance overtime controlling for prior year resistance. GEE, generalized estimating equations; FQ-R P. aeruginosa, fluoroquinolone-resistant Pseudomonas aeruginosa, MRSA, methicillin-resistant Staphylococcus aureus.
We thank Jim Letcavage and Annie Mahoney for providing antimicrobial drug-use data and the hospital pharmacists This is a list of notable pharmacists.
(1.) World Health Organization. WHO global strategy for containment of antimicrobial resistance. Geneva Geneva, canton and city, Switzerland
Geneva (jənē`və), Fr. Genève, canton (1990 pop. 373,019), 109 sq mi (282 sq km), SW Switzerland, surrounding the southwest tip of the Lake of Geneva. : The Organization; 2001.
(2.) 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. . A public health action plan to combat antimicrobial resistance. Part 1: domestic issues. Atlanta: The Centers; 2001.
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use. Rev infect infect /in·fect/ (in-fekt´)
1. to invade and produce infection in.
2. to transmit a pathogen or disease to.
1. Dis. 1983;5:1033-48.
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(5.) Dziekan G, Hahn A, Thune K, Schwarzer G, Schafer K, Daschner FD, et al. Methicillin-resistant Staphylococcus aureus in a teaching hospital: investigation of nosocomial transmission using a matched case-control study. J Hosp Infect. 2000;46:263-70.
(6.) El Amari EB, Chamot E, Auckenthaler R, Pechere JC, Van Delden C. Influence of previous exposure to antibiotic therapy on the susceptibility pattern of Pseudomonas aeruginosa bacteremic bac·te·re·mi·a
The presence of bacteria in the blood.
bacte·re isolates. Clin Infect Dis. 2001;33:1859-64.
(7.) Graffunder EM, Venezia RA. Risk factors associated with nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection including previous use of antimicrobials. J Antimicrob Chemother. 2002;49:999-1005.
(8.) Weber SG, Gold HS, Hooper hoop·er
A maker or repairer of barrels and tubs; a cooper. DC, Karchmer AW, Carmeli Y. Fluoroquinolones and the risk for methicillin-resistant Staphylococcus aureus in hospitalized patients. Emerg Infect Dis. 2003;9:1415-22.
(9.) Crowcroft NS, Ronveaux O, Monnet DL, Mertens R. Methicillin-resistant Staphylococcus aureus and antimicrobial use in Belgian hospitals. Infect Control Hosp Epidemiol. 1999;20:31-6.
(10.) Bhavnani SM, Callen WA, Forrest A, Gilliland KK, Collins DA, Paladino JA, et al. Effect of fluoroquinolone expenditures on susceptibility of Pseudomonas aeruginosa to ciprofloxacin in U.S. hospitals. Am J Health Syst Pharm. 2003;60:1962-70.
(11.) Zervos M J, Hershberger E, Nicolau DP, Ritchie DJ, Blackner LK, Coyle EA, et al. Relationship between fluoroquinolone use and changes in susceptibility to fluoroquinolones of selected pathogens in 10 United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. teaching hospitals, 1991 2000. Clin Infect Dis. 2003;37:1643-8.
(12.) Hardin J, Hilbe JM. Generalized estimating equations. Boca Raton Boca Raton (bō`kə rətōn`), city (1990 pop. 61,492), Palm Beach co., SE Fla., on the Atlantic; inc. 1925. Boca Raton is a popular resort and retirement community that experienced significant industrial development in the 1970s and 80s. (FL): Chapman & Hall/CRC; 2003.
(13.) Hooper DC. Emerging mechanisms of fluoroquinolone resistance. Emerg Infect Dis. 2001;7:337-41.
(14.) Deresinski S. Methicillin-resistant Staphylococcus aureus: an evolutionary, epidemiologic, and therapeutic odyssey Odyssey (ŏd`ĭsē): see Homer.
Homer’s long, narrative poem centered on Odysseus. [Gk. Lit.: Odyssey]
See : Epic
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(15.) Lipsitch M, Samore MH. Antimicrobial use and antimicrobial resistance: a population perspective. Emerg Infect Dis. 2002;8:347-54.
(16.) Diekema D J, Pfaller MA, Schmitz F J, Smayevsky J, Bell J, Jones RN, et al. Survey of infections due to Staphylococcus staphylococcus (stăf'ələkŏk`əs), any of the pathogenic bacteria, parasitic to humans, that belong to the genus Staphylococcus. The spherical bacterial cells (cocci) typically occur in irregular clusters [Gr. species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America Latin America, the Spanish-speaking, Portuguese-speaking, and French-speaking countries (except Canada) of North America, South America, Central America, and the West Indies. , Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997-1999. Clin Infect Dis. 2001:32(Suppl 2):S114-32.
(17.) Venezia RA, Domaracki BE, Evans AM, Preston KE, Graffunder EM. Selection of high-level oxacillin resistance in heteroresistant Staphylococcus aureus by fluoroquinolone exposure. J Antimicrob Chemother. 2001;48:375-81.
(18.) Bisognano C, Vaudaux P, Rohner P, Lew DP, Hooper DC. Induction of fibronectin-binding proteins and increased adhesion adhesion /ad·he·sion/ (ad-he´zhun)
1. the property of remaining in close proximity.
2. the stable joining of parts to one another, which may occur abnormally.
3. of quinolone-resistant Staphylococcus aureus by subinhibitory levels of ciprofloxacin, Antimicrob Agents Chemother. 2000;44:1428-37.
(19.) Friedrich LV, White RE, Bosso JA. Impact of use of multiple antimicrobials on changes in susceptibility of gram-negative aerobes. Clin Infect Dis. 1999;28:1017-24.
(20.) O'Brien TF. Emergence, spread, and environmental effect of antimicrobial resistance: how use of an antimicrobial anywhere can increase resistance to any antimicrobial anywhere else. Clin Infect Dis. 2002;34(Suppl 3):S78-84.
(21.) Safdar N, Maki DG. The commonality com·mon·al·i·ty
n. pl. com·mon·al·i·ties
a. The possession, along with another or others, of a certain attribute or set of attributes: a political movement's commonality of purpose. of risk factors for nosocomial colonization and infection with antimicrobial-resistant Staphylococcus aureus, enterococcus enterococcus /en·tero·coc·cus/ (en?ter-o-kok´us) pl. enterococ´ci an organism belonging to the genus Enterococcus.
Enterococcus /En·tero·coc·cus/ ( , gram-negative bacilli, Clostridium difficile Clostridium difficile A common cause of bacterial colitis; it is the causative agent in 99% of pseudomembranous colitis, and 20-30% of antibiotic-associated diarrhea , and Candida candida
Any of the parasitic imperfect fungi (see fungus) that make up the genus Candida, which resemble yeasts and occur especially in the mouth, vagina, and intestinal tract. . Ann Intern intern /in·tern/ (in´tern) a medical graduate serving in a hospital preparatory to being licensed to practice medicine.
in·tern or in·terne
n. Med. 2002;136: 834-44.
(22.) Polk RE, Johnson CK, McClish D, Wenzel RP, Edmond MB. Predicting hospital rates of fluoroquinolone-resistant Pseudomonas aeruginosa from fluoroquinolone use in US hospitals and their surrounding communities. Clin Infect Dis. 2004;39:497-503.
(23.) Monnet DL, Lopez-Lozano JM, Campillos P, Burgos A, Yague A, Gonzalo N. Making sense of antimicrobial use and resistance surveillance data: application of ARIMA and transfer function models. Clin Microbiol Infect. 2001;7(Suppl 5):29-36.
(24.) Monnet DL, MacKenzie FM, Lopez-Lozano JM, Beyaert A, Camacho M, Wilson R, et al. Antimicrobial drug use and methicillin-resistant Staphylococcus aureus, Aberdeen, 1996-2000. Emerg Infect Dis. 2004;10:1432-41.
(25.) Lopez-Lozano JM, Monnet DL, Yague A, Gonzalo N, Campillos P, Saez M. Modelling and forecasting antimicrobial resistance and its dynamic relationship to antimicrobial use: a time series analysis. Int J Antimicrob Agents. 2000; 14:21-31.
(26.) Mohr JF, Jones A, Ostrosky-Zeichner L, Wanger A, Tillotson G. Associations between antibiotic use and changes in susceptibility patterns of Pseudomonas aeruginosa in a private, university-affiliated teaching hospital: an 8-year-experience: 1995 2002. Int J Antimicrob Agents. 2004;24:346-51.
(27.) Gilbert DN, Kohlhepp SJ, Slama KA, Grunkemeier G, Lewis G, Dworkin RJ, et al. Phenotypic phe·no·type
a. The observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences.
b. resistance of Staphylococcus aureus, selected Enterobacteriaceae, and Pseudomonas aeruginosa after single and multiple in vitro exposures to ciprofloxacin, levofloxacin, and trovafloxacin. Antimicrob Agents Chemother. 2001;45:883-92.
(28.) Schwaber MJ, De-Medina T, Carmeli Y. Epidemiological epidemiological
emanating from or pertaining to epidemiology.
the associative relationships between the frequency of occurrence of a disease and its determinants, its predisposing and precipitating interpretation of antibiotic resistance antibiotic resistance,
n the ability of certain strains of microorganisms to develop resistance to antibiotics.
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(29.) Horvat RT, Klutman NE, Lacy MK, Grauer D, Wilson M. Effect of duplicate isolates of methicillin-susceptible and methicillin-resistant Staphylococcus aureus on antibiogram data. J Clin Microbiol. 2003;41:4611-6.
(30.) Zapantis A, Lacy M, Horvat RT, Grauer DW, Barnes BJ, O'Neal B, et al. Nationwide antibiogram analysis using the NCCLS M39-A guidelines guidelines,
n.pl a set of standards, criteria, or specifications to be used or followed in the performance of certain tasks. . In: Abstracts and Proceedings of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy Antimicrobial Agents and Chemotherapy (print-ISSN 0066-4804, CODEN AMACCQ; canceled ISSN 0074-9923, canceled CODEN AACHAX) is an academic journal published by the American Society for Microbiology. . San Diego San Diego (săn dēā`gō), city (1990 pop. 1,110,549), seat of San Diego co., S Calif., on San Diego Bay; inc. 1850. San Diego includes the unincorporated communities of La Jolla and Spring Valley. Coronado is across the bay. : American Society for Microbiology The American Society for Microbiology (ASM) is a scientific organization, based in the United States although with over 43,000 members throughout the world. It is the largest single life science professional organization and its members include those whose interests encompass basic ; 2003.
(31.) Harbarth S, Harris AD, Canneli Y, Samore MH. Parallel analysis of individual and aggregated data on antibiotic exposure and resistance in gram-negative bacilli. Clin Infect Dis. 2001;33:1462-8.
Conan MacDougall, * Spencer E. Harpe, * J. Patrick Powell, * Christopher K. Johnson, ([dagger]) Michael B. Edmond, * and Ron E. Polk *
* Virginia Commonwealth University Formed by a merger between the Richmond Professional Institute and the Medical College of Virginia in 1968, VCU has a medical school that is home to the nation's oldest organ transplant program. , Richmond, Virginia Richmond IPA: [ɹɯʒmɐnɖ] is the capital of the Commonwealth of Virginia, in the United States. , USA; and ([dagger]) Idaho State University Enrollment for fall semester 2006 was 12,676 students, including 8,848 undergraduates. ISU enrolls a large number of older, non-traditional students who live and work off-campus. , Boise, Idaho “Boise” redirects here. For other uses, see Boise (disambiguation).
Boise is the capital and most populous city of the U.S. state of Idaho. It is the county seat of Ada County and the principal city of the Boise metropolitan area. , USA
Bayer provides fellowship support to CM. REP received a grant from Merck and Bayer.
Dr. MacDougall is an infectious diseases infectious diseases: see communicable diseases. fellow at the Virginia Commonwealth University School of Pharmacy. His primary research interests are the relationship between antimicrobial drug use and resistance and the development and impact of antimicrobial stewardship programs.
Address for correspondence: Ron E. Polk, Virginia Commonwealth University School of Pharmacy, Smith Building, Room 454, 410 North 12th St, Richmond, VA 23298-0533, USA; fax: 804-828-8359: email: firstname.lastname@example.org