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Antibiotics' Multiple Actions
In the feature article "Intracellular Activity, Potential Clinical Uses of Antibiotics" (ASM News, October 1998, p. 570), Robert M. Rakita discusses the three-way interaction of the pathogens, host defense cells, and antimicrobial agents, especially inside the neutrophils and macrophages. The preparation of newer macrolide and quinoline antibiotics try to achieve higher intracellular levels with greater antimicrobial activities and with minimal cellular damage. The goal is the control and elimination of the infecting bacteria. What is often overlooked is the broad cellular reactions of antibiotics in addition to their antimicrobial and clinical response. Inhibiting a pathogen's growth with antibiotics usually includes the inhibition of cellular protein synthesis. The microbial elimination depends on its intracellular location and the host's immune responses.
Prior to the availability and application of antibiotics for the control of infectious diseases, various chemicals were used to ward off the offending bacterial pathogens without killing the patient. Later, when the broad-spectrum antibiotics became available, the new antibiotics were extensively prescribed. The choice and dosage of antibiotics were usually made after the isolation and identification of the infecting agent. The development of allergies and toxicities to some antibiotics limited their use in many patients. Such systemic reactions indicated antibiotics were more than just antimicrobial.
The initial use of antibiotics in some chronic disease patients may cause a flare or clinical worsening with a serologic rise in antibody titer to a suspected microbial agent such as mycoplasmas. This temporary flare of inflammatory symptoms following antibiotic (or gold salt) treatment is often referred to as a Jarisch Herxheimer reaction. Knowing this, the patients are encouraged by the temporary worsening following their antibiotic treatment. The delayed flare reaction resulting from the release of microbial antigen into the sensitized host tissue as in a "graft versus host" reaction is not the typical allergic or drug sensitivity. The flare reaction could result from the released microbial antigen complexing with its circulating antibodies to promote complement fixation.
The tetracycline antibiotics can also act like immunosuppressants by blocking the formation of the antibody-antigen complex that initiates inflammation. Many clinical disorders are considered immune complex diseases of probable infectious origin, such as rheumatoid arthritis and lupus. With its deposition in tissue membranes, the complex promotes the activation of complement with the proteolytic destruction of tissues. The tetracycline antibiotics are also potent metal-chelating agents comparable to the clinical use of ethylenediaminetetraacetate (EDTA), ascorbic acid, and penicillamine. Consequently the mode of antibiotic administration, i.e., intravenous or oral, could have an effect on the chelate composition of their absorption state and thus their reactivity. When complexed with divalent trace metals (Cu, Zn, Mg, Fe, etc.) the antibiotics become antioxidants and electron scavengers. As such the metal antibiotic complex becomes antiinflammatory, neutralizing free oxygen radicals. Although briefly tested, the Cu-aspirinate complex has greater antiinflammatory activity than plain aspirin. In microbes with low pathogenic activity, such as mycoplasmas, pulsed antibiotic therapy with lower doses over longer periods has proven more effective and with fewer side effects. In clinical trials the chronic immunologic disorders of probable infectious etiology respond to long-term pulsed antibiotics and without the loss of sensitivity. Although suspected of infectious origin, the clinical trials of minocycline antibiotic in rheumatoid arthritis was based on its inhibitory action of the destructive metalloenzyme collagenase. The effectiveness of antibiotic treatment was based primarily on its antiinflammatory action rather than its antimicrobial activity.
In cases where the microbial agent is not isolated and identified or the DNA cannot be matched, antibiotic treatment may elicit a specific antibody response to a known antigen. A rise in serum antibody level during the acute to convalescent phase while on antibiotic therapy would indicate a hidden infection with a persisting silent microbe. When used excessively in high doses the antibiotics, as protein synthesis inhibitors, could also inhibit the synthesis and function of essential cellular proteins and not just the pathogens. The use of generic antibiotics may have the same antimicrobial potency while their systemic action in the host may vary significantly. For example, in the treatment of rheumatoid arthritis the generic minocycline is reportedly less effective than minocin. In some patients this difference in antibiotic action could result from patient's heterogeneity.
Harold W. Clark
Mycoplasma Research Institute
Beverly Hills, Fla.
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