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March 2009
Vol. 19 No. 3
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IDSA Journal Club
March 2009

In this feature, a panel of IDSA members identifies and critiques important new infectious diseases studies in the current literature that have a significant impact on the practice of infectious diseases medicine.

Nephrotoxicity of Adjunctive Gentamicin for Staph Bacteremia and Endocarditis
Reviewed by Christopher Graber, MD

Initial, short-course, low-dose gentamicin as adjunctive treatment of S. aureus bacteremia and endocarditis was associated with a high rate of nephrotoxicity in an analysis published in the March 15 issue of Clinical Infectious Diseases

The study was a safety data analysis of the randomized trial comparing daptomycin to standard therapy (an antistaphylococcal penicillin or vancomycin combined with initial low-dose gentamicin, typically for four to five days), originally published in the New England Journal of Medicine in 2006.  Overall, 27 of 122 (22 percent) patients receiving initial low-dose gentamicin experienced clinically significant nephrotoxicity, including 15 of 34 patients (44 percent) with a baseline creatinine clearance of 50-80 mL/min.  The rate at which patients developed clinically significant nephrotoxicity was similar when low-dose gentamicin was given with antistaphylococcal penicillins or vancomycin.  Increase in serum creatinine peaked at day 7 in patients receiving antistaphylococcal penicillins, while serum creatinine increased over the 28-day study course in patients receiving vancomycin.

The findings call into question current American Heart Association guidelines that suggest the “optional” addition of initial low-dose gentamicin to antistaphylococcal penicillins for the treatment of native valve MSSA endocarditis. 

The study was limited by the fact that the randomized trial was not specifically designed to assess the effect of initial low-dose gentamicin on renal function, and only seven patients received standard therapy without initial low-dose gentamicin, thus preventing any analysis of its efficacy. 

This study follows another recent report in Clinical Infectious Diseases that estimated a 0.5 percent decrease in endogenous creatinine clearance per day of gentamicin adjunctive therapy used in the treatment of 373 patients with infective endocarditis caused by a variety of organisms (18 percent were S. aureus), a change that was not associated with post-discharge mortality. 

(Cosgrove et al, Clin Infect Dis 2009;48:713-21)

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Fluoroquinolone Resistance Seen in Meningitis Cases

Reviewed by Edward Dominguez, MD, FIDSA

Add another organism to the growing list of emerging fluoroquinolone-resistant pathogens in North America.

This brief report in the New England Journal of Medicine describes a cluster of three cases of meningitis caused by ciprofloxacin-resistant serogroup B Neisseria meningitidis in North Dakota and Minnesota. This particular isolate appears to have occurred via horizontal gene transfer of a DNA gyrase mutation (T91I) from a nasopharyngeal commensal, Neisseria lactamica. The cluster isolates had 99.9 percent similarity with N. lactamica in the 1,265 nucleotides surrounding the T91I mutation. Although the isolate of N. lactamica itself did not possess the mutation, the authors suggest that the probability of a point mutation was high given the use of ciprofloxacin in decolonizing contacts of an earlier case of meningococcal meningitis in the community.

Such resistance has been described in several other countries spanning several continents. However, no imported cases have yet been described. Although the T91I mutation is present in N. gonorrhea species, DNA sequence homology with N. lactamica implicated the commensal as the likely source of the resistant mutation.

Ciprofloxacin chemoprophylaxis for meningococcus is attractive in adults because it is a single dose with minimal side effects. However, regional health authorities recommended the alternatives of ceftriaxone or rifampin once ciprofloxacin resistance is identified.

Additionally, the authors describe a carriage survey in which three of the 40 (8 percent) meningococcal isolates identified had an MIC to azithromycin of 2.0 micrograms per milliliter, the limit of susceptibility. As azithromycin is another alternative for chemoprophylaxis, resistance to it may be just around the corner.

(Wu et al., N Engl J Med. 2009;360:886-892)

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MRSA Central Line-associated Bloodstream Infections Declining; Reasons Not Clear
Reviewed by Nina Kim, MD

The incidence of methicillin-resistant Staphylococcus aureus (MRSA) central line-associated bloodstream infections (CLABSIs) decreased from 2001 to 2007, according to a study by the Centers for Diseases Control and Prevention (CDC) and published in the February 18 Journal of American Medical Association.

This report originates from data collected by CDC’s National Nosocomial Infections Surveillance (NNIS), a voluntary hospital-based reporting network that evolved into the National Healthcare Safety Network (NSHN). A total of 33,587 CLABSIs were reported from 1,684 intensive care units and more than 16 million patient-days, of which 7.4 percent were MRSA and 4.7 percent methicillin-sensitive Staphylococcus aureus (MSSA). Aggregated percent MRSA (of all S. aureus CLABSIs) increased from 48 percent in 1997 to 65 percent in 2007. However, although the incidence of MRSA CLABSIs increased from 1997 to 2001, it later declined by almost 50 percent through 2007. The incidence of MSSA CLABSIs declined steadily from 1997 to 2007 by 60-78 percent. In addition, declines in the incidence of total (non-pathogen-specific) CLABSIs of 38-54 percent were observed across ICUs from 1997 to 2007. The authors emphasize the importance of examining the incidence of MRSA infections over percent MRSA as a more accurate metric of disease burden.

While the decline in MRSA CLABSIs is encouraging, it is worth noting that these bloodstream infections represent only a subset of all invasive nosocomial MRSA infections including other MRSA bacteremias. The study reviewed an impressive number of patient-years but reflects the voluntary self-report of only a fraction of hospital ICUs across the country. Many of these hospitals did not report continuously to the NNIS/NSHN database during the study years.

These results raise but do not answer the pressing question: What prevention and control measures contributed to this decline? In a time of increased public scrutiny and debate over the best way to control invasive MRSA infections in health care settings, this study underscores the importance of outcomes research in this area.

(Burton et al., JAMA 2009; 301:727-736)

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Trivalent Inactivated Flu Vaccine Better than Live-attenuated Flu Vaccine in Healthy Adults?
Reviewed by Nina Kim, MD

Trivalent inactivated influenza vaccine (TIV) was associated with fewer medical encounters related to pneumonia or influenza than live attenuated influenza vaccine (LAIV) in healthy military personnel who received annual immunization, according to a study from the March 4 issue of the Journal of American Medical Association.

The study was based on longitudinal data collected as part of routine surveillance of military health care and included more than 1 million active-duty service members aged 17-49 who were stationed in the United States during the 2004-5, 2005-6, and 2006-7 influenza seasons and able to receive either TIV or LAIV. The primary outcome measure was incidence of medical encounters for pneumonia or influenza by ICD-9-CM visit codes. The highest incidence occurred in unimmunized persons: 19.4, 10.9, and 11.7 events per 1000 person-years for the three consecutive seasons. The next highest incidence occurred in LAIV-immunized persons: 18.3, 10.6, and 11.1 per 1000 person-years. The lowest incidence was found in TIV-immunized persons with 8.6, 7.8, and 8.0 person-years respectively. Compared to the unimmunized group, the effect of vaccination with TIV was greater (28-55 percent) compared with LAIV (11-21 percent). Interestingly, LAIV appeared to perform better in vaccine-naïve cohorts and the difference between LAIV and TIV was not significant in this group for the 2005-6 and 2006-7 seasons.

This report stands in contrast to some observational data that suggest LAIV may be slightly more effective than TIV in children and highlights the importance of studying the effects of influenza immunization in different adult populations. A major limitation of this study, as with any observational study, is possible selection bias. The authors attempted to mitigate this by propensity-based matching but could not account for some key confounders such as smoking. Misclassification might also have been introduced with the use of diagnosis codes instead of lab confirmation.

Despite these limitations, this large study involved a closed population of healthy adults and provides reasonable estimates of incidence. Future studies should examine the relative efficacy of LAIV compared with TIV in other immunized groups such as health care workers.

(Wang et al., JAMA 2009; 301:945-953)

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Startling Rise of Multidrug-Resistant Gram Negatives
Reviewed by Paul Pottinger, MD

This paper serves as a sobering reminder of the importance of multidrug-resistant (MDR) gram-negative rods (GNR) in particular among elderly patients admitted to the hospital.

In this retrospective case-control study, the authors report the antimicrobial susceptibility patterns and clinical characteristics associated with gram-negative bacteremia diagnosed at admission among 724 patients aged 65 and older who were admitted to Beth-Israel Deaconess Medical Center from 1999-2007.  

Findings were striking: During the study period, the incidence of MDR increased from 1 percent of all gram negative bloodstream isolates to 16 percent.  Fifty-eight percent of patients were presumed to have a urinary source because the same organism grew in both urine and blood cultures.  Statistically significant risk factors for MDR GNR bacteremia included admission from a long term care facility [OR 4.9], presence of an indwelling device [OR 6.0], exposure to a week or more of antibiotics within the previous 90 days [OR 5.5], severe sepsis [OR 7.9], and delayed effective therapy [OR 12.8].  Indeed, the most significant finding of this paper is arguably the fact that 63% of case patients were started on empiric antimicrobial therapy that was ultimately found to be ineffective.  This is one possible explanation for the fact that patients with MDR GNR bacteremia had a higher incidence of mortality (18 percent) than their non-MDR controls (5 percent).  

At a glance, these findings may tempt us to prescribe broad-spectrum antibiotics routinely for elderly patients being admitted to the hospital.  Of course, this would be a recipe for accelerating the emergence of drug resistance.  The true strength of this study is its description of specific risk factors that should prompt careful consideration of early empiric broad-spectrum antibiotics—combined with early de-escalation of coverage once susceptibility data are available.  Put another way, carbapenems are may be good for what ails your patient, but their judicious use remains crucial for delaying or preventing the emergence of resistance.  In fact, the CDC has just updated its guidelines for controlling infections caused by carbapenemase-producing Enterobacteriaceae. (Also described in this issue of IDSA News.)

(Pop-Vicas et al.  Infect Control Hosp Epidemiol 2009;30:325–331)

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Meropenem-Clavulanate for the Treatment of XDR M. tuberculosis
Reviewed by Shireesha Dhanireddy, MD

Meropenem plus clavulanate is potentially effective against extensively-drug resistant (XDR) Mycobacterium tuberculosis, according to a study in the February 27 issue of Science.

Worldwide mortality remains high from M. tuberculosis. The increasing prevalence of multi-drug resistant (MDR) and XDR M. tuberculosis has led to limited treatment options and increased mortality.

Beta-lactam antibiotics have not been effective against M. tuberculosis due to the presence of a highly active, chromosomally encoded beta-lactamase. Recent genetic knockout studies demonstrated that M. tuberculosis strains lacking blaC-encoded beta-lactamase were more sensitive to beta-lactam antibiotics.

Clavulanic acid, a beta-lactamase inhibitor, irreversibly inhibits BlaC. Moreover, meropenem has the ability to inhibit BlaC as well as being a poor substrate for BlaC (leading to less inactivation of the drug).

In vitro studies using the combination of meropenem and clavulanate against M. tuberculosis found a low minimum inhibitory concentration and resulted in a rapid reduction in colony-forming units and complete sterilization by 9-12 days. The effect of this combination of antibiotics was also studied against “persistent” or viable non-replicative states of M. tuberculosis. All beta-lactam antibiotics, especially meropenem and imipenem, combined with clavulanate decreased viability of “persistent” M. tuberculosis. Meropenem and clavulanate in combination were equally effective against sensitive strains as XDR strains of M. tuberculosis in vitro.

This in vitro study provides promising data for the use of meropenem-clavulanate in the future treatment of M. tuberculosis, including MDR and XDR strains.

(Hugonnet JE et al. Science. 2009;223:1215-8)

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