In the JournalsPerspective

Each day of S. aureus bacteremia increases mortality risk by 16%

Annie Wong-Beringer, PharmD
Annie Wong-Beringer

Every day a blood culture returns positive for Staphylococcus aureus bacteremia, a patient’s risk for mortality increases, with a significant increase for risk beginning at day 3, according to findings from a multicenter, prospective, observational study.

Management of patients with S. aureus bacteremia should target bacterial clearance as soon as possible as each continued day of persistent bacteremia adds 16% risk for death,” Annie Wong-Beringer, PharmD, associate dean for research and graduate education at the University of Southern California School of Pharmacy, told Infectious Disease News.

Wong-Beringer and colleagues enrolled 884 adult patients aged 18 years or older who were hospitalized with S. aureus bacteremia (SAB). They compared risk factors and outcomes among the patients, whom they grouped by bacteremia duration:

  • short duration (1 to 2 days),
  • intermediate duration (3 to 6 days) and
  • prolonged duration (7 or more days).

According to the study, 63% of patients had short bacteremia, 28% intermediate and 9% prolonged. The mean age of all patients was 57 years, and 70% of the study population was male.

The researchers reported the highest proportion of methicillin-resistant SAB among the patients with prolonged bacteremia (P < .0001). They also found delayed time to source-control procedure among patients in the prolonged and intermediate groups compared with patients in the short-duration group. Specifically, it was 3.5 days to source control for patients in the prolonged group, 3 days for the intermediate group and 1 day for the short group (P < .0001). Choice of antibiotic therapy did not significantly affect duration of bacteremia, the researchers noted.

As bacteremia duration increased, Wong-Beringer and colleagues observed that metastatic complications, length of stay and 30-day mortality became “progressively worse.” Among the short, intermediate and prolonged groups, they reported metastatic complications for 12%, 23% and 33% of patients, respectively. Length of hospital stay increased from 9 days for those in the short group to 12 days for those in the intermediate group, and for those in the prolonged group, the length of stay doubled to 24 days. Moreover, 30-day morality was reported for 5% of patients in the short group, 11% in the intermediate group and 22% in the prolonged group (P < .0001).

Every day of persistent SAB was associated with a risk ratio for death of 1.16 (95% CI, 1.10-1.22), Wong-Beringer and colleagues underscored. Furthermore, a significant increase in risk for death was observed starting at day 3, according to an analysis.

“Clinicians need to alter management approach early in the course if bacteremia continues by day 3, especially with removal of infectious foci,” Wong-Beringer said.

The researchers also noted that consultation with an infectious disease specialist is “known to significantly improve clinical outcomes of SAB.” However, patients in the prolonged group had significantly delayed ID consultations, highlighting a critical target area to improve clinical practice. – by Marley Ghizzone

Disclosures: Wong-Beringer reports receiving grants from Allergan and Merck, and consulting fees from Achaogen, Bayer Healthcare, GlaxoSmithKline, INSMED, Nabriva Therapeutics, Paratek Pharmaceuticals, Rempex Pharmaceuticals and SIGA Technologies.

Annie Wong-Beringer, PharmD
Annie Wong-Beringer

Every day a blood culture returns positive for Staphylococcus aureus bacteremia, a patient’s risk for mortality increases, with a significant increase for risk beginning at day 3, according to findings from a multicenter, prospective, observational study.

Management of patients with S. aureus bacteremia should target bacterial clearance as soon as possible as each continued day of persistent bacteremia adds 16% risk for death,” Annie Wong-Beringer, PharmD, associate dean for research and graduate education at the University of Southern California School of Pharmacy, told Infectious Disease News.

Wong-Beringer and colleagues enrolled 884 adult patients aged 18 years or older who were hospitalized with S. aureus bacteremia (SAB). They compared risk factors and outcomes among the patients, whom they grouped by bacteremia duration:

  • short duration (1 to 2 days),
  • intermediate duration (3 to 6 days) and
  • prolonged duration (7 or more days).

According to the study, 63% of patients had short bacteremia, 28% intermediate and 9% prolonged. The mean age of all patients was 57 years, and 70% of the study population was male.

The researchers reported the highest proportion of methicillin-resistant SAB among the patients with prolonged bacteremia (P < .0001). They also found delayed time to source-control procedure among patients in the prolonged and intermediate groups compared with patients in the short-duration group. Specifically, it was 3.5 days to source control for patients in the prolonged group, 3 days for the intermediate group and 1 day for the short group (P < .0001). Choice of antibiotic therapy did not significantly affect duration of bacteremia, the researchers noted.

As bacteremia duration increased, Wong-Beringer and colleagues observed that metastatic complications, length of stay and 30-day mortality became “progressively worse.” Among the short, intermediate and prolonged groups, they reported metastatic complications for 12%, 23% and 33% of patients, respectively. Length of hospital stay increased from 9 days for those in the short group to 12 days for those in the intermediate group, and for those in the prolonged group, the length of stay doubled to 24 days. Moreover, 30-day morality was reported for 5% of patients in the short group, 11% in the intermediate group and 22% in the prolonged group (P < .0001).

Every day of persistent SAB was associated with a risk ratio for death of 1.16 (95% CI, 1.10-1.22), Wong-Beringer and colleagues underscored. Furthermore, a significant increase in risk for death was observed starting at day 3, according to an analysis.

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“Clinicians need to alter management approach early in the course if bacteremia continues by day 3, especially with removal of infectious foci,” Wong-Beringer said.

The researchers also noted that consultation with an infectious disease specialist is “known to significantly improve clinical outcomes of SAB.” However, patients in the prolonged group had significantly delayed ID consultations, highlighting a critical target area to improve clinical practice. – by Marley Ghizzone

Disclosures: Wong-Beringer reports receiving grants from Allergan and Merck, and consulting fees from Achaogen, Bayer Healthcare, GlaxoSmithKline, INSMED, Nabriva Therapeutics, Paratek Pharmaceuticals, Rempex Pharmaceuticals and SIGA Technologies.

    Perspective

    Persistently positive blood cultures (BC) are not uncommon in S. aureus infections (approximately one-third of moderate to severe infections), particularly in endocarditis, intravascular infections or those lacking source control. Persistently positive BC occur even when regimens are targeted appropriately to susceptibilities, thus the reference to S. aureus as the cockroach of bacteria. Infectious Diseases Society of America guidelines for treating MRSA suggest reconsidering antimicrobials and search for uncontrolled infection sources when BC remain positive at 7 days of treatment. Two small past studies suggested increases in poor outcomes for each added bacteremic day.

    Now a new 5-year prospective study in 884 adults with S aureus bacteremia/sepsis (mean age 57 years, 88% community acquired) suggests the need for more prompt ID consultation and source control to reduce deaths in persistently S. aureus bacteremic patients. The authors used published definitions of death risk (low, intermediate and high) and bacteremia duration: short (1 to 2 days), intermediate (3 to 6 days), and prolonged (7 days or more).

    The threshold for increased 30-day mortality risk was 3 days or more of persistently positive BC. More specifically, there was a 16% increase in 30-day mortality for each day of positive blood cultures. The risk rose to 20% per day in a sensitivity analysis undertaken to adjust for imprecision in defining numbers of positive BC days (not every patient had daily BC, and some had only one BC).

    Prolonged bacteremia increased 30-day mortality risk. As might be expected, the prolonged condition was associated with endocarditis, intravascular infections and bacteremic pneumonia, as well as ICU admission, concurrent infections and diabetes mellitus. Other predictors were delay in infectious disease consultation (1-day difference) and delay beyond the third day after admission for use of source-control procedures.

    Different antibiotic regimens, whether empiric or after tailoring to pathogen susceptibilities, did not seem to be predictors. MRSA had a higher risk for prolonged BC positivity than methicillin-susceptible S. aureus. Higher vancomycin minimal inhibitory concentrations (>1.5 µg/mL) were not associated with prolonged bacteremia.

    But in multivariate analysis, only two factors remained predictive of increased 30-day mortality: First,  3 days or more of persistent positive BC and, second, high Pitt bacteremia score (uses fever height, blood pressure, mechanical ventilation, cardiac arrest, and mental status for combined score).

    These data raise a conundrum. The trick has always been to decide who gets accelerated management (antimicrobial changes or source-control procedures before 5 to 7 days).  Most clinicians understand that severe/disseminated S. aureus is perhaps unique in that patients on the “correct” antibiotic or antibiotics that will ultimately result in clinical cure can remain persistently bacteremic. Mostly, clinicians feel content (although not always comfortable) to allow the correct drugs to eventually clear the pathogen if the patient is improving. However, if patients worsen or are not adequately improving in 5 to 7 days, a search is started for undetected infection foci, such as occult abscess, intracardiac vegetations or infected intravascular thrombus.

    Although waiting up to 7 days to change management is within current MRSA guidelines, these new data seem to indicate that 5 to 7 days may be too late for some patients. But should there be infectious disease consultation with all positive S. aureus BC and daily BC for at least 3 days? Are 3 bacteremic days (breakpoint for significantly increased mortality) a definitive trigger to consider antimicrobial changes and/or searches for foci, not just in patients who are not improving?

    In these days of cost containment and added attention to patient safety, we like to avoid unneeded, more expensive and, at times, adverse effect-producing procedures/antimicrobial changes. So, for now, it seems that daily BC for 3 days, early ID consultation and daily reconsideration of potential procedures for source control by day 4 are important, particularly with MRSA and in those with more severe presentations (ICU need, high Pitt bacteremia score or intravascular infections).

    But for clinically improving patients and before accelerated management becomes routine, we need confirmation of these data in adults and in children, plus clearer markers that discriminate between those who do and do not need accelerated management. Also, a cost-benefit analysis of accelerated management is needed.

    References:

    Liu  C,  et al. Clin Infect Dis. 2011;doi:10.1093/cid/ciq146.

    Rhee JY, et al. Shock. 2009;doi:10.1097/SHK.0b013e318182f98f.

    • Christopher J. Harrison, MD, FPIDS
    • Physician, division of infectious diseases
      Children’s Mercy Kansas City

    Disclosures: Harrison reports serving as an investigator on a study for which his institution receives funding from Merck to assess in vitro activity of ceftolozane-tazobactam against multidrug-resistant gram-negative pathogens, and that his institution received funding up to 1 year ago from Cubist/Merck and Allergan for clinical anti-staphylococcal antibiotic studies on which he was an investigator.