Benefit of Appropriate Empirical Antibiotic Treatment: Thirty-day ...

The American Journal of Medicine (2006) 119, 970-976

CLINICAL RESEARCH STUDY

AJM Theme Issue: Infectious Disease

Benefit of Appropriate Empirical Antibiotic Treatment: Thirty-day Mortality and Duration of Hospital Stay Abigail Fraser, MPH,a Mical Paul, MD,a,b Nadja Almanasreh, MD,c Evelina Tacconelli, MD,d Uwe Frank, MD,c Roberto Cauda, MD,d Sara Borok, MD,a Michal Cohen, MD,e Steen Andreassen, PhD,f Anders D. Nielsen, MSc,f Leonard Leibovici, MD,a,b on behalf of the TREAT Study Group a

Department of Medicine E, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, Israel; bSackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel Aviv, Israel; cDepartment of Clinical Microbiology and Hospital Hygiene, Freiburg University Hospital, Freiburg University, Germany; dDepartment of Infectious Diseases, A. Gemelli Hospital in Rome, Catholic University, School of Medicine, Italy; eDepartment of Medicine D, Rabin Medical Center; Beilinson Campus, Petah-Tiqva, Israel; fCenter for Model-based Medical Decision Support, Aalborg University, Denmark. ABSTRACT PURPOSE: We evaluated the effect of inappropriate antibiotic treatment on mortality and duration of hospital stay in medical inpatients with bacterial infections. SUBJECTS AND METHODS: Two cohorts of febrile adult patients (excluding patients with acquired immune deficiency syndrome and organ transplant recipients), hospitalized in three medical centers in Israel, Italy, and Germany, were included. Patients’ data were collected prospectively. Initial empirical treatment was defined as appropriate if an antibiotic prescribed within 24 hours of the first encounter with the patient matched the in vitro susceptibility of a pathogen deemed to be the likely cause of infection. The results of cultures and serologic or direct tests, and data on outcomes were collected 30 days after initiation of empirical treatment. RESULTS: A total of 920 patients (26% of 3529 included patients) had microbiologically documented infections, and mortality data were available for 895 patients (97%). Inappropriate initial antibiotic treatment was prescribed in 36% of patients (N ⫽ 319). All-cause 30-day mortality rates were 20.1% (N ⫽ 64) and 11.8% (N ⫽ 68) in patients who received inappropriate and appropriate treatment, respectively (odds ratio ⫽ 1.88, 95% confidence interval [CI], 1.29-2.72, P ⫽ .001). When adjustment was made for medical center and other variables, the association between inappropriate with mortality was significant (odds ratio ⫽ 1.58, 95% CI, 0.99-2.54, P ⫽ .058). In all 3 medical centers, the mean duration of hospital stay was at least 2 days longer for patients who were prescribed inappropriate antibiotic treatment (overall P ⫽ .002). This association was consistent after adjusting for other variables (P ⫽ .006). CONCLUSION: Appropriate empirical antibiotic treatment is associated with a better survival and shortened duration of hospital stay in medical patients with bacterial infections. © 2006 Elsevier Inc. All rights reserved. KEYWORDS: Appropriate antibiotic treatment; Mortality; Duration of hospitalization

Antibiotic treatment for moderate to severe bacterial infections is started early and empirically, before the pathogen and its susceptibilities to antibiotics are known. The physiSupported by EU 5th framework, Information Society and Media Directorate-General, contract number IST-9999-11459. Requests for reprints should be addressed to Leonard Leibovici, MD, Department of Medicine E, Beilinson Campus, Petah-Tiqva 49100, Israel. E-mail address: [email protected].

0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.03.034

cian has to balance the benefit of wide coverage against the costs of the antibiotic, adverse events, and induction of resistance.1 Studies assessing the impact of appropriate empirical antibiotic therapy have yielded variable results. Although some have demonstrated that inappropriate antibiotic treatment is an independent risk factor for mortality,2-9 others did not find appropriate antibiotic treatment to be associated with a significant benefit in terms of surviv-

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Benefit of Appropriate Antibiotic Treatment

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al.10-12 The majority of these investigations included critiblood cultures were drawn, regardless if the suspected incally ill patients hospitalized in an intensive care unit with fection was acquired in the community or the hospital. This bloodstream infections. study reports results for patients with microbiologically Only three studies4,6,7 evaluated the impact of appropridocumented infections, that is, patients fulfilling inclusion ate antibiotic treatment on duration of hospital stay. These criteria for whom a significant pathogen was isolated (Apstudies examined the association pendix 1). at the univariate level, that is, Excluded were human immuwithout controlling for possible nodeficiency virus-positive paCLINICAL SIGNIFICANCE confounders. All 3 studies found tients with a current (suspected or that the mean or median duration identified) opportunistic disease ● Approximately one-third of patients of hospitalization was higher in and/or acquired immune defiwith bacterial infections are given inappatients prescribed inappropriate ciency syndrome-defining illness propriate empirical antibiotic treatment. antibiotic treatment. currently or within the past 6 ● The benefit inherent in appropriate Whether appropriate antibiotic months; solid-organ or bone martreatment is indeed associated row transplant recipients; children treatment should dictate our efforts to with benefit and the magnitude of aged less than 18 years; those with improve the appropriateness of empirical benefit (how many patients need suspected travel infections or tuantibiotic treatment. to be treated to save 1 life, how berculosis; and pregnant women. ● Appropriate antibiotic treatment was asmany hospital days are saved) are Patients fulfilling inclusion crisociated with a significant decrease in crucial to decisions regarding anteria were prospectively identified mortality and hospital stay in patients tibiotic treatment. by daily chart review. At the time We aimed to assess the effect of empirical treatment we colwith bacterial infections. of inappropriate initial antibiotic lected data on the following: detreatment on mortality and duramography (eg, age, sex, place of tion of hospital stay in medical infection acquisition); background inpatients with bacterial infections. For this purpose we conditions (eg, diabetes mellitus, chronic obstructive pulused prospectively collected data for 2 cohorts of patients monary disease, malignancy, chronic heart failure, chronic with moderate to severe bacterial infections in three hospiand acute renal failure, acute coronary syndrome, immunotals in 3 different countries. deficiency); predisposing conditions (eg, recent surgery) and devices (eg, urinary catheter, intravenous catheter); general and focal signs and symptoms (eg, fever, chills, SUBJECTS AND METHODS cough, vomiting, rash); and all available routine laboratory Study Sample data (eg, blood count, creatinine, urea, electrolytes, albumin, liver function test results). At follow-up, 30 days after We analyzed a multinational database of patients from 3 initiation of empirical treatment, we collected data on surmedical centers: Rabin Medical Center, Beilinson Campus vival, final diagnosis, duration of hospital stay, fever days, (Israel): 6 departments of internal medicine (240 beds); duration of stay in the intensive care unit, treatment, adverse University Hospital of Freiburg (Germany): 2 gastroenterevents, and all microbiologic results. ology, 2 nephrology, and 2 intensive care wards (94 beds); and A. Gemelli University Hospital (Italy): 3 infectious Definitions disease wards (60 beds). Patients were enrolled as part of a Initial empirical treatment was defined as appropriate if an 2-phase study (observational and interventional) designed to antibiotic prescribed within 24 hours of the first encounter evaluate the effectiveness of TREAT, a decision support with the patient matched the in vitro susceptibility of a system for antibiotic treatment of common bacterial infecpathogen that was subsequently deemed to be a significant tions in medical inpatients.13,14 isolate, that is, being the likely cause of infection. If in vitro Data were collected during the following time periods: susceptibility results were unavailable for the antibiotic adbetween June and December 2002 in Israel and Germany, ministered, antibiotic treatment was adjudicated according between March and September 2003 in Italy (observational to predefined rules (Appendix 2). When appropriateness phase),13 and between May and November 2004 at all 3 could not be determined, the case was counted as inapprosites (randomized, controlled trial).14 Research ethics compriate. Assignment of clinical significance to isolated pathomittees in the 3 sites approved the study protocols. gens was performed with strict adherence to predefined Inclusion/Exclusion Criteria rules (Appendix 1). Evaluators of appropriateness of antiIncluded were patients fulfilling systemic inflammatory rebiotic treatment were blinded to departments and outcome sponse syndrome diagnostic criteria:15patients with a focus of patients. of infection; patients with shock compatible with septic Septic shock was defined as sepsis with hypotension shock; patients with febrile neutropenia; patients prescribed despite adequate fluid resuscitation, along with the presence antibiotics (not for prophylaxis); and patients from whom of perfusion abnormalities that may include, but are not

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The American Journal of Medicine, Vol 119, No 11, November 2006

limited to, lactic acidosis, oliguria, or an acute alteration in mental status.16 Immunodeficiency included human immunodeficiency virus infection, splenectomy, and terminal complement deficiencies. Functional capacity was measured on a scale of 0 to 3, with 0 indicating full functional capacity, 1 indicating limited capacity, 2 indicating limited in daily life activities, and 3 indicating bedridden.

Outcomes Mortality was defined as all-cause mortality at 30 days after the first encounter with the patient for the infection. Duration of hospital stay was defined as the number of days from admission to discharge or death for patients with community-acquired infections and as the number of days from onset of infectious episode to discharge or death for patients with hospital-acquired infections.

Statistical Analysis Proportions were compared using a Fisher exact test or chi-square test, and continuous variables were compared using a Student t test or Mann Whitney U test, as appropriate. Variables were considered for the multivariable analysis if they were found to be associated with mortality at the 5% significance level. A multiple logistic regression model was constructed to assess the impact of inappropriate antibiotic treatment on mortality while adjusting for medical center and other clinically significant variables. We forced appropriateness of antibiotic treatment and medical center into the model and then added variables using a forward stepwise method. Variables on medical devices (ie, central intravenous line, mechanical ventilation, and urinary tract catheter) were not entered into the model because they reflect the severity of a patient’s condition, which is accounted for by other variables. We also did not use information on local signs and symptoms because a variable describing the source of infection was entered in the model. A General Linear Model was used to examine the association between inappropriate antibiotic treatment and duration of hospitalization while controlling for medical center and other variables. For the primary analysis of variables associated with length of hospital stay, we used data on patients who were alive on day 30. A secondary analysis was performed on all patients. Analyses were performed using the Statistical Package for the Social Sciences 11.5 (SPSS Inc, Chicago, Ill).

RESULTS Of the 3529 recruited patients, 920 (26%) had microbiologically documented infections and mortality data were available for 895 (97.3% of 920). A total of 560 patients were enrolled in Israel, 180 patients were enrolled in Germany, and 155 patients were enrolled in Italy. A total of 435 patients were female (49%). The mean age was 66.7 ⫾ 18.2 years (standard deviation). A total of 182 infections were hospital acquired (20%). The most common sites of infection were the urinary

tract (315 patients, 35%), lower respiratory tract (168 patients, 19%), skin and soft tissue (80 patients, 9%), and endovascular infections (63 patients, 7%). Escherichia coli was isolated in 335 patients, Staphylococcus aureus was isolated in 101 patients, Pseudomonas aeruginosa was isolated in 82 patients, Klebsiella pneumoniae was isolated in 66 patients, streptococci was isolated in 36 patients, and Acinetobacter baumannii was isolated in 9 patients. In 159 patients, more than 1 pathogen was isolated. Overall, inappropriate initial antibiotic treatment was prescribed to 35.6% of patients (N ⫽ 319), with similar proportions in the 3 medical centers (Israel 37.7%, Germany 31.8%, Italy 35%, P ⫽ .33).

Mortality The all-cause, 30-day mortality rate was 14.7%. In patients who received inappropriate and appropriate empirical antibiotic treatment, mortality rates were 20.1% and 11.8%, respectively (P ⫽ .001). Thus, inappropriate empirical antibiotic treatment was associated with an increased risk of death (odds ratio [OR] ⫽ 1.88, 95% confidence interval [CI], 1.29-2.72). The characteristics of survivors and nonsurvivors at 30 days are presented in Table 1. None of the pathogens were significantly associated with 30-day mortality (data not shown). The multivariable logistic regression model is displayed in Table 2. Included in the model were all variables significantly associated with a fatal outcome (P ⬍ .05 , Table 1). When covariates were controlled, inappropriate antibiotic treatment was associated with an increased risk of death (OR ⫽ 1.58, 95% CI, 0.99-2.54, P ⫽ .058).

Duration of Hospitalization The impact of inappropriate antibiotic treatment on duration of hospitalization (in days) was studied in patients who were alive at day 30 and for whom data on duration of hospitalization were available (N ⫽ 677). Data on durations of hospital stay by appropriate antibiotic treatment and medical center are presented in Table 3. In all 3 medical centers, the mean duration of hospital stay was more than 2 days longer in patients prescribed inappropriate empirical antibiotic treatment. Overall, inappropriate empirical antibiotic treatment was significantly associated with prolonged hospital stay when controlling for medical center (P ⫽ .002). The following variables were found to be significantly associated with duration of hospitalization at the univariable level: sex, age, polymicrobial infection, bloodstream infection, septic shock, systolic blood pressure, hypothermia, chronic heart failure, acute coronary syndrome, acute and chronic renal failure, liver cirrhosis, being bedridden, and coma (data not shown). When these variables and the medical center were controlled in a General Linear Model, inappropriate empirical antibiotic treatment remained an independent risk factor for duration of hospitalization (F ⫽ 6.51, df ⫽ 17, P ⫽ .006). We repeated this analysis for

Fraser et al Table 1


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Baseline Patient Characteristics by 30-Day All-Cause Mortality (Univariate Analysis)*

Characteristic Demographics Age (mean ⫾ SD) Females Underlying disorders Malignancy Solid Hematologic Chronic heart failure Diabetes mellitus Liver cirrhosis Surgery within 30 d Acute coronary syndrome Immunodeficiency Functional capacity (median) Bedridden COPD Dialysis Chronic renal failure Acute renal failure Urinary tract catheter Mechanical ventilation Central IV line Characteristics of infection Hospital-acquired infection Bloodstream infection Source of infection Abdominal CNS Endovascular Lower respiratory Neutropenic Skin and soft tissue UTI Unknown Other Polymicrobial infection Septic shock Temperature ⱕ36°C Systolic blood pressure (mm Hg), mean (SD) Creatinine (mg/dL), mean (SD) Coma

Survivors (N ⫽ 763) % (n)

Nonsurvivors (N ⫽ 132) % (n)

P value

65.31 ⫾ 18.39 47.7 (363)

74.55 ⫾ 15.04 54.5 (72)

⬍.001 .15

16 4.5 12.8 24.3 4.7 5.5 3.8 4.8 0 15.2 9.2 4.3 15.0 13.0 16.3 2.6 8.3

(113) (33) (94) (180) (35) (40) (28) (35) (111) (67) (31) (110) (93) (118) (19) (60)

19 (145) 38 (290) 4.8 1.3 7.5 16.6 1.3 9.2 36.7 1.2 19.5 15.7 3.4 3.5 127.2 1.33 1.5

(37) (10) (57) (127) (10) (70) (280) (9) (149) (120) (24) (26) (24.83) (1.31) (11)

26.1 8.7 24.2 32.3 4.8 4.9 8.1 2.5 2 38.7 10.7 7.4 31.1 30.8 25.8 13.7 16.3

(30) (11) (30) (40) (6) (6) (10) (3) (48) (13) (9) (38) (37) (32) (17) (20)

28 (37) 47.7 (63) 4.5 0.8 4.5 31.1 2.3 7.6 26.5 6.1 16.7 28 13.7 7.1 122.3 1.55 11.7

(6) (1) (6) (41) (3) (10) (35) (8) (22) (37) (16) (9) (27.56) (1.16) (14)

.008 .044 .001 .058 .970 .792 .033 .246 .001 ⬍.001 .601 .135 ⬍.001 ⬍.001 .010 ⬍.001 .005 .017 .035 ⬍.001

.001 ⬍.001 .056 .047 .082 ⬍.001

IV ⫽ intravenous; CNS ⫽ central nervous system; UTI ⫽ urinary tract infection; COPD ⫽ chronic obstructive pulmonary disease; SD ⫽ standard deviation. *Because of missing values the total number of patients per risk factor may differ from the grand total.

all patients, regardless of survival. Duration of hospitalization remained significantly longer in patients prescribed inappropriate empirical antibiotic treatment (P ⫽ .024).

DISCUSSION We found inappropriate empirical antibiotic treatment to be associated with an increased risk for all-cause 30-day mortality in adult patients with bacterial infections hospitalized in three medical centers in three different countries (OR ⫽ 1.58, 95% CI, 0.99-2.54). Although this association has been found in subsets of patients (critically ill patients3,4,6,8,9and patients with bloodstream infections2,5,7), our results demonstrate that this association is also true of inpatients with bacterial infections.

Studies showing a benefit for appropriate empirical antibiotic treatment in terms of mortality have yielded effect estimates of varying magnitude, from OR ⫽ 1.6 to OR ⫽ 70.5.7,8 Our point estimate (OR ⫽ 1.58, 95% CI, 0.99-2.54) is of smaller magnitude. This is probably due to the relatively low-risk study population, although varying definitions, methodologic differences (prospective vs retrospective studies), and controlling for different variables are also possible reasons. However, even in this low-risk population, appropriate antibiotic treatment results in a benefit in survival, with an absolute risk reduction of 13%. It should be noted that a randomized, controlled trial evaluating the effectiveness of appropriate versus inappropriate antibiotic treatment is unethical.

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Table 2 Multiple Logistic Regression Model for Thirty-Day Mortality Variable

OR

95% CI

P

Inappropriate antibiotic treatment Age* Polymicrobial infection Bloodstream infection Respiratory and unknown sources of infection Septic shock Coma Bedridden Malignancy (any) Acute renal failure Chronic renal failure

1.58

0.99-2.54

.058

1.02 1.88 1.68 2.50

1.00-1.04 1.07-3.30 1.04-2.71 1.44-4.36

.010 .028 .036 .029

2.53 3.34 1.88 1.65 1.70 1.92

1.07-5.97 1.13-9.88 1.09-3.23 0.98-2.76 0.94-3.08 1.08-3.93

.034 .029 .023 .058 .081 .025

OR ⫽ odds ratio; CI ⫽ confidence interval. Model adjusted for medical center; Wald chi-square for the model 113, 11 df, P ⬍ .0001. *Continuous variable, increment of 1 year.

Therefore, data from well-conducted prospective studies are best suited to assess this question. Duration of hospitalization varied between the 3 participating medical centers. Yet in all 3 centers, inappropriate antibiotic treatment was associated with prolonged duration of hospital stay. This association was studied among patients who were alive at day 30. We chose this group for the primary analysis even though it excludes patients who were discharged and subsequently died before day 30, because such an outcome could be considered a positive one from a patient’s perspective. However, the association persisted when all patients, regardless of survival at day 30, were included in the analysis and has important implications when balancing the benefits and costs associated with ap-

Table 3

propriate antibiotic treatment. Hospitalization is costly, and prolonged duration of hospital stay has been found to be associated with increased rates of adverse events.17 This study has several strengths worth noting. It included a multinational, heterogeneous patient population, patients with both community- and hospital-acquired infections, and patients with isolates other than blood isolates. Eligible patients were identified by daily chart review, and data collection was performed prospectively. Data included information on both acute and chronic conditions at the onset of infectious episode. We are also unaware of previous studies that examined the effect of appropriateness of antibiotic treatment on duration of hospitalization while controlling for potential confounders. We assessed all-cause mortality and overall duration of hospitalization in survivors. Obviously, infection and empirical antibiotic treatment only partially account for death and hospital stay. However, these are the outcomes that can be assessed objectively and are meaningful to the patient. Our analysis was limited to patients with microbiologically documented infections, in whom we could assess the appropriateness of antibiotic treatment. We do not know whether our results apply to patients with community-acquired pneumonia, which is rarely documented microbiologically. We did not assess the rate or impact of superfluous antibiotic treatment, which has both fiscal and ecologic costs in terms of development of resistance. In addition, we did not measure quality of care other than antibiotic treatment in participating centers, which may affect mortality rates. The Council for Appropriate and Rational Antibiotic Therapy formulated the following criteria for accurate use of antibiotics: evidence-based results, therapeutic benefits, safety, optimal drug for the optimal duration, and costeffectiveness.18Use of these seemingly simple criteria actu-

Duration of Hospitalization by Medical Center and Appropriateness of Antibiotic Treatment

Rabin Medical Center, Israel No. of patients Mean (SD) Median (range) Freiburg University Hospital, Germany No. of patients Mean ⫾ SD Median (range) A. Gemelli University Hospital, Italy No. of patients Mean ⫾ SD Median (range) Total No. of patients Mean ⫾ SD Median (range)* SD ⫽ standard deviation. *Mann Whitney test, P ⫽ .048.

Appropriate Antibiotic Treatment

Inappropriate Antibiotic Treatment

282 7.97 (8.58) 5 (0-62)

151 10.77 (13.90) 7 (1-125)

90 15.63 (8.83) 14 (1-36)

31 18.42 (13.83) 14 (3-65)

84 14.25 (11.63) 10.5 (1-62)

39 16.62 (12.20) 12 (2-48)

456 10.64 (13.90) 7 (0-62)

221 12.87 (9.86) 8 (1-125)

Fraser et al


ally entails a complex decision-making process, involving many considerations, including the patient’s condition and local antibiotic resistance patterns. Our results highlight the importance of improving empirical antibiotic treatment of inpatients. Decision support systems can be effective in aiding physicians in these calculations.14,19 Such systems need quantitative data, as those derived from our study, to balance the costs of antibiotic treatment with its benefit. Further research is required to assess the impact of decision support systems or other interventions, such as rapid identification techniques, on the rate of appropriate empirical antibiotic treatment. To conclude, rates of appropriate antibiotic treatment were similar in 3 different countries. Even in a relatively low-risk patient population, appropriate antibiotic treatment is associated with benefit in terms of survival and duration of hospital stay.

TREAT STUDY GROUP Leonard Leibovici and Steen Andreassen conceived the TREAT project and basic concepts. Mical Paul, Leonard Leibovici, Brian Kristensen, Elad Goldberg, Anders D. Nielsen, Alina Zalounina, and Steen Andreassen built the model. Leif E. Kristensen, Karsten Falborg, Alina Zalounina, and Anders D. Nielsen built the interface, database, and supporting software. Abigail Fraser, Mical Paul, and Leonard Leibovici planned this study and analyzed data. Abigail Fraser, Mical Paul, Nadja Almanasreh, Evelina Tacconelli, Uwe Frank, Roberto Cauda, Sara Borok, Michal Cohen, Steen Andreassen, Anders D. Nielsen, and Leonard Leibovici wrote the article. Leonard Leibovici, Uwe Frank, Evelina Tacconelli, Mical Paul, Nadja Almanasreh, Steen Andreassen, and Roberto Cauda planned the clinical study. Mical Paul, Nadja Almanasreh, Evelina Tacconelli, Adriana Cataldo, Liat Vidal, Monika Strehlein, Michal Cohen, Elisheva Pokroy, Rita Citton, Anat Gafter-Gvili, Dafna Yahav, Erez Skapa, Sara Borok, Ram Ron, Yosi Manisterski, and Nir Hadari collected data. Professor Henrik C. Schonheyder contributed to the basic concepts of the TREAT system.

APPENDIX 1. RULES FOR APPLYING CLINICAL SIGNIFICANCE TO ISOLATED MICROORGANISMS The definitions for significant isolates were set a priori as follows: a culture that was taken on the day of the empirical encounter and up to 3 days afterward and showed: 1. Any growth in a blood culture, but for a growth of coagulase-negative staphylococci or Gram-positive rods in a single bottle or a single set. 2. Any growth from a normally sterile site (eg, gall bladder, bronchial lavage, peritoneal, and pleural fluid).

975 3. Growth in the urine of a patient with leukocyturia (⬎10 cells per high-power field) or hematuria (⬎5 cells per high-power field) in a patient with urinary tract symptoms, or with no symptoms but no other source of sepsis. 4. Growth of a single pathogen in a sputum sample of a patient with respiratory signs and symptoms, or a new infiltrate on chest radiography, with no other likely source of infection. 5. Growth from a biopsy or a deep aspirate of a finding in soft tissue or skin. 6. A positive immunoglobulin-M test for Mycoplasma sp., or a positive direct measurement of Legionella pneumophila in the urine; or Streptococcus pneumoniae, Neisseria meningitides, or Haemophilus influenza in the liquor were counted as indicating a true pathogen.

APPENDIX 2. RULES FOR ASSIGNING APPROPRIATENESS OF ANTIBIOTIC TREATMENT Whenever in vitro susceptibility results were available, these were used. When unavailable the following rules were applied: 1. Some bacteria are inherently resistant to specific antibiotics, and thus treatment was coded as inappropriate even if not tested: a. Enterococci to all cephalosporins and trimethoprim/sulfamethoxazole. Enterococcus faecalis to quinupristin-dalfopristin b. Fungi to antibacterials and bacteria to antifungals. 2. Some bacteria are inherently susceptible to specific antibiotics, and thus treatment was coded as appropriate even if not tested: a. Group A streptococcus to all beta-lactams. b. All Gram-positive bacteria except enterococci to glycopeptides (no cases of glycopeptide-resistant staphylococci were reported from participating locations). 3. Anaerobes were considered susceptible to metronidazole, piperacillin-tazobactam, and carbapenems. 4. Gram-positive bacteria were considered resistant to aminoglycosides alone. 5. If a patient with diarrhea and stool positive for Clostridium difficile toxin was treated with metronidazole or oral vancomycin, the treatment was coded as appropriate. 6. If a patient with pneumonia had positive serology or antigen test for mycoplasma, Chlamydia, or Legionella spp., treatment with macrolides or quinolones was counted as appropriate. 7. Similarly, treatment with tetracyclines or quinolones for rickettsial infections was considered appropriate. 8. Isolates susceptible to beta-lactams were considered susceptible to a combination of the same beta-lactam with a beta-lactamase inhibitor.

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9. Within bacteria morphology groups (eg, staphylococci), antibiotics belonging to the same class were graded by spectrum of coverage (eg, penicillin ⬍ oxacillin). Bacteria tested susceptible to an antibiotic within one class were considered susceptible to all antibiotics graded as equal or lower within that class. 10. Methicillin-susceptible/resistant Staphylococcus aureus was considered susceptible/resistant (respectively) to firstgeneration cephalosporins, cefotiam, and cefepime. 11. Streptococcus pneumoniae was considered susceptible to respiratory fluoroquinolones (levofloxacin, moxifloxacin).

10.

11.

12. 13.

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