(11.2) 0.142. Immunosuppression. Anti-thymocyte globulin. 35. (24.5). 66. (39.1) 0.007. IL-2 receptor antagonists. 44. (30.8). 47. (27.8) 0.618. Muromonab-CD3.
Inadequate Empiric Antibiotic Therapy among Canadian Hospitalized Solid-Organ Transplant Patients: Incidence and Impact on Hospital Mortality
by
Bassem Hamandi
A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Pharmaceutical Sciences University of Toronto
© Copyright by Bassem Hamandi (2008)
Inadequate Empiric Antibiotic Therapy among Canadian Hospitalized Solid-Organ Transplant Patients: Incidence and Impact on Hospital Mortality Master of Science (2008) Bassem Hamandi Graduate Department of Pharmaceutical Sciences, University of Toronto
ABSTRACT Background: The incidence of inadequate empiric antibiotic therapy (IET) and its clinical importance as a risk factor for hospital mortality in Canadian solid-organ transplant patients remains unknown. Methods: This retrospective cohort study evaluated all patients admitted to a transplant unit from May/2002-April/2004. Therapy was considered adequate when the organism cultured was found to be susceptible to an antibiotic administered within 24 hours of the index sample collection time. Univariate and multivariate regression analyses were conducted to determine associations between potential determinants, IET, and mortality. Results: IET was administered in 169/312 (54%) transplant patients. Regression analysis demonstrated that an increasing duration of IET (adjusted OR at 24h, 1.33; p < 0.001), ICUassociated infections (adjusted OR, 6.27; p < 0.001), prior antibiotic use (adjusted OR, 3.56; p = 0.004), and increasing APACHE-II scores (adjusted OR, 1.26; p < 0.001), were independent determinants of hospital mortality. Conclusions: IET is common and appears to be an important determinant of hospital mortality in the Canadian transplant population.
ii
ACKNOWLEDGEMENTS I would like to thank my supervisor, Dr. Anne Holbrook for her support and guidance during my graduate studies. Her constructive criticism and comments from the initial conception to the end of this work were highly appreciated. Thank you to my committee members, Dr. James Brunton and Dr. Manny Papadimitropoulos for their expert opinions, advice, and invaluable feedback at our meetings. Dr. Michael Gardam’s expertise and feedback were much appreciated. I would also like to thank Dr. Lehana Thabane for his statistical insight and advice. A special thanks to Dr. Atul Humar for his unique expertise in transplant infectious diseases.
I am indebted to Mr. Gary Wong for his support, suggestions, and feedback during the early planning and throughout the implementation of the study. I would also like to thank my colleagues in the Pharmacy Department at The University Health Network for their help and support.
Finally, I would like to thank my family and friends for their encouragement and support throughout my studies.
iii
TABLE OF CONTENTS
ABSTRACT ................................................................................................................................................................II ACKNOWLEDGEMENTS ..................................................................................................................................... III LIST OF ABBREVIATIONS .................................................................................................................................. VI LIST OF TABLES...................................................................................................................................................VII LIST OF FIGURES............................................................................................................................................... VIII LIST OF APPENDICES .......................................................................................................................................... IX 1.0
INTRODUCTION ........................................................................................................................................1
1.1
STATEMENT OF THE PROBLEM.....................................................................................................................2
1.1.1 Infection after Solid-Organ Transplantation.............................................................................................2 1.1.2 Antibiotic Resistance .................................................................................................................................3 1.1.3 Inadequate Empiric Antibiotic Therapy ....................................................................................................5 1.2
PURPOSE......................................................................................................................................................7
1.2.1 Objective 1.................................................................................................................................................7 1.2.2 Objective 2.................................................................................................................................................7 1.3
STATEMENT OF RESEARCH HYPOTHESIS .....................................................................................................7
1.4
RATIONALE FOR HYPOTHESIS .....................................................................................................................8
1.5
REVIEW OF THE LITERATURE ......................................................................................................................8
2.0
METHODS .................................................................................................................................................25
2.1
STUDY LOCATION AND POPULATION.........................................................................................................25
2.1.1 Inclusion Criteria ....................................................................................................................................25 2.1.2 Exclusion Criteria ...................................................................................................................................25 2.2
STUDY DESIGN ..........................................................................................................................................25
2.3
MICROBIOLOGY.........................................................................................................................................26
2.4
DEFINITIONS..............................................................................................................................................27
2.4.1 Infection vs. Contamination vs. Colonization ..........................................................................................27 2.4.2 Infectious Episodes..................................................................................................................................28 2.4.3 Healthcare vs. ICU vs. Community Associated Infections.......................................................................28 2.4.4 Primary Site of Infection..........................................................................................................................28 2.4.5 Empiric Antibiotic Therapy .....................................................................................................................29 2.4.6 Adequate vs. Inadequate Empiric Antibiotic Therapy .............................................................................29 2.4.7 Previous Antibiotic Therapy....................................................................................................................30 2.4.8 Previous Graft Rejection and Immunosuppressant Use ..........................................................................30 2.4.9 Multi-Drug Resistance.............................................................................................................................31
iv
2.5
OUTCOMES ................................................................................................................................................31
2.6
STATISTICAL ANALYSIS ............................................................................................................................31
3.0
RESULTS....................................................................................................................................................33
3.1
PATIENTS ..................................................................................................................................................33
3.2
INADEQUATE EMPIRIC ANTIBIOTIC THERAPY ...........................................................................................33
3.3
CHARACTERISTICS RELATED TO HOSPITAL MORTALITY ...........................................................................40
3.4
LOGISTIC REGRESSION ANALYSIS .............................................................................................................43
3.5
SECONDARY OUTCOMES ...........................................................................................................................44
4.0
DISCUSSION .............................................................................................................................................45
4.1
STUDY LIMITATIONS .................................................................................................................................48
4.2
IMPLICATIONS OF INADEQUATE EMPIRIC THERAPY...................................................................................49
5.0
CONCLUSIONS.........................................................................................................................................51
6.0
REFERENCES ...........................................................................................................................................52
7.0
PUBLICATIONS AND ABSTRACTS TO DATE ..................................................................................58
8.0
APPENDICES ............................................................................................................................................59
APPENDIX I – LITERATURE REVIEW SEARCH STRATEGY .........................................................................................59 APPENDIX II – RAW DATA .......................................................................................................................................60 APPENDIX III – MULTIVARIATE LOGISTIC REGRESSION MODELLING ......................................................................66
v
LIST OF ABBREVIATIONS AET
Adequate empiric antibiotic therapy
APACHE
Acute Physiology and Chronic Health Evaluation
ATG
Anti-thymocyte globulin
BAL
Bronchoalveolar lavage
CDC
Centers for Disease Control
CLSI
Clinical and Laboratory Standards Institute
CMV
Cytomegalovirus
CNS
Coagulase-negative staphylococci
CVC
Central venous catheter
HAI
Healthcare-associated infections
ICU
Intensive care unit
IET
Inadequate empiric antibiotic therapy
IL-2
Interleukin-2
MDR
Multi-drug resistant
MIC
Minimum inhibitory concentration
MOT
Multi-organ transplant
MRSA
Methicillin-resistant Staphylococcus aureus
NNIS
National Nosocomial Infections Surveillance
OR
Odds ratio
RR
Relative risk
SOT
Solid-organ transplant
UTI
Urinary tract infection
VAP
Ventilator-associated pneumonia
VRE
Vancomycin-resistant enterococci
vi
LIST OF TABLES
TABLE 1. A SUMMARY OF 22 NON-RANDOMIZED COMPARATIVE COHORT STUDIES ASSESSING THE ASSOCIATION BETWEEN IET AND MORTALITY. .........................................................................................................................11
TABLE 2. CHARACTERISTICS OF PATIENTS RECEIVING ADEQUATE OR INADEQUATE EMPIRIC ANTIBIOTIC THERAPY .....34 TABLE 3. CHARACTERISTICS OF TRUE INFECTIOUS EPISODES TREATED WITH ADEQUATE OR INADEQUATE EMPIRIC ANTIBIOTIC THERAPY ..........................................................................................................................................36
TABLE 4. ORGANISMS CULTURED FROM PATIENTS WITH INADEQUATELY TREATED INFECTIOUS EPISODES ..................38 TABLE 5. MULTI-DRUG RESISTANT ORGANISMS CULTURED AMONG PATIENTS RECEIVING ADEQUATE OR INADEQUATE EMPIRIC ANTIBIOTIC THERAPY ............................................................................................................................39
TABLE 6. INTRA-ABDOMINAL ORGANISMS CULTURED AMONG 17 PATIENTS RECEIVING ADEQUATE AND 30 PATIENTS RECEIVING INADEQUATE EMPIRIC ANTIBIOTIC THERAPY .....................................................................................39
TABLE 7. REASONS FOR ADMINISTRATION OF INADEQUATE EMPIRIC THERAPY ............................................................40 TABLE 8. PATIENT CHARACTERISTICS AMONG HOSPITAL SURVIVORS AND NONSURVIVORS .........................................41 TABLE 9. CULTURE CHARACTERISTICS AMONG HOSPITAL SURVIVORS AND NONSURVIVORS ........................................42 TABLE 10. MOST COMMONLY CULTURED ORGANISMS AND THEIR ASSOCIATED MORTALITY AMONG PATIENTS RECEIVING ADEQUATE OR INADEQUATE EMPIRIC ANTIBIOTIC THERAPY ..............................................................42
TABLE 11. LOGISTIC REGRESSION ANALYSIS PREDICTING HOSPITAL MORTALITY.........................................................44 TABLE 12. OUTCOMES OF PATIENTS RECEIVING ADEQUATE VS. INADEQUATE EMPIRIC ANTIBIOTIC THERAPY..............44
vii
LIST OF FIGURES
FIGURE 1. INDIVIDUAL MULTIVARIABLE REGRESSION ANALYSIS OR (95% CI) OF 20 NON-RANDOMIZED COMPARATIVE STUDIES ILLUSTRATING THE ASSOCIATION BETWEEN INADEQUATE ANTIBIOTIC THERAPY AND MORTALITY AT END OF FOLLOW-UP. STUDIES CONDUCTED IN CRITICALLY ILL UNITS ARE SHOWN SEPARATELY NEAR THE BOTTOM. .............................................................................................................................................................13
FIGURE 2. AN ILLUSTRATION DEPICTING THE TIMELINE FOR DETERMINING INADEQUATE EMPIRIC ANTIBIOTIC THERAPY. THERAPY WAS CONSIDERED ADEQUATE WHEN, FOR A GIVEN INFECTIOUS EPISODE, THE ORGANISM CULTURED WAS SUBSEQUENTLY FOUND TO BE SUSCEPTIBLE TO AN ANTIBIOTIC THAT WAS ADMINISTERED WITHIN 24 HOURS OF THE SAMPLE COLLECTION TIME. ........................................................................................30
FIGURE 3. INCIDENCE AND RELATIVE RISK OF MORTALITY FOR INADEQUATE VERSUS ADEQUATE EMPIRIC ANTIBIOTIC THERAPY AMONG HOSPITALIZED SOLID-ORGAN TRANSPLANT RECIPIENTS..........................................................34
FIGURE 4. DELAY IN ADMINISTRATION OF ADEQUATE EMPIRIC ANTIBIOTIC THERAPY AND ASSOCIATED MORTALITY RATES. ................................................................................................................................................................43
viii
LIST OF APPENDICES APPENDIX I – LITERATURE REVIEW SEARCH STRATEGY .........................................................................................59 APPENDIX II – RAW DATA .......................................................................................................................................60 APPENDIX III – MULTIVARIATE LOGISTIC REGRESSION MODELLING ......................................................................66
ix
1
1.0
INTRODUCTION
Healthcare–associated infections (HAIs) are infections that patients acquire in a healthcare setting, during the course of receiving treatment for another condition (1). HAIs have imposed significant burdens on our healthcare system, leading to increased morbidity, mortality, and healthcare costs (2-4). As a result, the optimal management of HAIs has become an important healthcare concern. HAIs typically affect patients who are immunocompromised, either because of their age, underlying disease, or as a result of medical or surgical treatments (2). Along with an aging population, the growing use of medical and surgical interventions, including invasive devices and organ transplantation, have resulted in patients who are quite susceptible. The pathogens involved and the body sites of infection are often related to the treatments and devices used in intensive care units (ICUs). As a result, the highest infection rates are found among ICU patients, who experience approximately three times higher rates than patients found elsewhere in the hospital (2).
Upon clinical suspicion of infection, antibiotic therapy is often started early and empirically, before pathogen identification, and before antibiotic susceptibilities are known. Deciding on the use of an antibiotic requires a balance between the benefits of more potent broad-spectrum antibiotics against their costs, including the potential for increased antibiotic resistance rates caused by their overuse. Once the decision to initiate antibiotic therapy has been made, it should ideally be directed at the most likely causative pathogens, taking into account local antibiotic susceptibility patterns. As antibiotic resistance rates continue to increase, it appears that the likelihood of administrating inadequate empiric antibiotic therapy (IET) also increases (5;6). Most clinicians consider therapy to be inadequate when the antibiotic agent initiated
2 demonstrates poor or no in vitro activity against the causative pathogen at the tissue site of infection (7). Several studies concentrating on the consequences of IET have been conducted in the ICU setting (5;6;8-11), however little information exists concerning outcomes of inadequate empiric therapy among hospitalized solid-organ transplant (SOT) patients.
1.1
Statement of the Problem
1.1.1
Infection after Solid-Organ Transplantation
Infection in SOT patients is an important determinant of clinical outcomes (12), consequently, the treatment of acquired bacterial infections with antibiotic therapy is recognized as being an essential component in improving outcomes (13). Kidney, liver, heart, lung, pancreas, and small bowel transplantation has become a therapeutic option for many end-stage organ diseases. Advances in surgical techniques, medical management, and immunosuppressants have enhanced both graft and patient survival rates and quality of life, however, infection continues to be a major cause of morbidity and mortality among SOT recipients (14-19). The use of newer and more potent immunosuppressants, particularly induction therapy with agents such as antithymocyte globulin (ATG) and interleukin-2 receptor antagonists, increases the level of immunosuppression and leads to increased susceptibility to infection in the early post-transplant period (20). The incidence of bacterial infections in SOT recipients ranges from 21 to 68% depending on the organ(s) transplanted, although the severity of the infection can vary among the different SOT groups (20). In liver transplant patients, bacterial infections of the liver, peritoneal cavity, biliary tree, bloodstream, and surgical wound are common (18). Lung and heart transplant recipients are susceptible to pulmonary infections and bacteremias, of which 50% are of pulmonary origin during the first post-transplant year (21). Infections among kidney transplant patients include wound, bloodstream, and more commonly, urinary tract infections (UTIs)
3 (15;17;19;22;23). Severe infections, such as bacteremia, continue to pose an increased risk of death in transplant patients, with 14-day mortality rates ranging from 11% in kidney, 24% in liver, 33% in heart recipients (14), and a 28-day mortality rate of 25% in lung recipients (21).
1.1.2
Antibiotic Resistance
The spread and rapid increase in antibiotic resistance rates has become a serious worldwide healthcare concern (13). In 1946, Sir Alexander Fleming suggested that, “It seems likely that in the next few years a combination of antibiotics with different antibacterial spectra will furnish a cribrum therapeuticum from which fewer and fewer infecting bacteria will escape.” Despite the advent of these potent antibiotics, the emergence and spread of antibiotic-resistant bacteria has become a tremendous burden on our healthcare system. In 1970, the Centers for Disease Control (CDC) established the National Nosocomial Infections Surveillance (NNIS) system, which receives monthly reports of nosocomial infections from a non-random sample of hospitals in the United States (24). With nearly 300 institutions currently reporting, data from the NNIS system shows that the nosocomial infection rate remains relatively unchanged. However, the gradual decline in the duration of inpatient stays has increased the rate of nosocomial infections per 1,000 patient days by 36%, from 7.2 in 1975 to 9.8 in 1995 (2). In 2002, nosocomial infections accounted for nearly 1.7 million infections, resulting in excess of 98,000 deaths in the United States (2;25). More than 70 percent of the bacteria that cause these infections are resistant to at least one antibiotic that is commonly used to treat them (3). Drug-resistant infections can be significantly more expensive to treat than non-resistant infections because they tend to result in a longer duration of hospitalization, increased rates of readmission, higher drug costs, more posthospital care, lost work days, and increased mortality (3). Hospital-treated infections are
4 estimated to cost $260-553 million each year in Canada, however, resistant infections may add 2.8 times more than what a drug-susceptible infection adds to the direct cost of care (26).
The excessive and inappropriate use of antibiotic agents continues to be one of the most important factors affecting antibiotic resistance patterns (13;27). In more and more cases, bacteria are becoming resistant to multiple drugs, leaving clinicians with few effective therapies, if any. Bacteria demonstrating multiple drug resistance were found to be responsible for 48% of bloodstream infections in a cohort of lung transplant recipients (21). Antibiotic resistance in hospitals may be increasing as a result of several factors, including the proliferation and prolongation of broad-spectrum antibiotic use, grouping of patients with higher disease acuity in segregated wards or units, and decreased staffing leading to increased person-to-person transmission (28). Several studies have shown an association between previous antibiotic use and the development of resistance in both gram-negative and gram-positive bacteria, especially in specialized settings such as ICUs (29-31;31-33). Conversely, colonization and infection with antibiotic resistant bacteria, increases the likelihood of administering IET (5), leading one to believe that a circular and confounding relationship may exist between antibiotic use, resistance and IET. Moreover, for some patients who receive IET, altering their antibiotic therapy later in the course of infection, based on subsequent culture susceptibility results, may yield little benefit with respect to in-hospital mortality, suggesting that adequate early treatment is vital (8). Overall, it seems that infections caused by antibiotic resistant bacteria are more difficult to treat and are associated with higher mortality rates and hospital costs (13).
5 1.1.3
Inadequate Empiric Antibiotic Therapy
Pharmacological treatment with antibiotics demonstrating bacteriostatic or bactericidal activity against the causative pathogen remains the cornerstone of managing infectious diseases. The aim of in vitro antimicrobial susceptibility testing is to predict the in vivo success or failure of a panel of antibiotics at standard concentrations. The results of antimicrobial susceptibility testing combined with clinical information and experience, allows clinicians to select the most appropriate antibiotic. The safety and efficacy of antimicrobial agents in treating infections caused by specific pathogens must be established in well-controlled clinical trials or studies. The degree to which in vitro susceptibility results may or may not correlate with the in vivo efficacy of antimicrobials has been previously studied (34). Apart from the minimum inhibitory concentration (MIC) for a particular isolate, clinicians must consider patient, antimicrobial and pathogen-specific factors in determining how to best treat an infection. Achieving levels at or above the MIC by itself does not provide any information on persistent effects of antibacterial agents, such as the post-antibiotic effect. For moderate or severe infections, clinicians commonly initiate antibiotic therapy early and empirically, before the results of cultures and their respective antibiotic susceptibilities are known. Empiric therapy for patients with suspected or confirmed infections should be prescribed after considering patient symptoms, laboratory findings and the patient’s past medical history, in the context of appropriate local and wider antibiotic resistance trends. As a consequence, there is a possibility then that situations may arise where the chosen antimicrobial agent demonstrates poor or no in vitro activity against the identified causative pathogen. This condition can be considered to be one of inadequate empiric antibiotic therapy. Thus, prescribing empiric therapy demands a balance between the benefits of using agents that have a broader spectrum of in vitro susceptibilities that may correspond to the isolated
6 pathogen’s profile, against the current financial costs, potential side-effects, and future costs of developing resistance.
Several factors have been shown to be problematic in the selection of adequate antimicrobial therapy. First, the complexity of the drug selection process may seem confusing, presenting a difficult challenge to many clinicians. Selecting adequate therapy involves early recognition of infection in a patient that may present with several confounding signs and symptoms, identification of the causative pathogen, and prescribing of an antimicrobial regimen that is efficacious, cost-effective and poses minimal toxicity. In addition, the types of pathogens, along with antibiotic resistance patterns, have been shown to vary among different hospitals and even within in-hospital units, suggesting the need to develop unit-specific reporting systems (35;36). But until the susceptibility profile of the pathogen is known, antibiotic selection occurs through an empiric process, based on local sensitivity patterns and the patient’s clinical presentation. Infections caused by antibiotic resistant bacteria can lead to the problem of IET (37;38). To further this dilemma, some organisms have become resistant to a point where few or no treatment alternatives exist (39). The escalating concern with regard to antimicrobial resistance in the hospital setting has led several investigators to examine how this and other factors have influenced the prescribing of inadequate treatment. However, even after controlling for other contributing risk factors, it may still be difficult to determine whether delayed or inadequate therapy or antibiotic resistance has led to poor outcomes. To complicate issues further, humans who are able to produce an innate immune response, may rid themselves of the infection and thus seem to respond to inadequate therapy or even no treatment at all. Unfortunately, few studies to date have addressed the issue of IET use in SOT recipients and its relationship to clinical outcomes.
7 1.2
Purpose
To date, little work has been done with respect to the incidence and clinical importance of IET as a risk factor for hospital mortality in SOT recipients. The purpose of this study was two-fold. Firstly, to determine the scale of the problem of IET among a cohort of Canadian hospitalized SOT recipients. Secondly, this study aimed to examine the extent to which IET contributes to inhospital mortality among SOT patients. Determining the incidence and impact of IET in this population may help in the decision-making process of prescribing empiric antibiotic therapy, and perhaps justify the use of broad-spectrum empiric antibiotics in this population.
1.2.1
Objective 1
Our first objective was to determine the incidence of inadequate empiric antibiotic therapy among Canadian hospitalized SOT patients.
1.2.2
Objective 2
Our second objective was to determine whether IET and the duration of IET are clinically important risk factors for in-hospital mortality in SOT patients.
1.3
Statement of Research Hypothesis
Null Hypothesis: There is no statistically significant difference (p < 0.05) in hospital mortality between SOT recipients receiving adequate versus inadequate empiric antibiotic.
8
1.4
Rationale for Hypothesis
Although the view that early adequate therapy should improve survival seems plausible, few studies exist to support this assumption outside the ICU setting. Many of these studies specifically evaluated bacteremic ICU patients who had been prescribed IET, a possible confounder given that bloodstream infections have been found to be an independent predictor for mortality (5). The ICU setting includes a variety of pressures that are not as prevalent in other settings, influencing the emergence and spread of antibiotic resistance. One of these pressures includes patients with prolonged hospitalization who may harbour these organisms for the duration of their stay. The presence of invasive devices, such as urinary catheters and endotracheal tubes, along with prolonged mechanical ventilation may also promote infections with resistant bacteria (24;40). Severity of illness may also be an important confounder among ICU patients, and as such, use of broad-spectrum antibiotics early in the course of infection may have a greater impact in this population. While SOT recipients are immunocompromised and may share some of the qualities of ICU patients, in general, they are not as acutely ill, suggesting that IET may not contribute to an excess risk for in-hospital mortality among this cohort.
1.5
Review of the Literature
We performed a literature search of the National Library of Medicine using the OVID MEDLINE database to find original English-language articles published from 1950 to April 2007. The search strategy is outlined in Appendix I. The aim was to find publications that included IET as a primary independent variable of interest, and mortality as a dependent variable. We used terms related to antibiotic use or infection in addition to transplantation, critical illness, and hospitalization to define our population of interest. We limited the search
9 with keywords for adequate or inadequate therapy and outcomes related to morbidity or mortality. Additional articles referenced in publications found in the MEDLINE search were also included. IET was considered to be a primary exposure of interest if it was explicitly stated as such in the study objectives and it was forced into a multivariate statistical analysis. We only included publications that accounted for the administration of empiric therapy, as defined by the receipt of the final antibiotic sensitivity profile of the organism isolated from the index culture.
No studies that met the search criteria with SOT recipients as their primary population of interest were found. We did find two studies that described the administration of ‘discordant initial’ and ‘inactive’ antibiotic therapy among SOT patients (21;41). In a prospective cohort of 56 bacteremic lung transplant recipients, discordant therapy (defined as therapy that was inactive in vitro for the first two days following the index blood culture) occurred in 12/56 (21%) of the patients (21). Six of the 12 patients receiving discordant died within 28-days, compared to a mortality rate of 8/44 (18%) among patients receiving concordant therapy (21). Another prospective examination of 66 SOT recipients who developed septic shock, revealed that empiric therapy was inactive in vitro in 14/66 (21%) of the cases, with a mortality rate of 64% versus 52% for those receiving active empiric therapy (41). Neither study included inadequate empiric therapy as a primary exposure of interest nor did they include the term in the final multivariable analysis.
Table 1 summarizes 22 non-randomized comparative cohort studies that did assess the association between IET and mortality (5;6;10;11;38;42-58). Two of these studies did not report the 95% OR obtained from the multivariate analysis (53;58). The reported incidence of IET among these studies ranges from 10-80%. Many studies assessing the impact of inadequate
10 empiric antibiotic usage have focused on the ICU population and have yielded more or less similar conclusions about the importance of adequate therapy in bloodstream infections, including sepsis and septic shock, and ventilator-associated pneumonia (VAP). The majority of these studies have demonstrated that hospital mortality for critically ill patients receiving inadequate antibiotic treatment is significantly greater than those receiving adequate therapy (5;6;10;11;42;56). However, one study did not find adequate antibiotic treatment to be associated with a significant mortality benefit in critically ill patients (58). We extracted the reported multivariable regression analysis odds ratio along with the associated 95% confidence interval from each individual study. Figure 1 depicts a list of the individual studies’ multivariable regression analysis OR (95% CI), illustrating the association between inadequate antibiotic therapy and mortality at end of follow-up. Compared to non-critically ill settings, studies conducted in critically ill patients had a stronger trend towards favouring the use of adequate therapy.
11 Table 1. A summary of 22 non-randomized comparative cohort studies assessing the association between IET and mortality.
Study
Design1
Byl et al. (38), 1999
P
Clec’h et al. (42), 2004
P
Fraser et al. (43), 2006
P
Harbarth et al. (44), 2003
P
Hyle et al. (45), 2005
R
Ibrahim et al. (6), 2000 Iregui et al. (11), 2002
P
Patient population
Infection/ pathogens
417 episodes 361 patients Tertiary care hospital 196 episodes 142 patients Six ICUs 895 patients 3 tertiary care hospitals 904 patients 108 hospitals
Bacteremia
Inadequate therapy definition 24 h
Inadequate therapy incidence 159/428 (37%)
Mortality definition Attributable in-hospital mortality
Mortality (adequate vs. inadequate therapy) 33/258 (13%) vs. 24/159 (15%)
Multivariable regression analysis OR (95% CI) 2.22 (1.09 - 4.55)
VAP
24 h
109/196 (56%)
In-hospital mortality
30/63 (48%) vs. 41/79 (52%)
7.24 (1.48-35.5)
All bacterial infections
24 h
319/895 (36%)
30-day mortality
68/576 (12%) vs. 64/319 (20%)
1.58 (0.99-2.54)
Severe sepsis or septic shock
24 h
211/904 (23%)
28-day mortality
168/693 (24%) vs. 82/211 (39%)
1.8 (1.2-2.6)
187 patients 2 Tertiary care hospitals 492 patients ICU
ESBL E. coli & Klebsiella species Bacteremia
48 h
112/187 (60%)
In-hospital mortality
8/75 (11%) vs. 24/112 (21%)
0.69 (0.19-2.53)
>72 h
147/492 (30%)
In-hospital mortality
98/345 (28%) vs. 91/147 (62%)
6.86 (5.09-9.24)
P
107 patients ICU
VAP
24 h
33/107 (31%)
8/74 (11%) vs. 13/33 (39%)
7.68 (4.50-13.09)
Kang et al. (46), 2005
R
Gram-negative bacteremia
24 h
151/286 (53%)
37/135 (27%) vs. 58/151 (38%)
3.64 (1.13-11.72)
Kim et al. (47), 2006
R
S. aureus bacteremia
48 h
117/238 (49%)
1.39 (0.62-3.15)
P
All bacterial infections
>72 h
169/655 (26%)
59/486 (12%) vs. 88/169 (52%)
4.26 (3.35-5.44)
Leibovici et al. (10), 1998 Lodise et al. (48), 2003
P
Bacteremia
48 h
1255/3440 (36%)
12-week attributable mortality Attributable in-hospital mortality In-hospital mortality
34/121 (28%) vs. 45/117 (39%)
Kollef et al. (5), 1999
286 patients Tertiary care hospital 238 patients Tertiary care hospital 655 patients ICU
Attributable in-hospital mortality 30-day mortality
436/2158 (20%) vs. 432/1255 (34%)
1.6 (1.3-1.9)
S. aureus bacteremia
48 h
48/167 (29%)
Attributable mortality
23/119 (19%) vs. 16/48 (33%)
3.8 (1.3-11.0)
R
3413 patients Tertiary care hospital 167 patients Level 1 trauma centre
12 Study
Design1
Lujan et al. (49), 2004
P
Micek et al. (50), 2005
R
Osih et al. (51), 2007
R
Paterson et al. (52), 2003 Roghmann (53), 2000
P R
Scarsi et al. (54), 2006
R
Schramm et al. (55), 2006 Valles et al. (56), 2003
R
Vidal et al. (57), 1996
P
Zaragoza et al. (58), 2003
P
1
P
Patient population 100 patients Tertiary care hospital 305 patients Tertiary care hospital 167 episodes 159 patients Tertiary care hospital 85 patients 12 hospitals 132 episodes 125 patients Tertiary care hospital 884 patients Tertiary care hospital 549 patients Tertiary care hospital 339 patients 30 ICUs 189 episodes 182 patients Tertiary care hospital 166 patients ICU
P = Prospective; R = Retrospective
Inadequate therapy definition 24 h
Inadequate therapy incidence 10/100 (10%)
P. aeruginosa bacteremia
>72 h
P. aeruginosa bacteremia
24 h
Infection/ pathogens S. pneumoniae bacteremia
28-day mortality
Mortality (adequate vs. inadequate therapy) 13/90 (14%) vs. 5/10 (50%)
Multivariable regression analysis OR (95% CI) 5.72 (0.72-45.26)
75/305 (25%)
In-hospital mortality
41/230 (18%) vs. 23/75 (31%)
2.04 (1.42-2.92)
68/167 (41%)
In-hospital mortality
35/99 (35%) vs. 26/68 (38%)
0.93 (0.45-1.92)
11/82 (13%)
14-day mortality
10/71 (14%) vs. 7/11 (64%)
11.11 (1.54-100)
Mortality definition
ESBL K. pneumoniae
>72 h
S. aureus bacteremia
48 h
105/132 (80%)
30-day mortality
28/102 (27%) vs. 5/23 (22%)
Not reported
Gram-negative bacteremia
24 h
125/884 (14%)
In-hospital mortality
122/759 (16%) vs. 17/125 (14%)
0.61 (0.31-1.18)
MRSA sterilesite infections
24 h
380/549 (69%)
In-hospital mortality
28/169 (17%) vs. 99/380 (26%)
1.92 (1.48-2.50)
Communityacquired bacteremia P. aeruginosa bacteremia
24 h
49/339 (14%)
In-hospital mortality
107/290 (37%) vs. 34/49 (69%)
4.11 (2.03-8.32)
>72 h
19/189 (10%)
All-cause mortality
24/170 (14%) vs. 10/19 (53%)
6.53 (1.10 - 48.80)
>72 h
39/166 (23%)
Attributable mortality
29/127 (23%) vs. 12/39 (31%)
Not reported
Bacteremia
13
Figure 1. Individual multivariable regression analysis OR (95% CI) of 20 non-randomized comparative studies illustrating the association between inadequate antibiotic therapy and mortality at end of follow-up. Studies conducted in critically ill units are shown separately near the bottom.
14 One of the earliest studies assessing the relationship between inadequate antibiotic treatment and hospital mortality, evaluated a prospective cohort of 2,000 patients admitted over an 8-month period to the medical or surgical ICU of a large urban teaching hospital in St. Louis, Missouri. Inadequate antimicrobial treatment was defined as the microbiological documentation of a pathogen causing infection, which was not effectively treated at the time of its identification. This included both the absence of antimicrobial agents and the administration of an agent to which the pathogen was resistant. Comparisons were made between patients receiving inadequate and adequate therapy and hospital survivors to non-survivors. Multiple logistic regression analysis was used to evaluate the relationship between the dependent variable of hospital mortality and the independent variable of inadequate treatment and to identify independent risk factors for the administration of inadequate treatment. Of the 655 patients with a nosocomial or community-acquired infection, 169 (25.8%) were found to have received inadequate antibiotic treatment. The infection-related mortality rate for infected patients receiving inadequate therapy (42.0%) was significantly greater than patients receiving adequate antibiotic treatment (17.7%) (RR, 2.37; 95% CI, 1.83 to 3.08; p < 0.001). In addition, a logistic regression model demonstrated that inadequate antibiotic treatment was the most important independent determinant of hospital mortality (adjusted OR, 4.27; 95% CI, 3.35 to 5.44; p < 0.001). The incidence of inadequate antimicrobial treatment was most common among patients with nosocomial infections, which developed after treatment of a community-acquired infection (45.2%), followed by patients with nosocomial infections alone (34.3%) and patients with community-acquired infections alone (17.1%) (p < 0.001). Among patients with nosocomial infections, inadequate therapy occurred most commonly as a result of Gram-negative bacteria that were resistant to third-generation cephalosporins. Inadequate treatment for methicillinresistant Staphylococcus aureus (MRSA), Candida species and vancomycin-resistant enterococci
15 (VRE) were also commonly found among nosocomial infections. Multiple logistic regression analysis revealed that the prior administration of antibiotics (adjusted OR, 3.39; 95% CI, 2.88 to 4.23; p < 0.001), presence of a bloodstream infection (adjusted OR, 1.88; 95% CI, 1.52 to 2.32; p = 0.003), increasing Acute Physiology and Chronic Health Evaluation (APACHE) II scores in 1point increments (adjusted OR, 1.04; 95% CI, 1.03 to 1.05; p = 0.002), and decreasing patient age (adjusted OR, 1.01; 95% CI, 1.01 to 1.02; p = 0.012) were independently associated with the administration of inadequate antibiotic treatment. This study established an association between the prescribing of inadequate therapy and hospital mortality, and demonstrated that previous antibiotic use may be an important risk factor for inadequate therapy among ICU patients.
Continuing the work of Kollef et al., Ibrahim et al. prospectively evaluated the relationship between the adequacy of antimicrobial treatment for bloodstream infections and the primary outcome of hospital mortality among a cohort of patients at the same university-affiliated urban teaching hospital. All patients admitted to the medical or surgical ICU were eligible for enrolment. Inadequate antimicrobial treatment was defined as the microbiological documentation of a pathogen causing infection, both bacterial and fungal, which was not effectively treated at the time the pathogen and its susceptibility profile were known. The primary analysis compared hospital survivors to non-survivors. Multiple logistic regression analysis was used to evaluate the relationship between the dependent variable of hospital mortality and the independent variable of inadequate antimicrobial treatment and to identify independent risk factors for the administration of inadequate treatment. Over a two-year period, 4913 critically ill patients were admitted, of whom 492 (10.0%) were found to have a bloodstream infection. Of the 492 patients, 147 (29.9%) received inadequate treatment. Furthermore, the hospital mortality for these patients was significantly greater than those receiving adequate therapy (61.9% vs. 28.4%; RR, 2.18; 95% CI,
16 1.77 to 2.69; p < 0.001). Multiple logistic regression analysis identified the administration of inadequate antibiotic treatment as an independent risk factor hospital mortality (adjusted OR, 6.86; 95% CI, 5.09 to 9.24; p < 0.001). The most commonly identified bloodstream pathogens along with their rates of inadequate antimicrobial treatment included: VRE (n = 17; 100%), Candida species (n=41; 95.1%), MRSA (n = 46; 32.6%), coagulase-negative staphylococci (CNS) (n = 96; 21.9%), and Pseudomonas aeruginosa (n = 22; 10.0%). A statistically significant correlation was found between the rates of inadequate antimicrobial treatment for individual micro-organisms and their associated rates of hospital mortality (Spearman’s correlation coefficient 0.8287; p=0.006). However, some organisms, such as Escherichia coli and Klebsiella species, were found to be associated with relatively low rates of inadequate antimicrobial therapy, though their associated hospital mortality rates were greater than 30%. Multiple logistic regression analysis also demonstrated that the following criteria were independently associated with the administration of inadequate antimicrobial treatment: Bloodstream infection attributable to Candida species (adjusted OR, 51.86; 95% CI, 24.57 to 109.49; p < 0.001); Prior administration of antibiotics during the current hospital stay (adjusted OR, 2.08; 95% CI, 1.58 to 2.74; p = 0.008); Decreasing serum albumin concentrations (adjusted OR, 1.37; 95% CI, 1.21 to 1.56; p = 0.014); Increasing central catheter duration (adjusted OR, 1.03; 95% CI, 1.02 to 1.04; p = 0.008). The study demonstrated that ICU patients with bloodstream infections receiving inadequate antimicrobial treatment were at an increased risk of death compared to patients receiving adequate treatment. The authors recommended initial empiric therapy with vancomycin for MRSA and CNS, along with combination therapy for the treatment of P. aeruginosa.
17 Most studies with bacteremia seem to support the importance of adequate empiric therapy, however, there are a few studies that do not come to this conclusion (51;54;58). These studies may include certain groups of organisms that may be less virulent and thus it may be more problematic in determining their role in morbidity or mortality. One such cohort study in Spain was conducted among 166 prospectively followed patients with bacteremia, 39 (23.5%) of which received inadequate antibiotic treatment, while 127 (76.5%) received adequate treatment (58). Bacteremia was determined to be nosocomial in nature in 92.3% of the inadequately treated cohort, and 79.5% of adequately treated group. The occurrence of coagulase-negative staphylococci isolates (OR, 2.62; 95% CI, 1.10 to 6.21; p = 0.015), and absence of a respiratory or abdominal source of infection (OR, 0.35; 95% CI, 0.12 to 0.97; p = 0.04) was greater in the cohort with inadequate treatment than in the group with adequate treatment. Neither crude mortality rates (56.4% vs. 50.3%; p = 0.512) nor bacteremia-related mortality rates (30.8% vs. 22.8%; p = 0.315) were significantly different among the inadequately and adequately treated groups, respectively. Multivariate analysis did not reveal inadequate treatment to be an independent predictor of mortality. The authors suggested that this was likely a result of microbiological factors and clinical features, such as the types of micro-organisms isolated and the sources of the bacteremia. Cultures from patients in the inadequately treated arm were more likely to have grown less virulent isolates and to have been sampled from sources of infections with typically better prognoses. As a result, this tended to dilute the effects on mortality, and produce a statistically non-significant difference.
In an application to non-critically ill patients, Leibovici et al. set out to determine whether empiric antibiotic treatment matching the in vitro susceptibility of the pathogen, which they termed as being appropriate treatment, improved survival in hospitalized patients with
18 bloodstream infections. This prospective and observational cohort study examined patients with bloodstream infections identified between 1988 and 1994 in an urban hospital in Israel. Empirical antibiotic treatment was defined as appropriate if it was started within two days of the first positive blood culture, and the infecting micro-organism was subsequently found to be susceptible to an intravenously administered drug. However, the authors decided that treatment of a pseudomonal infection with just an aminoglycoside would be considered inappropriate. This study analyzed the benefit presented by appropriate empiric treatment in stratified subgroups of patients defined by a set of other mortality risk factors. Logistic regression analysis was used to measure the independent contribution of inappropriate treatment to hospital mortality. Of the 3415 patients identified with bloodstream infections, 2158 (63.2%) were given appropriate empiric antibiotic treatment, of which 436 (20.2%) died, compared with the death of 432 (34.4%) of 1255 patients who were given inappropriate treatment (OR, 2.1; 95% CI, 1.8 to 2.4; p = 0.0001). The median duration of hospital stay for survivors was 9 days when given appropriate treatment and 11 days when given inappropriate treatment (p = 0.0001). The greatest relative reduction in the mortality rate associated with appropriate treatment versus inappropriate treatment in patients was seen most commonly in: Pediatric patients (4% vs. 17%; OR, 5.1; 95% CI, 2.4 to 10.7); Intra-abdominal infections (12% vs. 34%; OR, 3.8; 95% CI, 2.0 to 7.1); Skin and soft tissue infections (23% vs. 49%; OR, 3.1; 95% CI, 1.8 to 5.6); Infections caused by Klebsiella pneumoniae (17% vs. 39%; OR, 3.0; 95% CI, 1.7 to 5.1), and Streptococcus pneumoniae (22% vs. 42%; OR, 2.6; 95% CI, 1.1 to 5.9). Multivariable logistic regression analysis revealed that inappropriate empiric treatment was associated with a significant risk for in-hospital mortality (adjusted OR, 1.6; 95% CI, 1.3 to 1.9) independent of other risk factors. The investigators concluded that in this relatively large cohort of hospitalized patients with
19 bloodstream infections, inappropriate empiric treatment was associated with an increased risk of death, regardless of concomitant risk factors for mortality.
Infections resulting from certain groups of organisms, such as antibiotic-resistant gram-negative bacilli, have become more of a concern in recent years, as patients infected by these relatively virulent isolates may be at a higher risk of receiving inadequate therapy (45;46;52;55). To evaluate the effect of inappropriate initial antimicrobial therapy on mortality, Kang et al. retrospectively reviewed 286 hospitalized patients in Seoul, South Korea. They identified and included patients with nosocomial antibiotic-resistant gram-negative bacteremia: 61 patients with E. coli, 65 with K. pneumoniae, 74 with P. aeruginosa, and 86 with Enterobacter species. Initial antibiotic therapy was considered to have been appropriate if a patient received at least one agent within 24 hours of blood culture collection to which the causative pathogens were susceptible. Only the first bacteremic episode per patient was included. Antibiotic resistance was defined as in vitro resistance to either cefotaxime or ceftazidime, except for P. aeruginosa, which was required to be resistant to either piperacillin, ciprofloxacin, ceftazidime, or imipenem. High-risk sources of bacteremia were defined as the lung, peritoneum, or an unknown source. The main outcome measure was 30-day mortality. Of the 286 patients, 135 (47.2%) received appropriate initial empirical antimicrobial therapy, with the remaining 151 (52.8%) patients receiving inappropriate therapy. The inadequately treated group had a significantly greater mortality rate compared to the adequately treated cohort (38.4% vs. 27.4%; p=0.049). Multivariate analysis demonstrated that septic shock, a high-risk source of bacteremia, P. aeruginosa infection, and an increasing APACHE II score, were independent risk factors for mortality. In a subgroup analysis of patients with a high-risk source of bacteremia (n = 132), inappropriate initial antimicrobial therapy was independently associated with decreased survival (adjusted OR, 3.64; 95% CI, 1.13
20 to 11.72; p = 0.030). The results of this study suggest that inappropriate initial antimicrobial therapy is associated with adverse outcomes in patients diagnosed with antibiotic-resistant gramnegative bacteremia, specifically in those that are severely ill, have a high-risk source of bacteremia, or have isolates that are especially virulent.
Some evidence suggests that when adequate empiric antibiotic therapy (AET) is initiated early in the course of the infection and prior to the availability of susceptibility results, the associated mortality rates are significantly lower (8;11;48;55;59). Iregui et al. fixed their efforts on the clinical importance of delayed initial appropriate antibiotic treatment in critically ill patients with clinically diagnosed VAP. Their goals were to identify the occurrence of initially delayed appropriate antibiotic treatment for VAP, and to determine its effects on patient outcomes. They prospectively observed a cohort of patients requiring mechanical ventilation and admitted to the medical ICU of a large urban teaching hospital in St. Louis, Missouri. The primary outcome compared hospital mortality among those receiving initially delayed appropriate antibiotic treatment to all other patients in the cohort. Adequate initial treatment was defined as an antibiotic with in vitro susceptibility to the pathogen isolated in respiratory samples. Delayed therapy was defined as a time period of >24 hours between the time of VAP diagnosis, until the time that appropriate antibiotic therapy was administered. Thirty-three of 107 (30.8%) patients received appropriate antibiotic therapy that was delayed >24 hours after the clinical diagnosis of VAP. The most common cause of inadequate initial treatment was a delay in writing the medical orders (n = 25; 75.8%). The presence of a resistant micro-organism (n = 6) accounted for 18.2% of cases. Among these patients, the mean time delay between VAP diagnosis and the administration of an appropriate antibiotic was 28.6 ± 5.8 hours, compared to 12.5 ± 4.2 hours for all other patients (p < 0.001). Patients with initially delayed treatment had a significantly
21 greater hospital mortality compared to the other patients in the cohort (69.7% vs. 28.4%; p < 0.01). It is important to note that diagnostic delays were not counted, and that the authors utilized a clinical VAP diagnosis as opposed to using bronchoscopically obtained cultures. It was suggested that clinicians avoid delaying the administration of appropriate antibiotic therapy to patients with VAP to minimize their mortality risk.
The extent to which the timely use of adequate therapy impacts clinical outcomes in hospitalized patients may depend on the causative pathogens and populations studied, but may also depend on the actual time delay itself. In a study of episodes of nosocomial S. aureus bacteremia, Lodise et al. attempted to determine the effect of delayed therapy on morbidity and mortality in a retrospective cohort of 167 hospitalized patients at a trauma centre in Detroit, Michigan. If a patient had more than one episode of S. aureus bacteremia during a hospitalization, only the first episode was included. Classification and regression tree analysis was utilized to select the time interval (from the time the culture result was obtained until administration of adequate therapy) that classified patients as having either a low-risk or high-risk of infection-related mortality. The time breakpoint between delayed and early treatment was determined to be 44.75 hours. Accordingly, 48 (28.7%) patients did not receive appropriate treatment prior to the breakpoint time and were deemed to have received delayed treatment. The remaining 119 (71.3%) patients did receive appropriate treatment within 44.75 hours, and were classified into the early treatment group. A comparison of the infection-related mortality rates between the two groups revealed a 1.7-fold increase among patients receiving delayed therapy versus early treatment (33.3% vs. 19.3%; p = 0.05). A multivariate analysis revealed that delayed treatment was an independent predictor of infection-related mortality (adjusted OR, 3.8; 95% CI, 1.3 to 11.0; p = 0.01) and was associated with a longer hospital stay than early treatment (20.2 vs. 14.3 days; p = 0.05). For
22 patients with an APACHE II score >15.5 and a ‘high-risk’ source of infection (non-IV catheter related), mortality was 86.7% in the delayed treatment group compared with 44.7% in the early treatment group (p = 0.006). However, among patients with an APACHE II score 38°C), chills, or hypotension; and a positive culture from two or more blood cultures drawn on separate occasions, or from at least one blood culture from a patient with an intravascular line, with the physician instituting appropriate antimicrobial therapy (62). Otherwise, infection was defined as the entry and multiplication of micro-organisms in the tissues of the host leading to local or systemic signs and symptoms of infection. We defined colonization as the presence of micro-organisms in or on a host with growth and multiplication, but without tissue invasion or damage. Only true infections were included among the infectious episodes.
28 2.4.2
Infectious Episodes
An infectious episode was defined by the first true positive bacterial (index) culture collected per isolate per patient, or when identical isolates are cultured within 72 hours of each other, the culture collected from the primary body site of infection. The CLSI recommendation to exclude duplicates and include only the first isolate of a given species per patient, irrespective of body site or antibiotic pattern, was implemented (64).
2.4.3
Healthcare vs. ICU vs. Community Associated Infections
Each infectious episode was classified as being healthcare (nosocomial), ICU, or communityassociated, according to criteria established by the CDC (62). The NNIS system defines an HAI as a localized or systemic condition that results from an adverse reaction to the presence of an infectious agent or its toxin; and that was not present or incubating at the time of admission to a healthcare setting (1). For the purposes of this study, the infection must become evident (i.e. result in a positive culture) 48 hours or more post-admission to a non-ICU ward, unless the patient had been hospitalized within 30 days before admission, or had been transferred from another hospital or long-term care facility. Otherwise, positive cultures obtained within 48 hours of admission were categorized as being community-associated. An ICU-associated infection was defined as a positive culture drawn 48 hours after admission to the ICU or within 48 hours after transfer from the ICU (24).
2.4.4
Primary Site of Infection
The primary site of infection was confirmed by culture, clinical evidence, or not confirmed. If confirmed, the site of infection was categorized as one of the following, according to established CDC criteria (62): Pneumonia or lower respiratory tract infection; Urinary tract infection;
29 Bloodstream or IV catheter infection (e.g. central venous catheter); Central nervous system infection; Skin and soft tissue infection; Intra-abdominal infection; and Cardiovascular system infection. If the site was unconfirmed or determined solely by clinical evidence, then it was classified as ‘Other’.
2.4.5
Empiric Antibiotic Therapy
A multidisciplinary team of physicians and pharmacists determined requirements for antibiotic treatment and selection of specific antibiotics during the patients’ hospital course. Antibiotic therapy was defined as empirical when administered in response to an infectious episode, but before organism identification and susceptibility results were available.
2.4.6
Adequate vs. Inadequate Empiric Antibiotic Therapy
Empiric antibiotic therapy was critically assessed starting from the date of an infectious episode (index culture), up to the date of patient discharge from the hospital (Figure 2). Therapy was considered adequate when, for a given infectious episode, the organism cultured was subsequently found to have in vitro susceptibility to an antibiotic that was administered within 24 hours of the index culture collection time. A 24 hour period after cultures are taken was used as the cut-off point given that some evidence points to this period as being important for reducing mortality rates when adequate therapy is prescribed (8;11;48;55). Additionally, the patient must receive at least 3 days of therapy. Patients were classified into the inadequate therapy group if they had experienced at least one episode of inadequate empiric therapy during their hospital stay.
30
Adequate vs. Inadequate
Initiate empiric therapy + samples taken
Continue/change initial empiric therapy
24 hours
Time Patient admitted
Symptoms/clinical suspicion
Culture results
End of symptoms
Discharge or death
Figure 2. An illustration depicting the timeline for determining inadequate empiric antibiotic therapy. Therapy was considered adequate when, for a given infectious episode, the organism cultured was subsequently found to be susceptible to an antibiotic that was administered within 24 hours of the sample collection time.
2.4.7
Previous Antibiotic Therapy
Oral and intravenous antibiotics prescribed for patients for at least 3 days and up to 30 days prior to their hospital admission were recorded.
2.4.8
Previous Graft Rejection and Immunosuppressant Use
Previous episodes of graft rejection and anti-thymocyte globulin or basiliximab use were recorded for a period of up to six months prior to the patients’ admission date. Since all patients would be receiving maintenance immunotherapy, we limited data collection to these two potent immunosuppressants as they may have a greater effect on infection-related outcomes (15).
31 2.4.9
Multi-Drug Resistance
Some bacteria are inherently resistant to specific antibiotics. Organisms found to have in vitro resistance to two or more antibiotics to which they would normally be susceptible, were classified as being multi-drug resistant. The Sanford Guide to Antimicrobial Therapy was used as a reference in determining normal susceptibility patterns (65).
2.5
Outcomes
We compared the primary outcome of in-hospital all-cause mortality between those receiving adequate versus those receiving inadequate empiric antibiotic therapy. Secondary outcomes included duration of hospital stay (defined as the number of days from admission to discharge or death), need for ICU transfer, and duration of stay in the ICU.
2.6
Statistical Analysis
All data were collected and entered into a computerized database using Microsoft Access® (Microsoft Corporation, Redmond, WA) and analyzed using SPSS 14.0® (SPSS Incorporated, Chicago, Ill). Categorical data were compared using Fisher’s exact test, and normally distributed continuous variables were compared using the Student’s t-test. Alternatively, depending on the validity of the normality assumption, the Wilcoxon rank sum test was also utilized. All comparisons were unpaired, all tests of significance two-tailed, and equal variances were not assumed. Values are expressed as the mean ± standard deviation for continuous variables or as a proportion for categorical variables. Relative risks are reported along with their 95% confidence intervals. P-values of ≤ 0.05 were considered to be statistically significant. The primary data analysis compared infected patients who received inadequate antibiotic treatment to infected
32 patients receiving adequate antibiotic treatment. Binary logistic regression analysis was used to determine independent associations for the dependent outcome variable of in-hospital all cause mortality. Building of the model began with forced inclusion of IET as the exposure of interest. All clinically plausible variables with p0.999 0.515 0.121 0.065 >0.999
36 Table 3. Characteristics of true infectious episodes treated with adequate (AET) or inadequate empiric antibiotic therapy (IET) AET
IET
p
No. of Positive Cultures
326
(%)
248
(%)
Primary source Pulmonary Urinary Bloodstream/IV Catheter CNS Cardiovascular Intra-Abdominal Skin/Soft Tissue Other
100 72 39 0 2 25 20 68
(30.7) (22.1) (12.0) (0.0) (0.6) (7.7) (6.1) (20.9)
47 69 16 2 0 42 26 46
(19.0) (27.8) (6.5) (0.8) (0.0) (16.9) (10.5) (18.5)
0.002 0.142 0.031 0.187 0.508 24h after sample GPB therapy initiated >24h after sample (Other) GPB therapy initiated >24h after sample (CNS) GNB resistant to other empiric therapy GNB resistant to 3rd-Generation Cephalosporins GNB resistant to Ciprofloxacin GPB resistant to penicillins No GPB-specific antibiotic initiated TOTAL • • •
3.3
No.
(%)
85 53 39 24 14 13 11 9
(34.2) (21.4) (15.7) (9.7) (5.6) (5.2) (4.4) (3.6)
248
GNB = Gram-negative bacteria GPB = Gram-positive bacteria CNS = Coagulase-negative staphylococci
Characteristics Related to Hospital Mortality
Of the 312 patients evaluated, 52 did not survive their in-hospital stay. Univariate analyses revealed that lung transplant recipients (50.0% vs. 26.2%; p < 0.001), prior antibiotic use (69.2% vs. 44.2%; p < 0.001), and ICU-associated infections (59.1% vs. 16.3%; p < 0.001) were more likely to be associated among the 52 nonsurvivors (Tables 8 and 9). The in-hospital mortality rate for patients receiving at least one episode of inadequate empiric therapy was significantly greater than those receiving adequate therapy (24.9% vs. 7.0%; RR, 3.55; 95% CI, 1.85 to 6.83; p < 0.001; Figure 3). Furthermore, there was a significant association between increasing time to administration of adequate empiric therapy (measured in 24 hour increments) and increased hospital mortality rates (Figure 4). During the same two-year period, the mean mortality rate for all patients admitted to the transplant unit was 4.7%. Organisms cultured from patients receiving IET and their associated mortality rates are shown in Table 10. The most commonly cultured pathogens among non-survivors included Pseudomonas sp., Enterococcus sp., Escherichia coli, Citrobacter sp., Klebsiella sp., and Enterobacter cloacae.
41 Table 8. Patient characteristics among hospital survivors and nonsurvivors Nonsurvivors No. of Patients Age (yrs) Gender Male Female Diabetes requiring insulin
52
Survivors (%)
51.0 ± 13.3
260
p (%)
51.0 ± 12.5
0.995
31 21 2
(59.6) (40.4) (3.8)
166 94 16
(63.8) (36.2) (6.2)
0.637
Dialysis
4
(7.7)
27
(10.4)
0.799
Acute renal failure Neutropenia
3
(5.8)
13
(5.0)
0.736
2
(3.8)
8
(3.1)
0.675
Central IV catheter
37
(71.2)
72
(27.7)
0.999 0.321
Previous antibiotic use Carbapenems Aminoglycosides Macrolides Fluoroquinolones Piperacillin-Tazobactam Penicillins 3rd/4th Gen. Cephalosporins 1st/2nd Gen. Cephalosporins Cotrimoxazole
36 5 6 5 18 1 1 4 3 15
(69.2) (9.6) (11.5) (9.6) (34.6) (1.9) (1.9) (7.7) (5.8) (28.8)
115 8 16 15 41 4 8 13 3 50
(44.2) (3.1) (6.2) (5.8) (15.8) (1.5) (3.1) (5.0) (1.2) (19.2)
0.999 >0.999 0.499 0.060 0.135
42 Table 9. Culture characteristics among hospital survivors and nonsurvivors Nonsurvivors No. of Positive Cultures Primary source Pulmonary Urinary Line CNS Endocardium Intra-Abdominal Skin/Soft Tissue Other Bacteremia Gram Negative Cultures Multi-drug resistant organisms Location acquired Nosocomial ICU Community
Survivors
p
132
(%)
442
(%)
42 28 16 0 1 17 7 21 46 75 68
(31.8) (21.2) (12.1) (0.0) (0.8) (12.9) (5.3) (15.9) (34.8) (56.8) (51.5)
106 113 39 2 1 50 39 93 153 226 187
(24.0) (25.6) (8.8) (0.5) (0.2) (11.3) (8.8) (21.0) (34.6) (51.1) (42.3)
0.089 0.357 0.311 >0.999 0.407 0.643 0.272 0.216 >0.999 0.276 0.072
48 78 6
(36.4) (59.1) (4.5)
287 72 83
(64.9) (16.3) (18.8)
0.999
Pseudomonas aeruginosa
5/45
(11.1)
14/32
(43.8)
0.003
1/7
(14.3)
0/5
(0.0)
>0.999
Organism Acinetobacter species
Serratia sp.
43
p=0.001
80
P=0.049
70
p72
Time to administration of adequate empiric therapy (h)
Figure 4. Delay in administration of adequate empiric antibiotic therapy and associated mortality rates.
3.4
Logistic Regression Analysis
Binary logistic regression analysis was conducted to determine independent risk factors for hospital mortality (Table 11). Increasing time to administration of adequate empiric antibiotic therapy (per one hour increment) was found to be an independent determinant of in-hospital mortality (adjusted OR, 1.01; 95% CI, 1.006 to 1.018; p < 0.001). ICU-associated infections (adjusted OR, 6.27; 95% CI, 2.79 to 14.09; p < 0.001), antibiotic use 30 days prior to admission (adjusted OR, 3.56; 95% CI, 1.51 to 8.41; p = 0.004), and an increasing APACHE II score (adjusted OR, 1.26; 95% CI, 1.16 to 1.34; p < 0.001), were also identified as independent predictors of hospital mortality. Raw data and detailed results of the binary logistic model are found in Appendices II and III respectively.
44 Table 11. Logistic regression analysis predicting hospital mortality Predictor
B
Wald χ2
P-value
Adjusted Odds Ratio
95% CI Lower
Upper
IET (1 hour increment)
0.012
14.311
