Updates

By Carol A. Kemper, MD, FACP, Section Editor: Updates, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, is Associate Editor for Infectious Disease Alert.

Barriers to Preventing Infant HIV

Whitmore SK, et al. Correlates of mother-to-child transmission of HIV in the United States and Puerto Rico. Pediatrics 2012; 129 (1):e74-81

The number of infants born with HIV-infection in the United States reached its peak in 1991 with about 1650 HIV-infected infants, at which point the implementation of prevention guidelines resulted in a rapid reduction in neonatal infection. By 2004 and 2005, the number of cases of maternal-to-child-transmission (MTCT) resulted in 138 and 247 HIV+ infants, respectively, with an estimated transmission rate of 2.8%. Despite this improvement, barriers to elimination of MTCT remain, and approximately 250 infant HIV infections continue to occur annually in the United States. Most MTCT occurs as the result of a lack of prenatal care or failure to receive antiretroviral therapy (ART) during pregnancy. Newer guidelines published in 2006, and updated in 2011, attempted to address this problem, with recommendations for routine screening of all pregnant women, as early as possible in pregnancy; with additional testing for those at increased risk for HIV in the 3rd trimester (e.g., injectable drug users or partners of injectable drug users)1. Rapid HIV testing was recommended for mothers presenting for delivery who had not been screened during pregnancy, so that appropriate peri-partum ART could be administered (recognizing that a certain number of mothers and babies may receive inappropriate ART for a falsely-positive rapid test). Nonetheless, MTCT is still occurring, largely as result of "missed opportunities" for intervention.

Using the Enhanced Perinatal Suveillance System, these authors examined the data for live births to HIV+ mothers within 15 U.S. jurisdictions and Puerto Rico from 2005-2008, characterized those "missed opportunities". Missed opportunities were defined as a lack of prenatal care; lack of HIV testing during pregnancy; lack of prenatal HIV medication; lack of intrapartum HIV medication; lack of ART for the exposed infant; failure to perform cesarean section for women with detectable HIV viral loads > 1000 copies/mL; and breastfeeding.

Among 8054 live births to HIV+ mothers during the period of observation, 179 (2.2%) infants were diagnosed with HIV-infection. Overall, 52.6% of the 8,054 mother-infant pairs experienced at least one missed opportunity and all interventions were done in 32.3% (there was insufficient data available for 15.1%). Among HIV+ infants, 64.3% were attributed to at least one missed opportunity, for an overall transmission rate of 3.1%, compared with 1.1% for those receiving all of the interventions. The transmission rate was greatest for infants born to moms who did not get testing during their pregnancy (15.5%) compared with those who did (1.6%). A lack of ART during pregnancy resulted in a MTCT rate of 9.3% compared with 1.2% for those who were treated. A lack of prenatal care was associated with a MTCT rate of 8.5% compared with those who did receive prenatal care (1.6%). In addition, other factors significantly increased the risk of MTCT including the younger age of the mom (13-19 years), women with injectable drug use, and woman with CD4 counts < 200 cells/mL. For example, the transmission rate among HIV+ mother-infant pairs where the risk factor for HIV infection was injection drug use (22%) was 5.8% compared with those whose risk factor was listed as heterosexual exposure (45%) (2.1%).

Summarizing this data, MTCT could be attributed to a lack of maternal testing (either because of a lack of prenatal care or a lack of early testing during pregnancy) (26%), a lack of ART during pregnancy (45%), and breastfeeding (10%). These data indicate that 90% of maternal child HIV transmission can be prevented by getting women into prenatal care, prompt HIV testing during pregnancy, and appropriate treatment.

Reference

  1. Department of Health and Human Services Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States, September 14, 2011: http://1.usa.gov/xj7Qo8

The problem with C difficile Infection

Centers for Disease Control and Prevention. Vital Signs: Preventing Clostridium difficile infection. MMWR 2012;61(9): 157-162.

This report attempts to catalogue the ballooning number of cases of C difficile infection (CDI) in the United States using available resources, including data collected from the IDSA Emerging Infections Program (which has a catchment area of 111 acute-care hospitals and 310 nursing homes); the 2010 National Health and Safety Network data, which covers 711 acute care hospitals in 28 States; and data derived from 3 CDI prevention programs in 3 different states. A case of CDI was defined a positive test for CD in persons without a positive test within the previous 8 weeks. Enzyme immunoassay for toxin A and/or B was used to diagnose 51% of cases, while nucleic acid amplification test was used in 33% (other tests, not clarified, were used in 12%).

Based on the Emerging Infection Program data, 10,342 cases of CDI occurred in 2010, 44% of which occurred in people < 65 years of age. Based on available data, 94% of these had some kind of health care exposure within the preceeding 12 weeks. A total of 75% occurred outside of the hospital (44% were attributed to community-onset and 25% to nursing home onset), while 24% were hospital onset. The authors argue this data may, on the surface, be misleading and that deeper analysis reveals that 21% of hospital-onset cases occurred in nursing home residents and 67% of nursing home cases occurred in patients who had recently been hospitalized.

According to the 2010 NHSN data from acute care hospitals in 28 states, 42,157 laboratory-incidents of CDI were identified, 52% of which were present on admission to hospital (pooled hospital-onset CDI rate = 7.4/10,000 hospital days).

A collection of 71 hospitals in 3 different States participating in CDI prevention programs served as a third source. Using a variety of measures, these programs demonstrated a 20% reduction in CDI rates during a 21-month period of observation (from 9.3 to 7.5 per 10,000 hospital days). The specific measures were not detailed, but involved prompt testing of suspect cases, isolation of suspect and confirmed cases, improved environmental measures, and antibacterial stewardship.

The authors acknowledge problems with this data, including the definition of CDI — while some cases are defined based on laboratory test results alone, the NHSN data requires concurrent symptoms with 3 or more loose stools per day. Test assays with varying sensitivity also differ between facilities, yielding potentially different results (hospitals using the newer nucleic acid testing may get unfairly dinged for enhanced case detection). In addition, adherence to the case definition of hospital-onset if > 72 post-admission obviously biases the results towards implicating hospitals as the "source" for infection — since the inherent time delay in the recognition of symptoms, ordering the test, and submitting a sample all serve to push forward the time of diagnosis — at least based on a lab report and not symptom-onset.

While the effort to enhance reporting of CDI is laudable (CDI is not even listed as a "reportable" pathogen in our country) does anyone truly believe the problem begins with hospitals or that hospitals are to blame? The plan for Medicare and Medicaid Services Inpatient Prospective Payment System Quality Reporting Program to tie reimbursement to CDI hospital rates is preposterous — and only serves to take much needed dollars away from hospital efforts to prevent this infection.

These punitive efforts are missing the point: Every patient should feel comfortable their life is not in danger when receiving appropriate and necessary antibiotics — which is presently not the case. I recently saw a patient nearly die from CDI following receipt of a single dose of peri-operative cefazolin for a routine hip procedure. What we really need is a focus on how people acquire this organism, limiting exposure in long-term care facilities (where isolation and environmental hygiene is often lacking), eliminating CD from food sources, methods to quickly identify patients at risk before they receive antibacterials, and improving methods to prevent infection in patients at risk.

ID drug shortages threaten patient safety

Griffith MM, et al. The impact of anti-infective drug shortages on hospitals in the United States: Trends and causes. CID 2012: 54: 684-691

Recent efforts to treat a patient in hospital with acute pneumocystis pneumonia (PCP) were hampered by a lack of available injectable trimethoprim-sulfamethoxazole. The hospital pharmacy staff begged a few doses from the county and from the veteran's hospital in Palo Alto, but eventually I was forced to switch this patient to oral atovaquone, a second-line agent. At least the patient got through the more critical period of treatment, and gradually improved. Unfortunately, this scenario is becoming all too familiar to infectious disease specialists. Hardly a month goes by where I am not faced with a difficult therapeutic decision precipitated by a drug shortage of some kind. Coupled with the rise in antibacterial resistance, drug shortages can have a significant impact on medical care.

This salient article examines the clinical dilemmas created by the increasing frequency of critical drug shortages, and summarizes the current anti-infective drug shortages in the United States. Were you aware there is an entity called the Center for Drug Evaluation and Research (CDER) Drug Shortage Program of the FDA, which tracks the availability (or non-availability) of pharmaceuticals and anti-infectives in use? The CDER defines a drug shortage as "a situation in which the total supply of all clinically interchangeable versions of an FDA-regulated drug is inadequate to meet the current or projected demand..."

Such shortages often lead to clinical dilemmas, result in delays in initiation of treatment (while staff attempt to clarify availability of drug and hunt for a supply); often require an alternate and possibly less effective therapy, with the potential for worse outcome.

As of February 2011, a total of 193 agents were officially listed on the CDER's drug shortage list, 13% of which were anti-infectives. Some of these agents have been on the CDER list for months or years. In 2008, 5 anti-infective agents were listed on the CDER drug shortage list, one of which had not been resolved as of February 2011. Shortages of 6 of 11 agents listed in 2009 and 12 of 17 listed in 2011 had not been resolved and remain in short supply or are unavailable.

The government's role is mostly passive in this process, and can provide only oversight and monitoring, although they are charged with monitoring good manufacturing practice (GMP), and can help to precipitate a drug shortage by halting production of a drug or vaccine if a company fails to meet GMP standards. Drug shortages occur for a variety of reasons, including the lack of raw materials; a company can shut down manufacturing because of problems in a facility, or the FDA can interrupt production (as has been the case with Influenza vaccine and PCN G). For example, manufacturing issues hampered the production of injectable acyclovir, the only agent recommended for the treatment of HSV and VZV encephalitis. The shortage of PCN G in 2007, which is manufactured by a single company, created a serious problem for physicians attempting to treat neurosyphilis (inferior agents such as tetracycline and ceftriaxone had to be used). Manufacturing issues hampered production of injectable TMP-SMZ in May 2010, a problem that has still not been fully resolved; creating difficult decisions when attempting to treat PCP and infections due to Stenotrophomas maltophilia.

Occasionally, the demand for certain anti-infectives may outstrip production (as has occurred with Polymixin B, isoniazid, and mupirocin nasal ointment). Changes in clinical guidelines may also create an increased demand for certain agents, which existing production can not meet. Shortages of vaccines have also posed problems, including vaccines for Influenza, varicella, herpes zoster, yellow fever, and Hepatitis B.

In addition, a company can choose to halt or stop production of any agent for any reason, and they are not legally required to provide an explanation, nor are they required to provide status updates regarding any particular drug. Some drugs just disappear from the market, presumably as a marketing decision. Companies are required to provide 6 months notice to the FDA before ending production of a "medically necessary" drug. If they are the only manufacturer, the definition of medically necessary may be open for debate. For example, when Wyeth began marketing tigecycline in 2005, their other product, parenteral minocycline, was dropped from the market. It turns out that IV minocycline may prove to be one of the most useful agents against some strains of multidrug resistant Acinetobacter baumannii.

A panel of experts from several national associations has proposed changes to the FDAs current role, and a current U.S. Senate bill seeks to amend the law regarding manufacturer notification before halting production of any agent that could potentially lead to a shortage, as well as other recommendations made by a U.S House of Representatives Bill (Preserving Access to Life-Saving Medications Act). Those with opinions regarding this subject should contact their U.S. congressman or senator.