Vancomycin Still Very Strong In Infected Cancer Patients, New Analysis Shows

SAN DIEGO—There's good news and there's bad news for hospitalized infected oncology/hematology patients in the findings of the novel broad-based drug resistance surveillance program called CANCER (Chemotherapy Alliance for Neutropenics and Control of Emerging Resistance), now entering its second year. The good news is that contrary to general belief, resistance to antibiotics is no greater in cancer patients than in any other seriously ill patients with nosocomial infections. Another hopeful finding, reported lead author Ronald Jones, MD, formerly Chief of Microbiology at the University of Iowa and now Professor of Medicine at Tufts University School of Medicine and Head of JMI Laboratories, a surveillance and monitoring center in North Liberty, Iowa, is that vancomycin, known for more than 40 years as the drug of last resort in treating gram-positive bacterial infections, is still “a remarkably effective broad-spectrum agent”—-even more effective in some situations than several highly touted newer antibiotics. The bad news, however, is that vancomycin resistance in Enterococcus faecium, a common pathogen, remains a problem for neutropenic patients. “E. faecium is the only organism that has consistently challenged vancomycin,” Dr. Jones said in an interview. “About 90% of all vancomycin resistance comes from this one bug. If we ease off on infection control and antibiotic formulary management, other pathogens may turn resistant in the near future.” ‘Alarming’ Case He cited an “alarming” case recently reported by the Centers for Disease Control and Prevention in which resistance genes from E. faecium moved into an aggressive staphylococcus aureusorganism, making the patient nearly untreatable. Dr. Jones said he worries whether this was an anomaly or the harbinger of a trend. He and his colleagues recently presented three posters at this year's Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) here, analyzing the status of antibiotic resistance in cancer patients in 32 major hospitals nationwide—and one in Canada—in light of strong government-sponsored campaigns to fight resistance. “We focused on high-risk cancer patients especially to see how the newer drugs work compared with vancomycin,” Dr. Jones noted. Since most of the 2,000 isolates from bloodstream, respiratory, urinary, and skin infections submitted by the hospitals were gram-positive, the researchers devoted one study entirely to widely used gram-positive oriented agents, including an investigational new type of fluoroquinolone called garenoxacin. The following are the highlights: Vancomycin provided excellent coverage—96.5%—against common gram-positive microbes in neutropenic cancer patients, except for resistant enterococci (VRE). Teicoplanin, which resembles vancomycin structurally but is not available in the US, demonstrated 97% coverage. Linezolid showed 100% activity against all strains including enterococci (but see caveat below). Quinupristin/dalfopristin, and garenoxacin each provided about 88% coverage. Atifloxacin, usually very effective against gram-negative organisms, covered only 70% of gram positives. Dr. Jones observed: “This new report shows that infection control in hospitals is starting to work. The numbers of VRE strains are now increasing by less than 1% annually compared with the high rates five years ago. Perhaps clinicians can feel better about using vancomycin as a drug of last resort on occasion.”Figure: Ronald Jones, MD, said that vancomycin, known for more than 40 years as the drug of last resort in treating gram-positive bacterial infections, is still “a remarkably effective broad-spectrum agent”—-even more effective in some situations than several highly touted newer antibiotics.Role of Linezolid Since linezolid is the main therapeutic alternative to vancomycin, Alan H. Mutnick, PharmD, a member of Dr. Jones's team who is Associate Professor of Pharmacy at the University of Iowa College of Pharmacy, presented a separate analysis of data from concurrent clinical studies on emerging resistance to the drug. The findings were “terrifying,” he noted in an interview, although only eight patients with linezolid-resistant pathogens in the bloodstream were identified across the entire country. Most of the patients (who ranged in age from 11 months to 64 years) had received prolonged courses of the drug. However, a linezolid-resistant E. faecium strain was found in one man who never received linezolid. “The patients came from widely separated institutions from Washington [State] to New York, which means resistance is out there, albeit still very rare,” Dr. Mutnick emphasized. Also, “while five patients were found to harbor enterococci—the usual suspects—in three patients the gene mutation occurred in other common species.” These included coagulase-negative staphylococcus, S. aureus, and the viridans group of streptococci—the last with a history of being lethal to cancer patients. “Oncologists are wary of viridans species, which grow in the presence of prophylaxis and treatment and can kill a neutropenic patient in a few days,” Dr. Jones observed. He noted a recent study of infected cancer patients by Alan Tunkel, MD, and Kent A. Sepkowitz, MD, who cited severe neutropenia, oral mucositis, high-dose cytosine arabinoside, and prophylactic use of trimethoprim/sulfamethoxazole as key factors in the spread of viridans streptococci. The only good news in this scenario, added Dr. Mutnick, is that viridans group streptococci are not resistant to vancomycin. Both researchers noted that much of the resistance to linezolid can be traced to the health care environment—i.e., doctors, nurses, and aides—or to other patients. “Infected patients should be isolated,” urged Dr. Jones. “And the value of handwashing by caretakers still can't be overestimated. We don't want to see resistance to linezolid follow the same road as vancomycin resistance did a few years ago.” Drugs for Gram-Negative Pathogens Widely used piperacillin/tazobactam showed superior coverage over comparator penicillins against E. coli, the top-ranked gram-negative pathogen in the isolates of cancer patients studied. This drug also was lethal to Klebsiella spp., Pseudomonas aeruginosa, and Enterobacter spp. The rank order of killing power for cephalosporins against enteric bacilli began with cefepime (100% susceptibility) followed by ceftriaxone, ceftazidime, cefuroxime, cefoxitin, and cefazolin. Overall, imipenem showed the broadest spectrum of coverage. Among the fluoroquinolones, gatifloxacin, and levofloxacin were more effective than highly touted ciprofloxacin against the five most prevalent gram-negative organisms, and were potent (91% susceptibility) against dangerous but rare Stenotrophomonas maltophilia as well. “It's very helpful to know these susceptibility and resistance patterns,” said Dr. Mutnick. “Now we need a usage study—with data on the actual dosage of patients using these drugs—to relate to our findings and make them even more meaningful in clinical practice.” He emphasized in his summary that linezolid resistance has now extended beyond enterococcus species and that this resistance should not preclude the use of older antimicrobials. “It calls for sensitivity studies on a case-by-case basis to find the best drug,” he said. In addition, routine monitoring for linezolid resistance and prompt reporting to clinicians, are a must. “I believe there are a lot more than eight patients out there harboring linezolid-resistant organisms,” said Dr. Sepkowitz, Head of the Clinical Infectious Diseases Section of Memorial Sloan-Kettering Cancer Center. “The study shows the bare beginnings of a trend. Watch for a dramatic rise in the next few years.” CANCER Surveillance Program The Chemotherapy Alliance for Neutropenics and Control of Emerging Resistance (CANCER) Surveillance Program is a three-year study to monitor the effect of antibiotics in hematology-oncology centers. The study reported by Dr. Jones provides data from the first year. Asked to comment on the program's usefulness so far, Kent A. Sepkowitz, MD, Head of the Clinical Infectious Diseases Section of Memorial Sloan-Kettering Cancer Center, said it was off to a good start and suggests some important trends that should gain volume over time.”

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