Journal Club

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

• Benefits of Routine Screening for Cryptococcal Meningitis in Advanced HIV
• Cefazolin Inoculum Effect in MSSA Bacteremia: Impact on Mortality?

Benefits of Routine Screening for Cryptococcal Meningitis in Advanced HIV

Reviewed by Brian R. Wood, MD

Cryptococcal meningitis (CM) remains one of the most common and devastating HIV-associated opportunistic infections. Guidelines from several countries endorse screening for cryptococcal infection with serum cryptococcal antigen (CrAg) for asymptomatic persons living with HIV (PLWH) who have low CD4 counts (below 100 cells/mL and especially below 50 cells/mL). However, the strength of this recommendation varies by guideline and clinical practice seems variable. A new systematic review and meta-analysis in Clinical Infectious Diseases confirms the benefits of this approach and emphasizes that positive results should be followed by lumbar puncture (LP) to rule out occult CM and then fluconazole as CM prophylaxis.

Investigators reviewed the literature for studies in which antiretroviral-naïve PLWH with CD4 counts below 100 cells/mL were screened for cryptococcosis with a blood CrAg test in the absence of symptoms of CM. Thirty-one studies from 22 countries (mostly low-middle income, but also some from higher-income countries), including 35,644 participants, met inclusion criteria.

Pooled prevalence of blood CrAg positivity for PLWH with CD4 below 100 cells/mL was 6 percent (range 0-21 percent, 95 percent confidence interval [CI]: 5-7). Of participants with positive CrAg, an astounding 33 percent had evidence of subclinical CM on CSF examination (based on 276 participants who accepted LP out of 403 who were eligible). For those without evidence of CM on LP, fluconazole prophylaxis dramatically reduced the incidence of CM, from 21.4 percent with no prophylaxis (95 percent CI: 11.6-34.4) to 0 percent (95 percent CI: 0.0-0.8), an equivalent incidence to the CrAg-negative group (0.4 percent, 95 percent CI: 0.1-1). There was also a blood CrAg-positive group who received fluconazole with no LP and incident CM remained higher than the CrAg-negative group at 5.7 percent (95 percent CI 3.0-9.7). There was some evidence that fluconazole initiated at 800 mg/day reduced incidence more than initiation at lower doses and, interestingly, all-cause mortality was higher in CrAg-positive as compared to CrAg-negative PLWH regardless of prophylaxis (risk ratio 2.2, 95 percent CI: 1.7-2.9, P < 0.001).

The take-home message is that for asymptomatic PLWH with CD4 count below 100 cells/mL, routine screening of blood CrAg followed by LP for those with a positive result and fluconazole prophylaxis initiated at high-dose for those with no evidence of CM reduces the incidence of CM to null. The study has limitations, but the results are striking and underscore the importance of incorporating CrAg screening into routine clinical practice for individuals with advanced HIV. An important future question will be how best to incorporate CrAg titers into clinical decision making, as higher titers are more predictive of asymptomatic CM, but guidelines do not yet take this into account.

(Temfack et al. Clin Infect Dis. Published online: July 18, 2018.)

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Cefazolin Inoculum Effect in MSSA Bacteremia: Impact on Mortality?

Reviewed by Christopher J. Graber, MD, MPH, FIDSA

The choice between semisynthetic penicillins (oxacillin, nafcillin) and cefazolin as first-line agents for treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia is hotly debated. While cefazolin has better tolerability, less frequent dosing, and lower cost, some MSSA strains produce β-lactamases that degrade cefazolin more readily than semisynthetic penicillins, leading to an inoculum effect with cefazolin (CzIE). However, it has not been clear if this phenomenon is associated with worse clinical outcomes.

A recently published article in Open Forum Infectious Diseases summarizes the clinical experience with cefazolin in the management of 77 episodes of MSSA bacteremia at three Argentinian hospitals where semisynthetic penicillins were unavailable. Isolates were determined to have CzIE if an increase in minimum inhibitory concentration (MIC) to ≥ 16 µg/mL was observed via broth microdilution when a high (10⁷) colony forming unit (CFU)/mL inoculum was used instead of the standard 10⁵ CFU/mL inoculum. CzIE was observed in 42 patients (54.5 percent), was not specific to any MSSA genotype, and was most frequently observed in the presence of type A and C β-lactamases, though types B and D were also observed.  CzIE was observed more frequently in patients with catheter-associated or unknown sources of bacteremia (P = 0.033) and CzIE patients had higher creatinine (median 1.4 mg/dL versus 0.9 mg/dL, P = 0.005); patient demographics and clinical characteristics were otherwise similar. CzIE patients had higher 30-day all-cause mortality in a multivariate analysis including age, Charlson score, previous hospitalization, Pittsburgh bacteremia score, previous S. aureus infection, secondary source of bacteremia, and serum creatinine > 1.0 mg/dL (adjusted risk ratio 2.65, 95 percent confidence interval 1.10-6.42, P = 0.030). Specific causes of death were not described.

While not able to evaluate the effect of CzIE on treatment with semisynthetic penicillins, this article nonetheless lends some credence to the theory that CzIE may impact clinical effectiveness when cefazolin is used in the management of MSSA bacteremia. Several questions remain as grist for further debate: Is the high prevalence of CzIE in this study replicable to other settings? Should CzIE be routinely tested when cefazolin is considered for MSSA bacteremia? Should semisynthetic penicillins be first-line therapy for patients with endocarditis or persistent bacteremia with difficult-to-eradicate foci, with a switch to cefazolin down the line after blood cultures have cleared?

(Miller et al. Open Forum Infect Dis. 2018;5(6):1-9.)


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