Symposium on Drug Resistance

Reviewed by Frank J. Bia, MD, MPH

Organizers of the 6th cistm planned an extensive four-speaker symposium intended to cover new developments in the field of drug-resistant pathogens. These included enteric infections due to Salmonella species by Eduardo Gotuzzo from Lima, Peru; malaria standby therapy by Blaise Genton of Lausanne, Switzerland; sexually transmitted diseases by George Schmid, Atlanta, GA; and tuberculosis by E. Jane Carter, Providence, R.I.

Salmonellosis and Typhoid Fever

Gotuzzo began this symposium by noting that salmonellosis represents a typical zoonotic infection associated with acute diarrhea and, occasionally, systemic manifestations of infection. However, typhoid fever does not involve animals and is a systemic illness transmitted from human to human. This distinction is important, particularly when observing the beneficial effects of antibiotic therapy upon fecal excretion and transmission of S. typhi. Gotuzzo emphasized a now-predominant role for the fluoroquinolones in the therapy of both salmonellosis and typhoid fever based upon several important attributes of the quinolones. These include their convenience and efficacy—specifically, high fecal concentrations of orally administered quinolones (frequently reaching 1000-2000 mcg/g of feces), secretion of quinolones by bowel mucosa, low minimum inhibitory concentrations against Salmonella sp. including resistant strains, elimination of plasmid-carrying resistance genes, and excellent reduction in fecal excretion times and carrier rates along with prevention of relapses when these agents are used appropriately. The quinolones alleviate diarrhea and rapidly eliminate Salmonella sp. from stool, both reducing excretion and transmission while preventing complications of bacteremia such as osteomyelitis and splenic abscess formation.

In Latin America, chloramphenicol remains the standard for treatment of Salmonella infections due to both its low cost and efficacy. Gotuzzo warned that alternatives to chloramphenicol other than the quinolones, including as beta-lactams and folic acid antagonists, may not perform as well. Nor were all quinolones created equal with respect to the treatment of serious Salmonella infections. As the spectrum of quinolone coverage has increased to include more respiratory pathogens, their coverage for Gram-negative pathogens has not been enhanced, and in some cases it has decreased. Quinolones are not used to treat meningitis, especially in newborns. For treatment of Salmonella infections of the central nervous system, third-generation cephalosporins are best used.

In treating typhoid fever (S. typhi), there are important goals to keep in mind. One attempts to abort the complications occurring after the initial period of fever and prevent relapse rates that can reach 10%. The standard of therapy in Latin America has been two weeks of chloramphenicol therapy, which produces nearly 100% response rates, as do the alternatives, ampicillin and trimethoprim/sulfamethoxazole. However, these agents do not reduce either relapse rates or transient carrier state, and only produce 20% cure rates when used to treat resistant strains of S. typhi. When standard oral quinolone therapy with an agent such as ciprofloxacin is used, Gotuzzo recommends a full 10 days of therapy; this is required to prevent relapses occurring after treatment of S. typhi infections.

Those practicing in developed countries face an unusual situation in which more than 60% of typhoid fever represents imported cases—often resistant to antimicrobial agents other than the quinolones. Cases that do originate in developed countries and are not imported are more likely to be missed since they are not clinically suspected at first. Mortality is greater in this group, as it is for the elderly with typhoid fever.

When oral quinolones were used twice daily for 10 days, cure rates approached 100% in adults studied in Peru, and there were essentially no relapses as compared to a rate of 5-10% for chloramphenicol. Quinolones rapidly clear S. typhi from stool, reduce both fecal excretion and community exposure, possibly also decreasing the incidence of subsequent gall bladder cancers associated with chronic carriage. If quinolones are only used for 5-7 days, relapse rates approach 10% and Gotuzzo was firm in his recommendations for a full 10 days of therapy. Alternative agents include third-generation cephalosporins, but the monobactam, aztreonam, has been disappointing in the treatment of adults with typhoid fever, representing a third-line drug with only 70% cure rates.

Malaria and Stand-by Therapy

Swiss and German investigators have considerable published experience offering stand-by malaria therapy to travelers. Stand-by therapy is used in place of prophylaxis for treatment of fevers that might represent malaria in travelers who have resided in an endemic area for more than one week, but without ready access to medical care within. Patients are instructed to follow-up stand-by therapy with an appropriate medical evaluation. Blaise Genton summarized several issues regarding stand-by therapy for malaria and when to use such a strategy, rather than a prophylaxis regimen. Situations include travel to areas of low or moderate malaria endemicity, short-term travel, brief and repeated malaria exposure, or travel to areas where multiresistant malaria is present and stand-by therapy must be provided.

However, there are problems associated with the use of stand-by therapy for malaria that might not have been fully anticipated. Studies have shown approximately 8-10% of travelers in Swiss and German studies experienced episodes of fever. The prediction had been that stand-by therapy would be overused by such travelers, but the reverse actually occurred. Stand-by therapy appears to be underused since patients do not follow these recommendations, often waiting for symptoms to resolve on their own, and not seeking appropriate medical advice awaiting fever resolution. Often, travelers do not think their fever represents malaria, since it has not been made clear that fevers while residing in endemic regions are likely, rather than unlikely, to be caused by malaria. The inability to rapidly self-diagnose malaria with convenient diagnostic kits hinders many who might benefit. These kits are not easy to use and, even with diagnostic certainty, travelers may fear adverse drug effects while lacking better tolerated agents to choose from.

Two new agents that offer considerable promise for the future of stand-by therapy include Malarone (atovaquone/proguanil) and Riamet (artemether/benflumitol). Riamet will be discussed in our next issue by our Associate Editor, Maria Mileno, MD, and TMA Update for Jan/Feb 1997 (Vol. 7, no. 1) contains a summary of a recent Malarone symposium. Riamet provides rapid parasite clearance but, like halofantrine, it may also prolong the QTc interval. Two important advantages for Malarone stand-by therapy include its effects upon the liver stage (hypnozoite) of malaria parasites, making it a potential tissue schizonticide, or causal prophylactic agent—one that can be discontinued a week after leaving a malaria-endemic region. Its relative safety and lack of contraindications to use, other than resistance, make it an attractive possibility for stand-by therapy.

Sexually Transmitted Diseases

George Schmid from the CDC gave participants an extensive view of the status of antimicrobial resistance among organisms responsible for sexually transmitted diseases. The ideal goal is cure of infection with prevention of sequelae. This is readily achievable for bacterial and parasitic agents, but not for viral pathogens. He notes that for most viral agents in this group our goals are to alleviate and possibly cure symptoms while preventing sequelae of infection. As for antiviral resistance, there is currently no worldwide laboratory system for monitoring antiviral resistance.

Fortunately, antibiotic resistance is not yet a problem with regard to Treponema pallidum. For Neisseria gonorrhoeae, extended spectrum cephalosporins are effective worldwide. However, low-dose azithromycin is becoming an issue. The appropriate dosing for that agent is two grams, not one gram, for the treatment of gonorrhea, or treatment failures may occur. Resistance to agents other than the beta-lactams is appearing in the form of widespread quinolone resistance in Asia. The best studied agents are ciprofloxacin and ofloxacin. Resistance to quinolones is inducible, meaning that exposure to increasing levels of these agents in the laboratory will induce resistance by one of three mechanisms: decreased drug penetration due to porin channel alterations, active transport out of cells, and alterations in the target DNA gyrase. Quinolone resistance has become common in Asia since 1993. Resistance rates are so high that gonorrhea acquired in Asia cannot be assumed to be sensitive to the quinolones. In any case, when ciprofloxacin is used for the treatment of gonorrhea, the dose should be 500 mg, not 250 mg—similar to the situation for azithromycin.

Many in the audience learned from this presentation about the current situation with the genitourinary pathogen, C. trachomatis, an organism that is generally treated with tetracycline but for which cases of tetracycline resistance are being reported. There have been at least two clinical reports of resistance to the tetracyclines and, when treated, a small residuum (< 1%) of tetracycline-resistant C. trachomatis isolates are found. They only represent a fraction of the total population of organisms (so-called "heterotypic resistance"). Schmid addressed the issues of both clinical significance and whether this phenomenon is increasing over time. He shared unpublished data from currently available information in the treatment of adolescents showing that cure rates are lower when associated with isolation-resistant organisms, but could identify no real temporal trends toward increasing resistance or failure to cure. Hence, tetracycline resistance is a real phenomenon with clinical significance although the temporal trends do not yet indicate this is increasing.

Antituberculosis Drugs

Jane Carter brought her extensive experience in the area of tuberculosis control to conference participants with a thorough review of resistance of M. tuberculosis to currently available agents beginning with a discussion of known levels of spontaneously appearing resistance in virtually any population of M. tuberculosis. Unlike other bacteria, there is no evidence for horizontal gene transfer of antimicrobial resistance for M. tuberculosis. Hence, multidrug resistant tuberculosis (MDR-TB) is a manmade amplification of a natural phenomenon (i.e., spontaneous resistance with a defined frequency in a population of mycobacteria). It has been known since 1949 that we can select such organisms out with monotherapy.

No single gene is responsible for MDR-TB. If the spontaneous rate of resistance to any single agent is one in 108 mycobacteria (rifampin) and an average patient with cavitary tuberculosis harbors 1012 organisms, the potential for the emergence of resistance exists in such cases depending upon how they are treated with antituberculous agents, particularly if monotherapy is used. Why, then, is resistance becoming such a problem throughout the world? There are many contributing factors and to the extent that they can be eliminated, the problem can be lessened.

With regard to decisions made on the part of patients, the cost of available agents and their side effects hinder compliance, particularly when patient education is not included in a tuberculosis treatment program. Human nature being what it is, when patients feel better they often discontinue the very drugs that are producing the cure because of cost, inconvenience, or side effects. Physicians contribute to the problem by not understanding either the nature of spontaneous resistance or the prevalence of resistant tuberculosis in various populations—then adding a single drug to an already failing regimen. This is an all too common scenario that only ensures additional resistance will occur. In fact, monotherapy also effectively occurs when such a diagnosis is missed, or when monitoring is inadequate to detect a failing regimen.

The system for treatment of tuberculosis has several inherent problems. Drug supplies are not well controlled in some countries and can either be erratic or used indiscriminately. All antituberculous agents are not manufactured equally, and lack of quality control in drug production can place patients on a regimen that approaches monotherapy and predisposes to the emergence of an already present resistant subpopulation—a population that should have been eliminated by using a true multiple-drug regimen. Unforeseen events include variable drug absorption, drug-drug interactions, and the influence of underlying disease such as AIDS, diabetes, and malnutrition, which also influence host response to therapy and can predispose to the emergence of resistance. Carter noted that the current cure rates for multidrug-resistant tuberculosis are around 60%, which are only 10% above rates for the preantibiotic era. Fifty years of what has effectively been episodic monotherapy mean we cannot simply use two drugs but must initiate therapy with four drug regimens. Often, the course that must be continued is over two years for MDR-TB therapy to be curative and may have to include surgical resection.

Reference

1. Symposium S5—Drug resistance. Gotuzzo E, et al. 6th Conference of the International Society of Travel Medicine. Montreal, Québec, Canada, June 6-10, 1999.

The fluoroquinolones are increasingly indicated in the treatment of salmonellosis and sexually transmitted diseases for all of the following reasons or situations except:

a. Orally administered quinolones can achieve high fecal concentrations and rapidly eliminate fecal carriage.

b. The quinolones are the drugs of choice for the empiric treatment of gonorrhea acquired in Asia.

c. Quinolones are likely to prevent relapses of Salmonella infections when used for at least 10 days.

d. Quinolones are not indicated for the treatment of meningitis in children.

e. In Latin America, quinolones are useful in the treatment of drug-resistant salmonellosis.