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Infectious disease doctors tackle bad bugs with fewer drugs

Annual meeting unveils research, techniques that could help stem the tide of resistance and disease, particularly with the increase of ‘C-diff’

From the January ACP Internist, copyright © 2008 by the American College of Physicians.

By Jessica Berthold

SAN DIEGO—Much of the conversation at the Infectious Diseases Society of America annual conference in October dealt with a grim reality: the rise of drug-resistant infections and the dearth of new drug development. Yet the 4,200 attendees stayed mostly optimistic about the future of their field.

“We have more and more resistance, but we have fewer and fewer drugs,” said IDSA President Henry Masur, FACP, chief of critical care medicine at the National Institutes of Health Clinical Center. “Yet we have made a number of advances … in terms of drugs, understanding pathogenesis, advocacy and public policy.”

One oft-cited victory was Congressional approval of the FDA Prescription Drug User Fee Act Reauthorization, which should lead to faster updates of antibiotic breakpoints and clinical trial guidelines, and more money for orphan drug development, Dr. Masur said.

The recent introduction of the Strategies to Address Antimicrobial Resistance (STAAR) Act in the U.S. House (H.R. 3697) was also an encouraging sign, as it would help strengthen federal surveillance, prevention and control of antimicrobial resistance by establishing networks of consulting experts, he said.

George H. Talbot, MD, Chief Medical Officer and Executive Vice President of Cerexa, Inc, said he was heartened by the large number of studies unveiled at September’s Interscience Conference on Antimicrobial Agents and Chemotherapy meeting, where 120 new compounds were presented.

“I’m happy to say there are some glimmers of hope for antibiotic research and development,” Dr. Talbot concluded.

Curbing resistance

Development of new drugs isn’t the only means toward success, however. Physicians must take steps to reduce antibiotic resistance by being more careful with how they prescribe, noted Louis Rice, FACP, chief of medical services at Louis Stokes Cleveland VA Medical Center, during a lecture. As an example, he cited the common treatment strategy of rotating the type of antibiotic a patient uses so that resistance to any one drug doesn’t have enough time to develop.

“It’s like telling an alcoholic patient with liver disease to alternate drinking beer, whiskey and gin every three months,” Dr. Rice said. “It doesn’t work because it’s the alcohol, not the flavor that matters. Likewise, it’s the use of the antibiotic, not the type that matters.”

The best plan to prevent resistance is to stop irritating the bacteria, Dr. Rice said. Withhold antibiotics from those who don’t truly need them—admittedly a risky prospect for liability reasons and because patients may feel dissatisfied if they expect a prescription, he said. Physicians should also avoid using multiple antibiotics together when one type will suffice, which can also be tough since the nature of a pathogen is often unknown at the onset of therapy and “we want to cover our (rear ends),” Dr. Rice said.

Antibiotics shouldn’t be given longer than necessary, but that’s easier said than done, Dr. Rice noted. Certain conditions have fairly clear guidelines on treatment length, such as outpatient urinary tract infections, sexually transmitted diseases, tuberculosis, endocarditis and streptococcal pharyngitis. But for many others, the data is either limited, conflicting, or both, he said.

“The duration of therapy is a ‘known unknown’—we know we don’t know enough about it,” Dr. Rice said. “There is no magic to the current established durations of therapy.”

Happily, the IDSA has proposed three trials to the National Institute of Allergy and Infectious Diseases (NIAID) that would study the question of antibiotic treatment length—and the NIAID has given an encouraging response, Dr. Rice said. Recent studies showing infection rates can be improved through means like hand-washing protocols, as well as new hospital reporting requirements on infection rates, may also help nip infections in the bud before antibiotics are necessary, he added.

“There is hope,” Dr. Rice said. “But we need to continue to push for legislation and studies on this issue, and be consistent in our message (to prescribe responsibly).”

C-diff’s difficulties

Clostridium difficile was a repeated concern at the conference, with recent CDC data showing hospitalization rates from the illness more than doubled between 2000 and 2005.

“C-diff rates are going up, and there aren’t any good new drugs available yet. We need to see this epidemic decline, and soon,” said Dr. Dale Gerding, FACP, of ACOS Research and Development Hines VA Hospital in Chicago.

Experts debated whether to use oral metronidazole or vancomycin as the first course of treatment for C. difficile. John G. Bartlett, MACP, professor in the Johns Hopkins University School of Medicine Division of Infectious Diseases, noted that several recent studies have found vancomycin performed best in treating severe cases and had better hospital outcomes than metronidazole, though the drug results for mild and moderate cases weren’t significantly different.

Vancomycin’s only true disadvantage is that it is more expensive than metronidazole—which shouldn’t be an issue when morbidity and mortality are at stake, he said.

“In summary, you give vancomycin to your mother and metronidazole to your mother-in-law,” Dr. Bartlett said, quoting his colleague Sherwood Gorbach, FACP, a professor of medicine at Tufts University.

But Jacques Pepin, MD, of the University of Sherbrooke in Quebec, Canada, questioned the usefulness of the studies cited by Dr. Bartlett, saying their outcomes—such as not having diarrhea by day six of treatment—weren’t necessarily the most relevant. Audience members, who were asked to vote on which drug they’d prescribe in different scenarios involving C. difficile, seemed to prefer metronidazole for mild disease and vancomycin for serious disease.

Another talk focused on preventing recurrence of C. difficile, which is more likely among those receiving ongoing or new exposure to an antibiotic, those who are older than 65, those hospitalized for a long period of time, and those with a serum albumin of less than 2.5 g/dl, according to Thomas Moore, FACP, of Wichita, Kan. He presented material prepared by Johan S. Bakken, FACP, of St. Luke’s Infectious Disease Associates in Duluth, Minn., the scheduled speaker who stayed home to care for a very ill patient.

There is no proven treatment in the U.S. to prevent C. difficile recurrence, but fecal bacteriotherapy has become the first-line treatment in Scandinavia, Dr. Moore said. This non-traditional method restores colon homeostasis by reintroducing missing bacterial flora from a stool collected by a healthy donor through use of gastroscopy, X-ray tip verification, nasogastric tube, colonoscopy or enema.

Eleven published reports, comprising a total of 80 cases of treatment with fecal bacteriotherapy—usually through fecal enema—exhibit a cure rate that is “enviable,” said Dr. Moore. In nine of Dr. Bakken’s studies, the cure rate was 100%; in the other two, it was 94% and 81%. There are also many unpublished reports of success, Dr. Moore noted.

“Never underestimate the healing power of stool,” said Dr. Moore, who himself has performed at least 65 fecal enemas and seen a 97% success rate. Sick elephants in the wild are fed stool from their mothers, he noted, so the treatment idea is “nothing new.”

Bacteriotherapy’s other benefits include the fact that it is inexpensive, has no known side effects and reduces the risk of antibiotic-associated bacterial resistance. It also breaks the cycle of antibiotic usage, and may save costs when compared to repeat courses of antibiotic therapy. Normal bowel function is usually restored within 24 hours of the treatment, Dr. Moore said. Pre-treatment with oral vancomycin and omeprazole is “probably a good idea,” he added. The donor is usually a patient’s spouse or loved one.

“Fecal transplant is ‘dirt cheap,’” Dr. Moore quipped. “It is a low-tech therapy that can be administered in most hospitals … and re-treatment usually isn’t necessary.”

Potential obstacles to the treatment include the possibility that new pathogens could be introduced with the donor sample; a potential for physical complications from the instillation procedure, such as perforation of the hollow viscus; and perceived medico-legal implications imposed by the local institutional review board at the treatment facility, Dr. Moore said. Medicare doesn’t cover donor stool screening and instillation procedures either, he said.

But the biggest problem with the treatment may be the “ick” factor, Dr. Bartlett said at an earlier session.

“Stool implants work best with recurrent c-diff,” Dr. Bartlett said. “But aesthetically, they suck.”

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Research highlights at IDSA

The IDSA meeting brought new research on HIV/AIDS, Lyme disease and Rocky Mountain spotted fever.

One study found that Rocky Mountain spotted fever cases nearly tripled between 2001 and 2005 in the U.S., from 695 to 1,936 cases. The illness was most common in men aged 50-59 years and in the Southern Atlantic states, but there was a substantial increase in adults over age 50, women and suburban dwellers.

“This is the highest level of the disease in the history of its surveillance,” said John Openshaw, MS, study co-author and an Applied Epidemiology Fellow at the Centers for Disease Control. “It likely reflects a combination of factors, including greater physician awareness, more people spending time outdoors and habitat modification.”

Meanwhile, the first study to evaluate molecular evidence of recurrent Lyme disease found that people who experience a second episode of erythema migrans were probably bitten by another tick rather than experiencing a relapse of the first infection. Out of 272 patients from whom skin biopsies were taken, 28 had exactly two occurrences of Lyme disease (while some had more). In six of the patients, researchers obtained genotypes information that showed two different variations of the bacterium caused the infection.

“Our findings underscore the importance of preventing exposure to ticks,” said Robert Nadelman, MD, the study’s lead author and professor of medicine at New York Medical College, Valhalla. “It appears that even when people have already had Lyme disease, they are not taking sufficient steps to avoid being bitten again.”

Two HIV/AIDS studies challenged previous perceptions about the disease. While “wasting”, or excessive weight loss, was once a key characteristic of HIV/AIDS, a new study found that 63% of HIV-positive patients are overweight or obese, about the same percentage as the general population. Use of highly active retroviral therapy (HAART) wasn’t related to weight gain, it found.

“Doctors have been caught up in saving people’s lives and keeping opportunistic infections at bay, but those these rates are low and people are living longer,” said Nancy Crum-Cianflone, MD, MPH, lead author of the study and HIV research physician with TriService AIDS Clinical Consortium in San Diego. “Now we need to start focusing on regular health issues like cancer prevention, blood pressure control and excess weight gain.”

A separate study found HIV-positive people over age 50 on HAART were no more likely to have heart disease, diabetes, osteoporosis or cognitive deficits than the general population. They were more likely to have high blood pressure (51%) compared to a control group (31%), however.

“Earlier studies have shown that patients on HAART had a higher risk of heart attack, but we didn’t see that,” said Nur Onen, MD, lead author of the study and an infectious diseases fellow at Washington University School of Medicine. “But those studies looked at younger people, and those in our study were over 50, and were on therapy for an average of seven years.”

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