Resistance tracking upward in latest study

1998 tracking figures highlight conference

Resistance of Streptococcus pneumoniae has either increased or held steady against a host of commonly prescribed antibiotics, according to an in vitro resistance tracking study presented at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy held in late Sep tember in San Diego.

The national tracking study compared 1996-1997 data to 1997-1998 data at 161 U.S. hospitals involved 6,625 total samples, including more than 4,000 samples of S. pneumoniae.

The study monitored the resistance of S. pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis against penicillin, amoxicillin-clavulanic acid, ceftriaxone, vancomycin, cefuroxime, clarithromycin, and levofloxacin. Of the drugs studied, levofloxacin and vancomycin fared well, while S. pneumoniae resistance to macrolides increased the most, and resistance to penicillin remained constant.

But remaining constant was not seen as good news. "These data not only highlight our continuing dilemma with resistance to penicillin, but they raise concerns about trends we are now beginning to see with other classes of widely used drugs," says Clyde Thornberry, PhD, a professor in the department of pathology at Vanderbilt University in Nashville, TN. Thornberry was the lead investigator in the study, which was partly funded by Ortho-McNeil. (See his overview statement to the conference, p. 206.)

Thornberry’s comments, and the conference, end a particularly anxious year over issues of anti biotic resistance and drug development, heightened this summer by deadly cases of vancomycin- resistant Staphylococcus aureus. Agen cies such as the Centers for Disease Control and Prevention in Atlanta quickly responded with usage guidelines, while hospitals raced to evaluate their formulary protocols. Newly approved antibiotics such as Synercid and Trovan helped assuage some of the resistance fears, but an even more deadly outbreak of a virulent Group A streptococcus killed two dozen people in Texas, keeping the issue on the front pages of health care and commercial publications. (Drug Utilization Review was no exception; see related cover story packages in the May and July 1998 issues.)

The conference also included discussions concerning the fears of cross-resistance, especially with regard to vancomycin. For example, concerns are increasing that genes conferring vancomycin resistance, found in vancomycin-resistant enterococci, may be transferable to methicillin-resistant S. aureus, creating a more virulent and untreatable bacteria.

Thornberry’s tracking study did find that S. pneumoniae strains with strong penicillin resistance also were resistant to other penicillins, cephalo sporins, and macrolides, but no associated resistance was found to vancomycin or levofloxacin.

The tracking study also found:

o S. pneumoniae resistance, after doubling in recent years, remained constant at 14% in 1997-1998 compared to the previous year.

o The largest jump found was S. pneumoniae resistance to the macrolide clarythromycin, which increased from 18% in 1996-1997 to 22% in 1997-1998.

o S. pneumoniae resistance to the fluoroquinalone levofloxacin did not increase. The drug also was active against all isolates of Haemophilus influenzae and Moraxella catarrhalis.

o H. influenzae and M. catarrhalis strains, though, did produce the enzyme B-lactamase, which could make penicillins ineffective. Specif ically 33% of H. influenzae strains and 92% of M. catarrhalis strains produced B-lactamase.

Oxazolidine, a new class of antibiotic aimed at inhibiting protein synthesis of gram-positive bacteria earlier than other antimicrobials, debuted at the Interscience Conference on Antimicrobial Agents and Chemotherapy. Line zolid, from Pharmacia & Upjohn in Bridgewater, NJ, is the first drug in this class to be tested in Phase III clinical trials.

Researchers hope that oxazolidine-class drugs will preventing bacterial reproduction at an earlier phase, thereby avoiding cross-resistance between the drug and other antibiotics.

Pharmacia & Upjohn has oral and IV formulations in development, aimed at treating gram-positive infections and vancomycin-resistant enterococci (VRE), methicillin-resistant S. aureus (MRSA), and penicillin-resistant Streptococcus pneumoniae (PRSP). In a preclinical study by the company and the Mayo Clinic in Rochester, MN, susceptibility tests were done of resistant bacterial isolates to Linezolid and vancomycin. The testing was possible because of gene amplification techniques developed at the clinic, which allow researchers to sensitively detect vancomycin-resistance-associated genes, then identify isolates of VRE and group them by genetic differences.

Clinicians established minimum inhibitory concentrations (MIC) and minimum bacterial concentrations (MBC) of linezolid and vancomycin as a collection of resistant bacterial isolates, with the MIC being the lowest concen tra tion of antimicrobial agent that inhibits the growth of an organism, while the MBC is the lowest concentration that kills the bacteria. An MIC value of four mg/ml or less of vancomycin was interpreted as sensitive or susceptible. A similar value for linezolid has not been determined. (See chart, p. 216, for the breakdown of the susceptibility of resistant bacterial isolates to linezolid and vancomycin.)

Also at the conference, early efforts to develop a vaccine and antibody process against vancomycin-resistant strains of S. aureus were presented by the biopharmaceutical firm Nabi in Boca Raton, FL.

In a paper titled, "In Vivo & In Vitro Evalua tion of Previously Isolated Vancomycin Inter mediate Strains of Staphylococcus aureus," researchers explained how, through in vitro assays, antibodies killed S. aureus strains showing a reduced sensitivity to vancomycin and offer protection to animals carrying resistant bacteria. The company’s experimental vaccine, StaphVAX, is in Phase III trials for hemodialysis patients, while its preventive antibody, Altastaph, is in Phase I/II trials for low birth weight babies.

The rush to attack vancomycin-intermediate resistant S. aureus (VISA) was heightened this summer when a hemodialysis outpatient died after developing the resistant strain. That followed two other U.S. cases this year. In all the cases, the patients were either on hemodialysis or peritoneal dialysis or were experiencing some form of renal failure. (For details, see DUR, July 1998, p. 109.) Vanco mycin became the drug of choice against S. aureus after infectious strains became resistant to methicillin.

The American College of Gastroenterology (ACG) in Arlington, VA, is recommending the use of oral metronidazole over that of vanco mycin for the common treatment of Clostridium difficle-associated disease (CDAD) to help reduce the risk of vancomycin resistance. That position has been endorsed by the American Society of Health-System Pharmacists in a therapeutic position paper aided by the Centers for Disease Control and Prevention and the Society of Infectious Disease Pharmacists. The organizations say vancomycin should be considered only for life-threatening cases or in cases where patients have failed to respond to metronidazole, as both drugs are equally effective in treating the majority of CDAD cases. According to the ACG, many cases of mild CDAD can be treated by simply taking the patient off a given antibiotic that may have sparked the condition, followed by fluid and electrolyte treatment.

Largely a hospital- or nursing home-born condition, CDAD is a gastrointestinal bacterial infection resulting from bacteria pooling in the colon, creating toxins that lead to mild to serious diarrhea.