Infectious Disease Updates by Carol Kemper, MD

Infectious Disease Alert: Updates

By Carol A. Kemper, MD, FACP

Fluconazole during pregnancy, does lower dose lower risk?

Molgaard-Nielsen D et al. Use of oral fluconazole during pregnancy and the risk of birth defects. New Engl J Med 2013;369:830-839.

I keenly remember a young Asian woman, 4 months pregnant with her first child, admitted to hospital in the 1990's with severe pulmonary coccidioidomycosis. Her husband, a local dentist, had conscientiously taken her on a pre-baby vacation to Phoenix, Arizona for a golf trip a few weeks earlier. At the time, it was just recognized that fluconazole was associated with teratogenicity — although there was not as much information available then as there is now. She developed severe hypotension with an initial attempt at treatment with Amphotericin. Fearing the consequences of azole therapy, I held my breath, and attempted a single rechallenge 2 days later with Ampho. She nearly died from hypotension. With little else to offer — high dose fluconazole was administered. Her infection resolved, and baby was fine.

Studies have since provided more information on the teratogenicity of fluconazole in pregnancy. Fifteen birth defects have been linked to fluconazole therapy during pregnancy, including craniofacial defects, middle-ear defects, cleft palate, cleft lip, limb defects, limb-reduction defects, polydactyly, syndactyly, diaphragmatic hernia, heart defects overall, pulmonary-artery hypoplasia, VSD, and hypoplastic left heart. Most of the risk has, however, been associated with higher doses (400 800 mg daily) for sustained periods of time during the first trimester. In contrast, itraconazole during pregnancy does not appear to confer a significant increased risk of fetal defects, and ketoconazole is not known to be teratogenic. Less is known about the use of lower dose fluconazole for limited durations in the first trimester.

These investigators examined the risk of birth defects identified in the Danish National Registry, cross- checking them against prescriptions for azoles. Only those prescriptions filled within 4 weeks of pregnancy onset were examined. Most of the use was single dose fluconazole 150 mg or 300 mg — presumably given for yeast vaginitis prior to recognition of pregnancy in these women.

A total of 976,300 live births were included in the study, 7,352 of which were exposed to fluconazole; 687 were exposed to itraconazole (44 of whom also received fluconazole); and 72 were exposed to ketoconazole (3 also received fluconazole).

Compared with unexposed pregnancies, there was no statistically significant increase in the overall prevalence of birth defects in pregnancies exposed to fluconazole (prevalence 2.6%, prevalence odds ratio 1.06). Analysis of the risks associated with each of the 15 recognized birth defects above failed to show any increased risk with one exception: 7 cases of Tetralogy of Fallot occurred in fluconazole — exposed cases (prevalence 0.03%, prevalence odds ratio 3.16) compared with 287 cases in unexposed pregnancies. There was no observed increase in craniosynostosis, cleft palate, or other craniofacial defects, more frequently associated with fluconazole administration during pregnancy. There was also no evidence of increased birth defects in patients receiving either itraconazole or ketoconazole. And there was no observed risk associated with fluconazole exposure in the second or third trimester.

A potential limitation of this study was the absence of data related to fetal death or spontaneous miscarriage due to birth defects. Pregnancies terminated specifically for birth defects were examined, and no unusual activity was observed in women receiving fluconazole, with the possible exception of births terminated for hypoplastic left ventricle.

ID consultants lower mortality and cost of hospital stay

Schmitt S, et al. Infectious Disease specialty intervention is associated with decreased mortality and lower healthcare costs. Clin Infect Dis, 2013 Sep 25. [Epub ahead of print]

The most heavily curb-sided specialty may also be one of the more valuable, especially in an era of cost-consciousness, and focus on quality markers such as shorter stays and fewer 30-day readmissions. The impact of ID consultation on important markers, such as length of ICU stay, length of hospital stay, mortality, and frequency of 30-day readmission was assessed for patients admitted to an acute care hospital (ACH) with at least one of 11 specific infections between January 2008 and November 2009. These common infections were selected based on the ability to query fee-for-service Medicare claims based on DRG code (bacteremia, C difficile infection, central line-associated bloodstream infection, bacterial endocarditis, HIV, meningitis, osteomyelitis, prosthetic joint infections, septic arthritis, septic shock, and vascular device infections).

A total of 101,991 ACH stays with ID consultation and 170,366 without ID involvement (59.8%) were examined. Patients with ID consultation generally had more than one infection, and were more likely to be male, they were younger, more likely to be admitted to ICU, and were more likely admitted to a teaching hospital compared to those without ID intervention. A matched cohort of more than 120,000 cases was created, and those patients with ID consultation also appeared more likely to have orthopedic infection, were more likely to have had surgery, and were less likely to have respiratory infections compared with the non-ID intervention cohort. Prior to adjusting for any risk factors, patients with ID intervention generally appeared more ill, had longer lengths of hospital stay, more days in ICU, but a lower index stay mortality.

After adjustment for risk factors, cases with ID involvement had statistically significantly lower rates of index stay (odds ratio, .89), lower rates of 30-day mortality (OR, .86), and lower rates of 30-day readmissions (OR, .96). In addition, stays with ID involvement within the first 2 days of hospitalization were associated with a significantly lower 30 day mortality (OR, .87) and readmission rate (OR, 0.92). Furthermore, those cases were associated with a 3.8% reduction in overall hospital stay, 5.1% fewer ICU days, and significantly lower cost of hospital charges, Medicare payments to ACH, and Medicare payments to all providers. These differences were small (on the order of 2.9% to 6.2%) but highly statistically significant.

In a multivariate analysis using case controls, involvement of an ID specialist in the care of patients admitted to ACH resulted in improved outcomes and a lower cost of care, especially when the ID consultant was involved early in the hospitalization.

Antiphospholipid Syndrome masquerading as infection

Erkan DE, et al. Long term outcome of catastrophic antiphospholipid syndrome survivors. Annals of Rheum Dis 2013.

A previously healthy young man was admitted to an ICU with apparent sepsis, with multiple brain and lung abscesses. He received broad-spectrum empiric antimicrobials, including amphotericin for a week in ICU, and failed to improve. Despite vigorous attempts to identify an etiology, including bronchoalveolar lavage, lumbar puncture, lung needle biopsy, bone marrow biopsy, and finally a lung biopsy, as well as numerous cultures and serological studies — no specific infection or agent could be identified. The lung biopsy strangely showed "cold" microabscesses with an absence of neutrophils, and fibrin deposition with vascular structures; and he began to develop evidence of thrombus in several vessels. Catastrophic antiphospholipid syndrome (CAPS) was put forward as a diagnosis — and the patient improved with high dose steroids and plasmapheresis although remains critically ill with a guarded prognosis.

CAPS is a poorly understood but overwhelming illness consisting of microangiopathy, multiple organ thrombosis, and tissue death. Mortality occurs in about 50% of patients. While some cases are preceded by infection or trauma, which seems to act as a trigger, the cause is not understood but likely related to a systemic inflammatory response syndrome with overwhelming cytokine cascade in the setting of positive anti-phospholipid antibodies. There may be an underlying history of lupus or other connective tissue disease. Patients develop peripheral thrombosis in both veins and arteries, and involvement of all major organ systems may occur.

The Catastrophic Antiphospholipid Syndrome Registry Group Project has been created to obtain more information about this disease. A total of 130 cases of CAPS in the registry were examined to determine the long-term outcome of survivors of this devastating condition. Sixty-three (46%) of the patients died with the initial event. Sufficient information was available for 58 of the 73 survivors. Of these, 38 (66%) had no further APS-related events during an average follow-up of 67 months. Recurrent APS events occurred in 15 cases, resulting in 4 deaths. In addition 5 patients died of other causes, including 3 patients who died from multi-organ system failure, and one each from myelofibrosis and pneumonia. Therefore, of the patients who survived their initial CAPS episode, 9 (16%) died within an average of ~5 years.

Even in patients who survive an initial CAPS event, who presumably have the benefit of a recognized diagnosis and better attempt at treatment, the risk of future events is high (26% of survivors developed recurrent APS events), with a significant risk of mortality within a few years.