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

Clostridium sordellii Toxic Shock

MMWR. July 22, 2005; 54:1.

The FDA has issued a public Health Advisory regarding the identification of 4 cases of toxic shock following medical abortion with Mifepristone (formerly RU-486) and intravaginal misoprostol in the United States. Two of the cases occurred in 2003, but the recent cases occurred in 2004 and 2005. Although 2 of the cases are still being investigated, at least 3 were associated with toxic shock and endometrial infection, secondary to Clostridium sordellii, an anaerobic spore-forming bacterium similar to C. perfringens. C. sordellii has most recently been described as a cause of toxic shock and sepsis in persons receiving contaminated orthopedic allografts. A fifth and fatal case of C. sordellii sepsis was reported in a Canadian women following medical abortion with Mifepristone and intravaginal misoprostol in 2001. Three of these cases were associated with intravascular hemolysis, hypotension, and leukocytosis, but were notable for a lack of fever.

While cases of toxic shock-like syndrome in obstetric patients are often related to C. perfringens, C. sordellii has also been previously described as a cause of severe and life-threatening endometritis and toxic shock in a variety of obstetric-related conditions, including spontaneous abortion, second trimester amniocentesis, septic abortion, as well as post-partum patients. Thus, its occurrence in the setting of medical abortion using RU-486 may not be too surprising. Cases of toxic shock and endometritis in the obstetric setting should receive empiric coverage with agents with anti-anaerobic activity against clostridial species, at least until culture data is available. The FDA has asked that suspect cases of toxic shock occurring postpartum or post-abortion be reported (www.fda.gov/medwatch/index.html).

What the Tsunami Brought to Cologne

Maegele M, et al. Crit Care Med. 2005; 33:1136.

Physicians at the Merheim Medical Center in Cologne, Germany, who provided care to German survivors from the Tsunami in Asia, provide an expansive guest list of microbial agents air-transported along with the victims. Maegele and colleagues describe the catastrophe from traumatic injuries, including infected wounds from contact with seawater, coral, and vegetation, which resulted in infection from vibrio spp and aeromonas; patients swept inland were also exposed to inland pools and swamps, with potential for infection from pseudomonas, aeromonas, legionella, chromobacterium, and leptospira. Patients were also in contact with fecally contaminated water and raw sewage, resulting in a variety of Gram negative infections.

Many victims were found to have wound infections with highly resistant bacteria, including MRSA, and about 20% of wound infections were due to a multiple drug resistant strain of Acinetobacter baumannii. Acinetobacter is quite hardy and can survive on moist or dry surfaces for days (it has also been seen with increased frequency in soldiers evacuated from Iraq during both the Gulf War and the current conflict). Burkholderia and melioidosis causing wound infection were also seen in several patients.

Respiratory infections complicating submersion and aspiration were also not uncommon, with unusual organisms such as aeromonas and pseudomonas not infrequently identified. A number of highly resistant pseudomonas, aeromonas, and stenotrophomonas spp. causing pulmonary infections were isolated. In addition, the usual respiratory nosocomial infections were encountered.

In addition to these, patients also carried home a number of interesting enteric pathogens, including shigella, salmonella, giardia, and amoeba.

A significant problem encountered was the lack of contact precautions during evacuation and transport; although Maegele et al learned to provide respiratory and contact isolation immediately upon arrival to subjects, until culture results were available. The Tsunami victims sadly provided a crash course in microbiology, with a wide variety of respiratory, enteric, and endemic pathogens, but with a higher frequency of antibiotic resistance than anticipated.

Update on Tenofovir

Delaunay C, et al. J Virol. 2005;79:9572-9578; Wirden M, et al. J Virol. 2005;76(3):297-301; Nevins AB, et al. Antiviral Therapy. 2005,10:S18.

Emergence of K65R during therapy: Triple nucleoside combinations have been discouraged, based on reports of high rates of early virologic failure, especially in patients receiving various combinations of abacavir, 3TC, ddI, and tenofovir. Such failure was often associated with the emergence of K65R and M184V/I mutations. Newer data suggests that the early emergence of K65R in patients receiving triple nucleoside/tide combinations may be more common than previously suspected.1 A group of treatment-naïve patients received a combination of abacavir, 3TC, and tenofovir once daily for 12 weeks. Before initiation of treatment, bulk genotypic sequencing and a more sensitive clonal analysis of each patient showed only virus with a wild type RT sequence.

In 21 patients with detectable viral loads at 4 and/or 12 weeks of treatment, bulk sequencing analysis of the RT gene was performed. This demonstrated the presence of M184V/I in 12 of 19 patients (63%) and K65K/R in 2 patients (10.5%) at 4 weeks of therapy. At 12 weeks of therapy, M184V/I was detected in 18 of 20 patients (90%) and K65R in 13 patients (65%). However, using the more sensitive clonal analysis, the K65R mutation was found in 0.6 to 48% of 5 clones studied at week 4 and in 30% to 100% of clones examined at week 12. This finding suggests that the emergence of K65R may occur more frequently and more rapidly than previously suspected. The 2 mutations appeared to arise independently within separate clones.

In the second study above, Wirden and colleagues assessed the frequency of thymidine analog mutation (TAMs) before and after initiation of tenofovir.2 None of the patients had K65R present at baseline. Following initiation of therapy, K65R developed in 19 of 96 patients (20%). In regression analysis, K65R occurred significantly more frequently in patients without pre-existing TAMs compared with those with TAMS, as well as in those treated only with triple nucleoside regimens. Five patients had emergence of K65R in conjunction with TAMs or L74V at the time of failure. Most of the mutational changes detected, occurred at codons 74, 75, 115, and 118.

Salvage therapy in those with K65R: The significance of the K65R reverse transcriptase (RT) mutation on virologic response in patients receiving salvage therapy has not been well-examined, especially in patients with additional resistance to other TAMs. In the abstract above from Stanford University, these authors identified 144 patients with K65R from a bank of archived data for 6147 HIV-infected patients in California. Only 39 of these had sufficient information available regarding their treatment history and, following a change in their regimen, at least one measurement of plasma viral load. Most of these 39 patients had been heavily pre-treated, including prior use of (in descending order) 3TC (92%), ddI (72%), tenofovir (64%), and abacavir (46%); 49% had used both ddi and tenofovir in combination. Baseline RT mutations were detected in 34 of 39 (87%), including 44% who had at least one TAM and 13% who had ³ 3 TAMs.

Of the 39 patients, 36 (92%) were switched to a protease-inhibitor containing regimen. Eleven patients received tenofovir, despite evidence of K65R in all. Compared with baseline, the median decrease in viral load was ~1.7 logs at 3 months and ~2 logs at 5 months of therapy. About one-third achieved plasma viral loads < 50 copies/mL. Thus, the presence of K65R did not appear to diminish short-term outcome in this group of heavily pre-treated patients who were predominately salvaged with a protease inhibitor containing regimen. This data suggests that about one-third of patients with the K65R mutational change can be successfully virologically suppressed with a change in their regimen, despite a history of extensive pretreatment and frequent TAMs. Whether continued treatment with tenofovir in the presence of K65R is of value was not assessed in the study.