What do we really know about antibiotic pharmacodynamics?

Antibiotic pharmacodynamics is an evolving science that focuses on the relationship between drug concentration and pharmacologic effect, which is an antibiotic-induced bacterial death that also can manifest as an adverse drug reaction. The pharmacologic action of antibiotics usually can be described as concentration dependent or independent, although such classifications are highly reliant on the specific antibiotic and bacterial pathogen being studied. Quantitative pharmacodynamic parameters, such as ratio of the area under the concentration-time curve during a 24-hour dosing period to minimum inhibitory concentration (AUC0-24:MIC), ratio of maximum serum antibiotic concentration to MIC (Cmax:MIC), and duration of time that antibiotic concentrations exceed MIC (T>MIC), have been proposed as likely predictors of clinical and microbiologic success or failure for different pairings of antibiotic and bacteria. Thus far, most pharmacodynamic data reported have focused on fluoroquinolones, but work has been conducted on vancomycin, beta-lactams, macrolides, aminoglycosides, and other antibiotics. Despite the development of a number of different pharmacodynamic modeling systems, remarkable agreement exists between in vitro, animal, and limited human data. Although still somewhat premature and requiring additional clinical validation, antibiotic pharmacodynamics will likely advance on four fronts: the science should prove to be extremely useful and represent a cost-effective and efficient method to help develop new antibiotics; formulary committees will likely use pharmacodynamic parameters to assist in differentiating antibiotics of the same chemical class in making antibiotic formulary selections; pharmacodynamic principles will likely be used to design optimal antibiotic strategies for patients with severe infections; and limited data to date suggest that the application of pharmacodynamic concepts may limit or prevent the development of antibiotic resistance. The study of antibiotic pharmacodynamics appears to hold great promise and will likely become a routine part of our daily clinical practices.

Comparison of once-daily versus twice-daily administration of cefdinir against typical bacterial respiratory tract pathogens.

In an in vitro pharmacodynamic model, a twice-daily cefdinir dosing regimen was more effective than a once-daily regimen against common bacterial respiratory pathogens in producing 3-log(10) killing and preventing the occurrence of regrowth at 24 h. Twice-daily administration is likely the more appropriate cefdinir dosing strategy for the treatment of community-acquired pneumonia.

Fluoroquinolone resistance in anaerobic bacteria following exposure to levofloxacin, trovafloxacin, and sparfloxacin in an in vitro pharmacodynamic model.

This investigation explored pharmacodynamic characteristics of fluoroquinolones against Bacteroides thetaiotamicron and the potential for development of resistance. An in vitro model was used to generate kill curves with three fluoroquinolones at various area under the concentration-time curve (AUC)/MIC ratios. Concentration-independent killing was observed. Increases in MICs were noted following exposure to fluoroquinolones at AUC/MIC ratios of 6 to 14.

In vitro pharmacodynamic analysis of single daily dosing versus conventional dosing of gentamicin administered with penicillin against Enterococcus faecalis.

STUDY OBJECTIVE: To compare the effectiveness of single daily dosing (SDD) versus conventional dosing of gentamicin when administered with penicillin to treat enterococcal infections. DESIGN: In vitro pharmacodynamic model. SETTING: Hospital laboratory. MEASUREMENTS AND MAIN RESULTS: A 24-hour in vitro pharmacodynamic model was employed to simulate SDD and 3 times/day dosing of gentamicin, in conjunction with continuously infused penicillin, against Enterococcus faecalis. Duplicate 24-hour kill curves were generated with varying concentrations of penicillin and gentamicin alone and in combination. No difference in the rate of kill was seen between any combination of penicillin and gentamicin. Regrowth occurred only with drug combinations in which penicillin was administered continuously at the minimum inhibitory concentration. Variations in the gentamicin dosing regimen did not affect regrowth. CONCLUSION: In the treatment of enterococcal infections, an SDD regimen for gentamicin shows no efficacy benefit compared with conventional dosing.

Neurotoxicity in single photon emission computed tomography brain scans of patients reporting chemical sensitivities.

The subset of patients reporting chemical sensitivity with neurocognitive complaints usually exhibits specific abnormalities of brain metabolism consistent with neurotoxicity, on imaging with single photon emission computed tomography (SPECT). These recurrent neurotoxic patterns are characterized by a mismatch in tracer uptake between early- and late-phase imaging, multiple hot and cold foci throughout the cortex, temporal asymmetry and increased tracer uptake into the soft tissues and, sometimes, the basal ganglia. Previous studies confirm these neurotoxic findings in patients with neurotoxic chemical exposures and breast implants. Affective processes such as depression do not, alone, show this pattern. These abnormalities in SPECT images correlate with documented neurocognitive impairment. Controlled challenges to ambient chemicals can induce profound neurotoxic changes seen on SPECT imaging in chemically sensitive patients. Detoxification treatment techniques frequently produce significant improvement on brain SPECT brain imaging in these patients. Neurotoxicity appears to be characteristic in many cases of chemical sensitivity.

Clinical characteristics of chemical sensitivity: an illustrative case history of asthma and MCS.

A case history of the induction of asthma and chemical sensitivity in a 42-year-old registered nurse illustrates several of the characteristic features of multiple chemical sensitivity (MCS). This patient's problems started shortly after moving into a new home under construction, with associated chemical exposures. Other MCS patients report the onset of the condition with other chemical exposures such as those encountered at their places of work or use of pesticides at their residences. Patients often describe a spreading phenomenon of increasing intolerance to commonly encountered chemicals at concentrations well tolerated by other people. Symptoms usually wax and wane with exposures, and are more likely to occur in patients or families with preexisting histories of migraine or with classical allergies. Idiosyncratic medication reactions (especially to preservative chemicals) are common in MCS patients, as are dysautonomia symptoms (such as vascular instability) and poor temperature regulation. Myalgia and joint pains and food intolerance are common features as well. Contamination with xenobiotic chemicals is frequently found in these patients when they are tested. Reactive airways dysfunction syndrome is a recently identified condition that exhibits features of both asthma and chemical sensitivity. MCS patients frequently have patterns of neurotoxic brain metabolism that can be confirmed on single photo emission computed tomography imaging.

Mitogenic effects of mycotoxins on T4 lymphocytes.

Mycotoxins have compromising effects on varied biological systems, even when ingested at levels which do not evoke manifestations of clinical mycotoxicoses. No data have been previously found as to the therapeutic and mitogenic effects of mycotoxins. This was the objective of the present work. Human peripheral T4 lymphocytes were obtained by venipuncture, propagated in RPMI 1640 medium and challenged with varied concentrations of aflatoxins, B1, B2, G1, and G2. The cells were stained with propidium iodide and fluorescent isothiocyanate (FITC) and examined microfluorometrically. All the mycotoxins were significantly mitogenic on the basis of dose response. No adverse effects were observed when doses of 10, 50 and 100 micrograms were administered on a modest clinical basis to volunteers.

Single photon emission computed tomography of the brain in patients with chemical sensitivities.

Chemical sensitivities display a recurrent pattern on scintigraphic examinations of the brain. The pattern can include mismatching between early and late imaging, multiple hot and cold foci distributed throughout the cortex without regard to lobar distribution (salt and pepper pattern), temporal asymmetries, and sometimes increased activity in the basal ganglia. This study used Desert Shield/Desert Storm veterans who present with abnormal neurological and psychological symptoms as a model to exhibit abnormalities by brain scintigraphy. These are typical of those seen in patients with documented exposure to neurotoxic compounds who develop a clinical syndrome that has been termed "chemical sensitivity." Exposure to cocaine, alcohol, and other substances of abuse can result in abnormal scintigrams of the brain using tracers such as [technetium-99m]hexamethylpropyleneoxime. This study used techniques combining regional cerebral blood flow data with delayed distributional data after the intracellular conversion of the tracer into a hydrophilic molecule. In addition to delayed image abnormalities, a mismatch occurs in the regional activity between the two image sets of the veterans. This degree of mismatch was not seen in control subjects who were screened for avoidance of neurotoxic agents. Patterns identified from examinations performed on patients with known exposure to petroleum distillates, pesticides and other materials linked with neurotoxicity were identified in some veterans of the Desert Shield/Desert Storm operation. A single case of repeated examinations on a veteran showed a reversion of these patterns toward normal after therapy. This reversion followed independent assessments of clinical improvement.

History and clinical presentation of the chemically sensitive patient.

Although no one has all the answers to the mystery of chemical sensitivity, the reality of this condition, most recently called multiple chemical sensitivities, is not in doubt. Evidence is increasing of its possible physiologic mechanisms, which will be discussed later in this volume. From the evidence and from personal and professional experience, the author believes that chemical sensitivity is not a diagnosis of exclusion, and that fixed-name diseases may have environmental triggers or complicating factors (Rea, 1990b). With appropriate preparation and environmental controls, MCS can be investigated and diagnosed in a scientific and reproducible manner.

Treatment options in multiple chemical sensitivity.

The essential features of treatment for chemical sensitivity are: 1) Encouraging the provision of clean air, food, water, and surroundings. 2) Identifying substances to which the patient is sensitive, with subsequent a) enhanced avoidance, or b) specific immunotherapy to reduce the patient's reactivity to those substances. 3) Assessing and enhancing the patient's nutritional status to maximize the body's ability to detoxify and to minimize the free-radical production and oxidative stress of xenobiotics. 4) Addressing concurrent problems such as infections, immunosuppression, and other medical conditions in an appropriate fashion. 5) Evaluating the patient's psychologic status and addressing any social and emotional problems in a compassionate manner. The author believes that multiple chemical sensitivity is a real condition with documented physiologic abnormalities. It is not a functional or psychologic illness or a belief system of the patient. Second, this condition is diagnosable and treatable by various means. These treatment options not only make common sense but usually result in significant improvement for these unfortunate patients, who deserve the very best efforts of their health care providers.

Chemical sensitivity in physicians.

By the nature of their work environment, physicians may be exposed to potentially toxic substances that can trigger chemical sensitivity. Nineteen physicians with chemical sensitivity were evaluated at the Environmental Health Center - Dallas regarding: type of specialty, history of chemical exposure, symptoms produced, food and water tolerance, immune parameters and double-blind chemical inhalation challenge. Food and chemical sensitivities were demonstrated in these physicians by oral, intradermal and inhalation challenges. After treatment, fifteen of the nineteen physicians were able to resume medical practice. Potential sources of chemical exposure in medical environments are evaluated.

Confirmation of chemical sensitivity by means of double-blind inhalant challenge of toxic volatile chemicals.

Fifty chemically sensitive patients with vascular, asthmatic and arthritic signs, ranging in age from 21 to 61, were exposed to double-blind challenges of ambient doses of inhaled toxic chemicals in a specially designed booth in an Environmental Control Unit (ECU). Primary signs and symptoms were recorded before and after challenge with five chemicals and three placebos. Inhaled challenges included phenol (less than .0025 ppm), petroleum-derived ethyl alcohol (less than .5 ppm), formaldehyde (less than .2 ppm), chlorine (less than .3 ppm), and pesticide (2, 3,-D at less than .0034 ppm). Placebos were water or saline. A set on testing criteria were evaluated for maximizing the likelihood of well-defined, reproducible information from these ambient-dose double-blind challenges. For best results, these testing criteria include: Before testing, the patient must be housed in a chemically less polluted environment. The individual must have been de-adapted to food, air, and water pollutants by means of a water fat for three to four days. At the time of the challenge, the patient must be on food and water previously determined to be safe. An enclosed non-pulluted challenge booth must be used for these chemical exposures. Sign and symptom scores appropriate for that patient must be recorded, before and after challenge. Appropriate doses of the chemical in question (determined by air concentration and length of exposure) are necessary to investigate a particular problem. The conclusion of the study is that in these patients, chemical sensitivity clearly does exist (pulse rate differences between positive responses and placebo - p .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Food and chemicals as environmental incitants.

Susceptibility to environmental incitants such as air, food and water components is becoming an increasingly recognized health problem. These sensitivities and reactions can induce a spectrum of symptoms affecting smooth muscle, mucous membranes and collagen in the respiratory, gastrointestinal, genitourinary and vascular systems. These reactions may be mistaken for hypochondriasis, but actually are due to reactions to foods and chemicals found in the patient's home and work environments. Careful clinical histories should alert the nurse and physician, who can confirm suspicions by eliminating and challenging the patient with potentially offending agents under controlled circumstances.

Food and chemicals as environmental incitants.

Susceptibility to environmental incitants such as air, food and water components is becoming an increasingly recognized health problem. These sensitivities and reactions can induce a spectrum of symptoms affecting smooth muscle, mucous membranes and collagen in the respiratory, gastrointestinal, genitourinary and vascular systems. These reactions may be mistaken for hypochondriasis, but actually are due to reactions to foods and chemicals found in the patient's home and work environments. Careful clinical histories should alert the nurse and physician, who can confirm suspicions by eliminating and challenging the patient with potentially offending agents under controlled circumstances.