Updates

by Carol A. Kemper, MD, FACP

Management of Lipodystrophy in HIV: A Mini-Update

Source: Abstracts of the Fifth International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. July 8-11, 2003. Paris.

Several recent abstracts from the Fifth International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, which was held just prior to the Second IAS Conference on HIV Pathogenesis and Treatment in Paris, highlighted recent advances in the management of lipoatrophy/lipodystrophy in patients with HIV infection. Preliminary reports have suggested that rosiglitazone may improve insulin resistance, thereby facilitating improved glucose use and lipid metabolism. A randomized, double-blind, placebo-controlled study of rosiglitazone in HIV-infected patients with lipoatrophy/dystrophy found significant increases in insulin sensitivity, increased body fat, and increased levels of adiponectin in treated patients compared with controls (Hadigan C. Oral Abstract 12). By 3 months of therapy, body fat had increased 15% in the treatment group compared with 5% in the placebo group. Increased levels of cholesterol were also observed in treated subjects. In a second smaller open-label study, improved insulin resistance, increases in subcutaneous body fat, and decreases in visceral fat were observed in 4 patients with lipodystrophy receiving 3 months of rosiglitazone (Visnegarwala F. Poster Abstract 74).

Recombinant growth hormone (rGH) has become increasingly popular on the West Coast for the treatment of lipodystrophy. In one larger study, 555 patients were randomized to receive either rGH 6 mg daily or 6 mg every other day or placebo for 8 weeks (Kottler. Poster Abstract 93). Increased body weight and lean body mass were observed in both of the treatment groups compared with placebo recipients, although the effects appeared to be greater in patients receiving daily rGH. Trunk fat increased disproportionately to limb fat, thereby increasing the trunk:limb fat ratio. This is exactly the opposite of what would be hoped for in patients with limb lipoatrophy.

Two smaller studies found progressive increases in body fat in patients after switching from d4T to another reverse transcriptase inhibitor. Increases in body fat by both DEXA and computed tomographic scanning were observed in one group of patients 48 weeks after switching from d4T to either abacavir or zidovudine (McComsey G. Poster Abstract 90); virologic control was reportedly maintained. Similar effects were observed in patients enrolled in the MITOX study in Sydney: Limb fat increased 36% in patients switched from either a d4T- or zidovudine-containing regimen to an abacavir-containing one. Incremental increases in fat accumulation were observed throughout the 2-year period of observation, suggesting that a long period of time is required to reverse the process.

Although some physicians may be inclined to dismiss progressive changes in body habits as superficial, studies suggest that lipoatrophy may significantly adversely affect compliance with HIV medications. Two-thirds of patients in one survey indicated their willingness to give up one year of life from HIV therapy if it meant avoiding lipodystrophy. Although avoiding regimens with the potential for lipoatrophy/dystrophy may not always be possible, consideration should be given to switching regimens that are resulting in progressive lipodystrophy whenever possible. Although the above data looks promising, we’re a long way from knowing how to effectively reverse this condition in affected individuals.


Yersiniosis Outbreak From Chitterlings

Source: Jones TF. Emerg Infect Dis. 2003;9(8):1007-1009.

Yersiniosis is an uncommon cause of food-borne disease and generally accounts for only a small number of sporadic cases of infection in the United States. An outbreak of Yersiniosis limited solely to black infants in Tennessee therefore prompted an investigation as to the cause. During a 3-month period from November 15, 2001, to February 15, 2002, 12 cases of Yersinia infection occurred in infants younger than 1 year of age in Tennessee. All of the patients were black and had presented to local medical centers with severe diarrhea, and all of them had positive stool cultures for Y enterocolitica.

A case-controlled study was conducted to identify a potential cause. Ten infants (who could be located) and their caregivers and 51 controls were interviewed. Of the 10 cases, 8 (80%) had reported fever, 7 (70%) reported blood stools, 7 (70%) reported vomiting, and 4 (40%) required hospitalization. Interestingly, 6 of the cases occurred within days of Thanksgiving, Christmas, or New Year’s. Chitterlings had been prepared in the homes of every one of the case patients compared with only 35% of controls. (Chitterlings are that part of the pig small intestine that is often fried and served with special sauce, especially around the holidays.) At least 4 different brands of chitterlings were purchased at 5 different grocery stores. Ten to 80 pounds of raw intestines (possibly contaminated with feces) were prepared at any one time, with several hours of thawing, cleaning, and cooking in and around the sink and kitchen area. The caregivers variously described washing children’s bottles in the sink, handling children and their bottles and pacifiers while doing food prep, and small children in and around the food prep area.

Nine of the Yersinia isolates from the children were available for analysis. All were identified as serotype 0:3 biotype 4 (swine are the major reservoir for serotype 0:3, which has largely replaced serotype 0:8 as the most common serotype in human infections). Pulsed-field gel electrophoresis revealed 7 distinct patterns; 1 pattern was shared by 3 infants, 1 pattern was shared by 2 infants, and 1 infant had 2 distinct isolates. Of 13 samples of chitterlings purchased by Jones and associates from various stores in Tennessee, 2 tested positive for Y enterocolitica, and 5 were positive for various species of Salmonella.

These data suggest that no one common source is responsible for these cases; simply exposure to the food prep area was sufficient exposure for these small children. None of the infants actually ate the chitterlings. Jones states that attempts to educate the public about the risk of preparing chitterlings in this traditional fashion around the holidays have been unsuccessful, despite the risk to smaller family members.


Compassionate-Use Daptomycin Now Available

Newer antimicrobial agents in development for the treatment of VRE and MRSA infections include daptomycin, oritavancin, and tigecycline, as well as ramoplanin for potential decolonization of the intestinal tract of VRE. Daptomycin (Cidecin®, Cubist Pharmaceuticals), a lipopeptide, is rapidly cidal against a range of Gram-positive organisms, including those resistant to vancomycin and methicillin, as well as Staphylococcus pneumoniae.1 The activity of daptomycin in vitro against S aureus and enterococcus is similar to linezolid and quinupritistin-dalfopristin.2 In a murine model of chronic foreign body infection due to S aureus, a low dose of daptomycin was similarly effective to vancomycin, although emergence of decreased susceptibility was observed in some animals treated with daptomycin.3 In an experimental model of endocarditis due to MRSA, daptomycin plus rifampin was more effective in reducing vegetation bacterial colony counts > vancomycin plus rifampin > rifampin alone > daptomycin alone.4

Daptomycin appears to be relatively safe and well tolerated. The half-life in serum is ~ 9 hours, and 54% of the drug is excreted unchanged in the urine within 24 hours of administration. Protein binding is ~ 92%. Dose-escalation studies suggest that once-daily dosages up to 8 mg/kg are well tolerated. In ~ 1400 patients treated with daptomycin in various clinical trials, daptomycin was discontinued in ~ 1.5% of patients due to adverse events. Common side effects in up to 3-6% of patients include headache, nausea, vomiting, abdominal pain, diarrhea, constipation, injection site reactions, rash, edema, and abnormal liver function tests. Overall, daptomycin is likely to prove to be a very useful agent against resistant Gram-positive organisms, although more comparative studies are needed, especially in infections resulting in endocarditis and osteomyelitis.

Daptomycin is presently being reviewed by the FDA for the treatment of skin and soft-tissue infections due to Gram-positive organisms. It was also recently made available on a compassionate-use basis for the treatment of serious and life-threatening infections due to Gram-positive bacteria in patients intolerant or refractory to currently available therapies. Patients with renal impairment (creatinine clearance < 40 mL/min) or those receiving hemodialysis or peritoneal dialysis are not eligible for the compassionate-use protocol. (For more information, contact the Daptomycin Study Hotline at 888-327-8630.)

References

1. Critchley IA, et al. Antimicrob Agents Chemother. 2003;47: 1689-1693.

2. Richter SS, et al. J Antimicrob Chemother. 2003;52:123-127.

3. Vaudaux P, et al. J Antimicrob Chemother. 2003;52:89-95.

4. Sakoulas G, et al. Antimicrob Agents Chemother. 2003;47: 1714-1718.