Inadequate Empiric Antibiotic Therapy

Inadequate Empiric Antibiotic Therapy
Mazen Kherallah, MD, FCCP King Faisal Specialist Hospital & Research Center

Terms Infection SIRS Bacteremia and BSI Sepsis Severe sepsis

Sepsis Syndromes 1992: SCCM/ACCP
Parasite Severe Sepsis Virus Infection SIRS Sepsis Fungus Severe SIRS Trauma Shock Bacteria BSI Burns

The Sepsis Continuum SIRS Sepsis Severe Sepsis Infection/ Trauma
A clinical response arising from a nonspecific insult, including 2 of the following: Temperature 38oC or 36oC HR 90 beats/min Respirations 20/min WBC count 12,000/mm3 or 4,000/mm3 or >10% immature neutrophils SIRS due to Infection Most normal cells have two copies of the HER2 gene and small amounts of HER2 protein on their surfaces (Hynes and Stern, 1994). For reasons not currently known, cells may produce many copies of the HER2 receptor, a condition known as overexpression. HER2 protein overexpression is associated with increased cell division and a high rate of tumor growth. It may also be associated with transformation to the cancer cell phenotype (Kraus et al, 1987; DiFiore et al, 1987; Hudziak et al, 1987). HER2 protein overexpression has been reported in malignancies other than breast cancer, including ovarian cancer (Slamon et al, 1989) gastric cancer (Yonemura et al, 1991) colon cancer (Holzmann et al, 1992) endometrial cancer (Hetzel et al, 1992; Saffari et al, 1995) lung cancer (Kern et al, 1993; Pastorino et al, 1993) salivary gland cancer (Press et al, 1994) pancreatic cancer (Peiper et al, 1997) prostate cancer (Ross et al, 1997; Zhang et al, 1998) The significance of HER2 protein overexpression in these cancers is not yet known. SIRS = systemic inflammatory response syndrome. Bone et al. Chest. 1992;101:1644.

The Sepsis Continuum SIRS Sepsis Severe Sepsis Infection/ Trauma
Sepsis with 1 sign of organ dysfunction *Cardiovascular (refractory hypotension) *Renal *Respiratory *Hepatic *Hematologic *CNS *Unexplained metabolic acidosis Shock Most normal cells have two copies of the HER2 gene and small amounts of HER2 protein on their surfaces (Hynes and Stern, 1994). For reasons not currently known, cells may produce many copies of the HER2 receptor, a condition known as overexpression. HER2 protein overexpression is associated with increased cell division and a high rate of tumor growth. It may also be associated with transformation to the cancer cell phenotype (Kraus et al, 1987; DiFiore et al, 1987; Hudziak et al, 1987). HER2 protein overexpression has been reported in malignancies other than breast cancer, including ovarian cancer (Slamon et al, 1989) gastric cancer (Yonemura et al, 1991) colon cancer (Holzmann et al, 1992) endometrial cancer (Hetzel et al, 1992; Saffari et al, 1995) lung cancer (Kern et al, 1993; Pastorino et al, 1993) salivary gland cancer (Press et al, 1994) pancreatic cancer (Peiper et al, 1997) prostate cancer (Ross et al, 1997; Zhang et al, 1998) The significance of HER2 protein overexpression in these cancers is not yet known. SIRS = systemic inflammatory response syndrome. Bone et al. Chest. 1992;101:1644.

Sepsis: A Complex Clinical Challenge
Infection/ Trauma SIRS Sepsis Severe Sepsis High mortality rate (35%-45%) Heterogeneous patient population Unpredictable disease progression Unclear etiology and pathogenesis Most normal cells have two copies of the HER2 gene and small amounts of HER2 protein on their surfaces (Hynes and Stern, 1994). For reasons not currently known, cells may produce many copies of the HER2 receptor, a condition known as overexpression. HER2 protein overexpression is associated with increased cell division and a high rate of tumor growth. It may also be associated with transformation to the cancer cell phenotype (Kraus et al, 1987; DiFiore et al, 1987; Hudziak et al, 1987). HER2 protein overexpression has been reported in malignancies other than breast cancer, including ovarian cancer (Slamon et al, 1989) gastric cancer (Yonemura et al, 1991) colon cancer (Holzmann et al, 1992) endometrial cancer (Hetzel et al, 1992; Saffari et al, 1995) lung cancer (Kern et al, 1993; Pastorino et al, 1993) salivary gland cancer (Press et al, 1994) pancreatic cancer (Peiper et al, 1997) prostate cancer (Ross et al, 1997; Zhang et al, 1998) The significance of HER2 protein overexpression in these cancers is not yet known. Wheeler and Bernard. N Engl J Med. 1999;340:207.

Sepsis: A Deadly Healthcare Challenge
Study Condition Mortality Rate (N) Brun-Buisson, 1995* Abraham, 1997† Natanson, 1998‡ Friedman, 1998§ Severe sepsis Septic shock Severe sepsis/ septic shock 56%-60% (1052) 36% (78) 42% (62) 38% (4356) 49.7% (10,694) *Prospective survey, 28-day mortality; †Randomized placebo-controlled trial, 28-day mortality; ‡Analysis of placebo arms in 21 recent clinical trials; §Analysis of 131 studies. Brun-Buisson et al. JAMA. 1995;274:968; Abraham et al. JAMA. 1997;277:1531; Natanson et al. Crit Care Med. 1998:26:1927; Friedman et al. Crit Care Med. 1998;26:2078.

Severe Sepsis: A Significant Healthcare Challenge
Severe sepsis has a high mortality rate and represents a significant healthcare challenge. Reported incidence figures from several recent studies vary from 28% to 50%. Angus et al reported an overall hospital mortality of 28.6%. Mortality rates were higher for patients with comorbidities and increased progressively with the number of organ systems that were affected. For example, while the mortality rate was 21.1% in patients with the dysfunction of a single organ, the death rate climbed to 76.2% when four or more organ systems were involved. Sands et al performed a prospective, multi-institutional, observational study of the epidemiology of severe sepsis in eight academic, tertiary care centers. In this population, the 28-day mortality was 34%. At 5 months, an additional 11% of the patients had died. Zeni et al evaluated the outcomes in 18 clinical trials of nonglucocorticoid antiinflammatory agents in patients with shock. Placebo mortality rates ranged from 29% to 60% with a combined mortality of 39%. In this review, patients treated with platelet activating factor had a 50% overall placebo mortality. In a study not on the slide, Brun-Buisson et al evaluated the outcome of severe sepsis in an inception cohort study of 11,828 consecutive admissions to adult ICUs of public hospitals in France. The 28-day mortality in this group was 56%. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Incidence, cost, outcome of severe sepsis in the United States. Crit Care Med (In Press). Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. JAMA. 1995;274: Sands KE, Bates DW, Lanken PN, et al. Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA. 1997;278: Zeni F, Freeman B, Nathanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med. 1997;25: †Angus DC et al. Crit Care Med ‡Sands KE et al. JAMA. 1997;278: §Zeni F et al. Crit Care Med. 1997;

Reduction of Mortality
Infection specific treatment Appropriate antimicrobials Sepsis specific treatment Drotrecogin alpha: activated protein C Supportive treatment Early goal directed therapy Intensive insulin therapy Low tidal volume ventilation Low dose steroids

Empiric Antimicrobial Regimen
Initial antibiotic regimen chosen for suspected infection based on clinical presentation and local epidemiological data, pending the results of obtained cultures. When culture results are obtained: Appropriate initial regimen is the regimen which included antibiotics turned out to be covering the isolated organism(s) Inappropriate initial regimen is the regimen which did not include antibiotic(s) covering the isolated organism(s), and change of antibiotic is necessary to cover those organisms

Inappropriate Initial Antimicrobial Therapy

Mortality Associated with Initial Inadequate Therapy

Inadequate Treatment and Mortality: (BSI) Resistant Pathogens
Ibrahim EH, et al. Chest 2000;118:

Inadequate Antimicrobial Therapy
2000 consecutive MICU/SICU patients 655 (25.8%) with infections 169 (8.5%) with inadequate therapy Kollef MH, et al chest. February 1999;115(2):

Infection Classification
Kollef MH, et al chest. February 1999;115(2):

Cohort of Infected Patients and Inadequate Therapy

Most Common Pathogens Inadequate therapy (n=169)
P. aeruginosa: 53 MRSA: 45 VRE: 13 Adequate therapy (n=486) Escherchia coli: 76 MSSA: 88 Kollef MH, et al chest. February 1999;115(2):

Clinical Outcomes Kollef MH, et al chest. February 1999;115(2):

Hospital Mortality of Infected Patients

Inappropriate Empiric Antibiotic Therapy: KFSHRC-Jeddah
Total of 105 patients with clinically significant, microbiologically documented infection

Inappropriate Initial Antimicrobial Therapy

Inappropriateness based on Infection Setting: KFSHRC-Jeddah
KFSHRC-Jeddah, QM data 2002

Inappropriateness as per Site of Infection
KFSHRC-Jeddah, TQM data 2002

Based on Previous Antibiotic Use

Inappropriate Empiric Antibiotic Therapy: KFSHRC-Jeddah
Total of 27 patients with hospital acquired infections and previously on antibiotics KFSHRC-Jeddah, TQM data 2002

Inappropriate Coverage as per Organism
3 3 11 10 6 18 23 KFSHRC-Jeddah, TQM data 2002

Reasons for Inappropriateness

Reasons for Inappropriateness
Bacterial Resistance KFSHRC-Jeddah, 2002

Rates of Resistance Among Nosocomial Infections Reported in Intensive Care Patients, Comparison of 1999 (January-July) with Historical Data If we look at the rates of resistance of nosocomial pathogens in our intensive care unit patients in our National Nosocomial Infection Surveillance System and look at 1993 to 1997 which is shown here in gray versus January to November 1998, we see that the number of infections caused by vancomycin-resistant Enterococci have increased tremendously. Methicillin-resistant Staph aureus has also increased to the point where over 50% of the infections in our intensive care unit patients in our hospitals are resistant to methicillin. Third-generation cephalosporin, E.coli-resistant, Klebsiella-resistant has not changed too much. Imipenem-resistant Pseudomonas aeruginosa and Acinetobacters is starting to increase, as is quinolone-resistant Pseudomonas aeruginosa. So we are seeing increasing resistance and pathogen in our hospitals. January-July 1999

Antibacterial Resistance in Nosocomial Infections Gram-Negative Pathogens
Fridkin and Gaynes. Clin Chest Med. 1999:20:

Antibacterial Resistance in Nosocomial Infections Gram-Positive Pathogens
Fridkin and Gaynes. Clin Chest Med. 1999:20:

Methicillin Resistant Staphylococci by setting
Now it's important to look at the different setting in which patients acquire these infections. It's primarily a problem with coagulase negative Staphylococci in intensive care units, but also it's a problem with Staph aureus both in the ICU and non-ICU. You've heard the role of the outpatient setting for MRSA, and to a certain extent it's a semantics issue whether a patient truly has an outpatient infection or not; and I think the most appropriate way to talk about it is, is it healthcare-associated or not? If a patient is coming back and forth to a dialysis unit three times a week and develops an MRSA infection, is that community-acquired or not? Clearly it's healthcare-associated. Fridkin. Clin Infect Dis.1999

Use of Vancomycin in US and Rate of VRE
Kirsl et al. Historical usage of vancomycin. Antimicrob Agent Chemo 1998 National Nosocomial Infection Surveillance System (CDC)

Enterococcal Resistance by Species
There's some differences with regards to resistance based on the species, and it really emphasizes the importance of identifying enterococcal down to the species level because most of the resistance is among Enterococcus faecium. In fact, you could almost screen for faecium by looking at ampicillin resistance; 80% of all Enterococcus faecium are ampicillin-resistant. About half of Enterococcus faecium are vancomycin-resistant in contrast to Enterococcus faecalis, where it's about 3% for both vancomycin resistance and ampicillin resistance. Jones. Diagn. Microbiol Infect Dis. 1998

Independent Predictors of Vancomycin-Resistant Enterococci in Adult Intensive Care Units
If we look at ICU patients and look at independent predictors of vancomycin use, one of the major factors is how much VRE do you have in the rest of your institution so that patients can get colonized and then go into the ICU? Use of third-generation cephalosporins, use of vancomycin, and then the type of ICU with medical ICU being a stronger risk factor than surgical ICU. NNIS

Outcome of Enterococcus faecium Bacteremia
And finally, how does infection with this organism impact patient outcome? And this is data that we published in the Archives a couple of years ago looking at mortality in patients with vancomycin-susceptible Enterococci versus a vancomycin-resistant Enterococci. One of the things that you need to be cognizant of when you look at the literature is not only the crude mortality rate but the attributable mortality because so many of these patients are critically ill, have underlying diseases. The question is are they dying with this infection or from this infection? And at least in our institution the mortality directly related to VRE bacteremia was statistically higher than patients who had acceptable enterococcal bacteremia. Equally as important, we had about a $30,000 difference in total healthcare costs resulting from patients who had VRE bacteremia. Stosor. Arch Intern Med. 1998

Reduce Inappropriate Initial Antimicrobial Therapy
Efforts to reduce rate of resistance Guidelines Broad spectrum and combination antibiotics ID consultation Automated antibiotic consultant More selective and sensitive diagnostic methods

Efforts to Decrease the Rate of Emergent Antimicrobial Resistance
CDC guidelines and barrier precautions Antibiotic restriction Selective bowel decontamination Rotation antibiotics Short course antibiotic course But if outbreaks can be limited throughout control programs, there is still a lack of agreement about the efficacy of control measures. All the interventions mentioned in this slide had some degree of efficacy in large reported outbreaks. First, such as barrier precautions including cohorting of infected or colonized patients. Second, measures based in antibiotic policy, particularly third-generation cephalosporin restriction; and third, measures such as selective bowel contamination.

Impact of CDC Guidelines on Endemic VRE
When we've looked at three different studies where we have gone in and reinforced the CDC recommendations, we have seen that they do have an impact. In a New York Hospital on an oncology ward where VRE was endemic and 30% of patients were colonized at any one time and the number of bloodstream infections in this hospital was the highest of virtually any in the United States, we first found that barrier precaution before the intervention was implemented was only 28%. So you can't expect that it's going to work. With the implementation of reinforcement of policies, they increased to 92%. There was not a major effort to control vancomycin use. Vancomycin use probably results in the emergence of strains, but then the increase in transmission is more of an infection control problem. By merely improving infection control, colonization was decreased by 50%, and infections were decreased by 35%; and both of these were statistically significant. A similar intervention in a Maryland hospital where initial precaution compliance was about 64% -- a more major influence on antimicrobial use with a decrease in IV vancomycin use by 59%. It decreased colonization, but it did not decrease it statistically significantly. And part of the problem was this intervention was over the entire hospital, and it's much more difficult to police an intervention over the entire hospital. The third intervention was in an Indianapolis, Indiana, hospital where VRE precaution compliance increased from 22 to 88% when we moved all VRE patients to one ward rather than scattered throughout the hospital. They were able to decrease colonization by 80% and virtually eliminate infections. M. Montecalvo et al. Ann Int Med. 1999 J Morris et al. Ann Int Med. 1995 E Jochimsen et al. ICHE 1999

Impact of Formulary Change on VRE Empiric therapy for febrile neutropenia
This is based on a presentation looking at empiric therapy for the febrile neutropenic. And at this hospital they had primarily used piperacillin as their empiric therapy for patients with fever and neutropenia. They switched from piperacillin to cefepime in 1999, and you can see there was appropriate differences between the use of the agents and that one intervention alone with nothing else being done resulted in an increase in their VRE colonization rate from 1.5 per thousand patient days up to 5.5 per thousand patient days. But equally as important, not only were patients becoming more and more colonized with this organism, they've got a three-fold increase of bloodstream infections related to VRE. Lisgaris. IDSA (abstract). 2000

Prevention of GRE Therapy for Febrile Neutropenia
Purpose: reduce glycopeptide resistant enterococci (GRE) Situation: 50% colonization rate in oncology units Methods: Phase 1: no intervention (ceftazidime) Phase 2a and 2b: replace ceftazidime with piperacillin/tazobactam Phase 3: return to ceftazidime This is results from a study that came from the U.K. looking at glycopeptide-peptide resistant Enterococci in an oncology unit. The situation in this oncology unit was that about half of all the patients were colonized with glycopeptide-resistant Enterococci. And they participated in a three-phase study. In Phase 1 there was really no intervention, and ceftazidime was used for the initial therapy of febrile neutropenia. During Phase 2 which was divided into 2 4-month blocks, ceftazidime was replaced with piperacillin/tazobactam; and then during Phase 3 piperacillin/tazobactam was changed back to ceftazidime. Bradley. JAC. 1999

Results Phase 1 vs 2b (P<0.001) Bradley. JAC. 1999
And these are the results. During Phase 1 the colonization rate was 57%. There were five patients that were infected. During Phase 2A, 29%. During the last 4 months, down to 8%. And then when they switched back from piperacillin/tazobactam to ceftazidime, their colonization rate bump back up to 36%. Again, probably equally or perhaps more important than the colonization rate was during the use of piperacillin/tazobactam. There were no infections in contrast to five infections and three infections respectively during Phases 1 and Phase 3. Phase 1 vs 2b (P<0.001) Bradley. JAC. 1999

Antimicrobial Utilization and Resistance
Interdisciplinary team in Indianapolis to control resistant organisms Interventions: Reduce third generation cephalosporin use Reduce imipenem use Encourage use of ampicillin/sulbactam and piperacillin/tazobactam Enhance compliance with infection control Education regarding antimicrobial resistance How did that impact outcome? Was it better, worse, or the same? Well, the reality is it was the same. There was no adverse patient outcome, and some people have even argued that the outcome was better because you reduce your nosocomial infection rate in half and you eliminated a resistant organism. So this is really an important illustration of how controlling antibiotics can address problems of resistance. This is a paper from the group in Indianapolis that looked at a multidisciplinary approach to controlling resistance, and what they decided was that they needed to target a couple antibiotics. They needed to reduce their use of third-generation cephalosporins, they needed to reduce the use of imipenem, and then they said that we have to have some alternative. So they encouraged the use of ampicillin/sulbactam for community-acquired infection and then piperacillin/tazobactam primarily for moderate to serious infection or for healthcare-associated infections. You've already heard that controlling antibiotics alone is probably not adequate and it does require an approach that includes both infection control and antibiotic control. And then they educated their staff regarding the problems of emerging antibiotic resistanc

Antimicrobial Utilization and Resistance
And these are the results from their intervention that occurred over a 3-year period. They reduced vancomycin-resistant Enterococci from 16% down to 6%, some issues of gram-negatives, and they reduced their MRSA rate from 34% down to 23%.H Piperacillin/tazobactam resistant Smith. Pharmacotherapy 1999

Reduce usage of cephalosporins, imipenem, clindamycin and vancomycin
Impact of Formulary Changes on MRSA and Ceftazidime Resistant K. Pneumoniae Reduce usage of cephalosporins, imipenem, clindamycin and vancomycin Increased use of -lactam/-lactamase inhibitors And this is Landman's study that suggested that prior antimicrobial therapy may be a risk factor for MRSA. And what they showed was that reducing the use of cephalosporins, imipenem, clindamycin, and vancomycin could result in a reduction in MRSA as well as ceftazidime-resistant Klebsiella. Landman. Clin. Infect Dis. 1999

Ceftazidime Resistant K. pneumoniae Cleveland VA Medical Center

Blood Stream Infections
KFSHRC-Jeddah: Infection Control Data 2002

KFSHRC-Jeddah: Infection Control Data 2002
Nosocomial Pneumonia KFSHRC-Jeddah: Infection Control Data 2002

Urinary Tract Infection
KFSHRC-Jeddah: Infection Control Data 2002

Clinical Guidelines for the Treatment of Ventilator Associated Pneumonia
Prospective study: 50 patients were evaluated in the before group and 52 in the after group Administration of vancomycin/imipenem/ciprofloxacin within 12 hours of clinical diagnosis Antibiotic modification after hrs Seven-day course of therapy (>7 days if symptoms and signs are persisted) Ibrahim EH et al. Crit Care Med, 2001;29:

Inadequate Antibiotics for VAP
Ibrahim EH et al. Crit Care Med, 2001;29:

De-escalation Therapy: Broad Spectrum Initial Regimen: VAP
Plus vancomycin and amikacin Trouillet. Am J Resp Crit Care Med. 1998

ID Consultation Byl B. Clin Inf Dis; 1989

Automated Antibiotic Consultant
Evans Arch Int Med 1994

Rate of inappropriate initial antimicrobial regimen is high
In Conclusion: Rate of inappropriate initial antimicrobial regimen is high

Guidelines Broad spectrum and combination antibiotics ID consultation Automated antibiotic consultant More selective and sensitive diagnostic methods

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Inadequate Empiric Antibiotic Therapy

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