by Carol A. Kemper

The High Cost of MRSA

Source: Rubin RJ, et al. Emerg Infect Dis. 1999;5:9-17.

Although this article is older, its message is timely, and for this reason, I elected to include it. The increasing prevalence of MRSA in both community-acquired and nosocomial staphylococcal infections is placing a greater burden on an already over-burdened, costly medical system. The proposed United States’ Public Health Service guidelines for MRSA advocate more aggressive screening, identification, and isolation of MRSA cases in hospitals. Shouldering the cost of these measures will, however, largely fall to hospitals.

Rubin and colleagues modeled estimates of the incidence, duration of hospital stay, death rates, and medical cost of Staphylococcal aureus infection, and the relative impact of methicillin-resistance in the New York metropolitan area in 1995. At that time, Rubin et estimated that, of the total number of S. aureus infections, 54% were community-acquired and 46% were nosocomial, of which 10% and 29% were methicillin-resistant, respectively. Death rates were significantly higher for MRSA compared with MSSA (21 vs 8%). The duration of hospital stay varied, with surgical site infections requiring the least number of days and endocarditis requiring the most, with an average hospital stay of ~20 days. The direct average cost was about $32,100 per case of S. aureus infection (in 1995 dollars). Overall, costs for MRSA infection were 6% to 10% higher than those associated with MSSA, largely due to the higher cost of vancomycin and the cost of isolation procedures, not because of any difference in the severity of infection or duration of hospitalization.

Based on today’s estimates in our area, where one-third of community-acquired staphylococcal infections and more than half of nosocomial staphylococcal infections are MRSA, the number of MRSA cases has easily tripled

those 1995 estimates. In addition, Rubin et al were not factoring in the additional costs of the most recent recommendations, which include screening high risk patients on admission to hospital (or possibly all admissions) for MRSA, performing susceptibility tests and E-tests on all S. aureus isolates, the use of more costly agents, such as linezolid, plus the increased bed space needed for isolation all of these people. And, to what end? MRSA is quickly becoming the new norm, not the exception in most hospitals. Can hospitals bear the burden of these recommendations without some kind of additional compensation?

Treatment of Latent TB: A High Priority

Source: Horsburgh CR Jr. N Engl J Med. 2004;350:2060-2067.

Reduction in the number of cases of TB in the United States is one of the United States Public Health Department’s highest priorities. In order to achieve this goal, the numbers of patients who undergo testing and treatment for latent TB must be increased. I’ve always encouraged patients to accept treatment by providing a rough estimate of their lifetime risk of reactivation (~5-10%), but specifically encourage 3 groups of patients, irrespective of age, to accept treatment: those with 1) recent skin test conversion, 2) evidence of old healed disease on chest radiograph, or 3) those with immunosuppression, corticosteroid use, or HIV. Of course, any infant or child < 5 years of age with household exposure should be presumptively treated with INH; such patients are at high risk for primary progressive disease, and it is too late to wait for skin test conversion.

It has always been assumed that the risk of reactivation is generally greatest in the 2-3 years following conversion, then begins to decrease over the next decade, and remains fairly stable at low levels thereafter. Recent data suggests that ~10% of patients lose their tuberculin reactivity each decade; these individuals do not contribute to the overall risk of reactivation TB. Therefore, estimates of the risk of reactivation may actually be lower than previously assumed especially in younger persons, but the effect of this statistical finding on risk diminishes as patients age.

Believing that more precise information on the risk of reactivation can allow clinicians to target groups at highest risk, Dr. Horsburg constructed a risk model based on age, degree of induration on tuberculin skin test, and whether there was recent conversion, evidence of old healed TB, immunosuppressive therapy, or HIV. Five groups at significant lifetime risk for reactivation TB were identified: 1) children <5 years of age with >10 mm of induration have a 10-20% risk; 2) younger persons <35 years of age with >15 mm of induration and recent conversion have a 10-20% risk; 3) younger persons <35 years of age with >15 mm of induration receiving immunosuppressive therapy have a 10-20% risk; 4) persons with >10 mm of induration and evidence of old healed TB have >20% risk; and 5) persons with HIV and >5 mm of induration have >20% risk.

Interestingly, in Horsburg’s model, persons >66 years of age have <10% risk of reactivation under any circumstance (except HIV infection); this suggests that it may be reasonable to defer treatment in persons over the age of 65.

I suspect the reason that too few patients are treated for latent TB is because clinicians still have 3 bad rules stuck in their heads: these include patients with a history of a positive test for many years do not need treatment, a history of BCG means you don’t need treatment, you have a false-positive PPD, and anyone older than 35 is at higher risk for side effects and should not be treated. This backwards approach ensures that immigrants from a country endemic for TB (especially one where BCG is common), and anyone over the age of 35, is less likely to receive treatment for latent TB, even if they have risk factors. Confronting these fallacies, convincing clinicians that the benefits of INH prophylaxis outweigh the risks, disregarding a history of BCG, and keeping the rules of who should be treated as simple as possible may ensure that more patients receive treatment for latent TB.

The APRICOT HCV/HIV Co-infection Study

Source: Torriani FJ, et al. N Engl J Med. 2004:351(5):438-450.

While treatment with pegylated-interferon plus ribavirin has been shown to successfully suppress HCV infection in ~56-63% of mono-infected patients, virologic responses have been poorer in patients with HCV/HIV co-infection. In this multicenter study, conducted at major HIV centers around the world, 868 patients with HCV/HIV co-infection were randomized to receive 1 of 3 different HCV treatment regimens for 48 weeks [peginterferon alfa-2a (180 µ/week) plus ribavirin (800 mg daily) vs peginterferon alfa-2a plus placebo, or interferon alfa-2a (3 million IU 3 times weekly) plus ribavirin]. The primary endpoint was sustained virologic response (SVR) at 72 weeks. Eligible patients had detectable HCV RNA, CD4 counts >100, stable HIV disease, with or without antiretroviral therapy, and no prior HCV therapy. The study was conducted at 95 centers in 19 different countries and took 3 years. Patients were stratified based on HCV genotype, liver histology, HIV treatment, and CD4 count (< or >200 cells/mm3). The groups were remarkably balanced with regard to HCV RNA, degree of abnormal liver histology, HIV viral load, CD4 count, and use of antiretroviral therapy.

Treatment responses were poor but better than expected: the overall rate of SVR was significantly higher in patients receiving peginterferon with RBV (40%) compared with patients receiving peginterferon alone (20%), or interferon plus RBV (12%) (P < .001, both comparisons). Patients infected with HCV genotype 1 (GT-1) had significantly lower rates of response than those with other genotypes (GT). Among patients with GT-1, SVR occurred in 29% of those receiving peginterferon plus RBV, compared with peginterferon alone (14%), or interferon plus RBV (7%). In patients with GT-2 or GT-3, responses were much better (62%, 36%, and 20%, respectively).

Treatment was associated with the usual toxicities: neutropenia (~27%) and thrombocytopenia (6-7%) were more common in patients receiving peginterferon, and anemia was more common in patients receiving ribavirin (11-16%). Notably, these patients were receiving a lower dose of RBV than used in other studies. One percent or fewer in each arm developed pancreatitis and lactic acidosis, and about 1% in each arm developed hepatitic decompensation.

While 75% of patients receiving peginterferon with RBV completed 48 weeks of therapy, only 69% of those receiving peginterferon alone, and 61% of the interferon plus RBVgroup did. This was due to both treatment toxicity and a lack of treatment response and early withdrawal. Patients with a > 2 log drop in HCV viral load by week 12 were much more likely to have SVR (56% in the pegasys plus RBV group). This negative predictive response was not improved if responses at week 24 were examined. Only 2 patients without an early virologic response at week 12 went on to have a SVR (only 1 of whom had GT-1). Thus, consideration should be given to stopping treatment at week 12 in those who fail to achieve a good virologic response by 12 weeks of therapy. In addition, although earlier data suggests that patients with non-GT-1 virus may respond favorably to only 24 weeks of therapy, these data suggest there may be additional benefit in continuing treatment in these patients for 48 weeks.