Requirements for Successful Antimicrobial Therapy

Requirements for Successful Antimicrobial Therapy

Clinical Diagnosis

                Successful chemotherapy usually requires a specific diagnosis, even though a reasonable preliminary diagnosis is often all that is possible, at least initially.

Microbiologic Diagnosis

                Treatment should be aimed at a specific pathogen whenever feasible. However, polymicrobial infections are common. The ideal is a conclusive microbiologic diagnosis, but frequently this must be presumptive (at least initially), and treatment must be based on experience. Rational deduction may be necessary under field conditions. Empirical antimicrobial therapy, that is, the ability to predict the infecting microbe based on site of infection and the drugs to which that microbe are susceptible, without the support of culture and susceptibility data, is increasingly problematic. Older data upon which empirical therapy is based often failed to discriminate between infecting pathogens and normal flora, making it difficult to predict the actual cause of infection. More importantly, microbial resistance has eliminated many drugs that originally were considered effective against the infecting pathogen.

                The use of cytology should not be overlooked. Examination of a direct smear stained with Wright's or Gram's stain may help to establish the types of pathogens involved (gram-positive or gram-negative rods or cocci).

Culture and Susceptibility Testing

Isolation and characterization of the causative pathogen, susceptibility testing, and determination of the MIC provide a sound foundation from which to select the antimicrobial drug, as well as the dosage regimen. However, under field conditions, it is often difficult to attain laboratory support for antimicrobial therapy. Package insert data or recent literature may be helpful for designing a dosing regimen under these conditions.

Ideally, the selection of an appropriate drug and dosing regimen will be based on the minimum inhibitory concentration (MIC) of the drug toward an isolate of the infecting organism that has been cultured from the patient. However, some organisms are too slow-growing for MIC determination, limiting reports to S (susceptible), I (intermediate), or R (resistant) designation. The validity of susceptibility data is only as good as the sample itself. Care should be taken to assure that the sample reflects the infected tissue and that proper cleansing accompanies sample collection. Differences in testing among laboratories can markedly impact interpretation. Ideally, testing will be performed by a laboratory that follows guidelines and interpretive criteria promulgated by the Clinical Laboratory Standards Institute.

Data from even appropriately collected samples tested under ideal conditions remain subject to limitations. Testing cannot take into account the impact of distribution to the site of infection, host factors such as inflammation, or microbial factors, including the size of the inoculum. These and other factors may indicate a need to modify the dosing regimen to assure adequate concentrations at the site of infection. Positive factors not evident during testing include the impact of subinhibitory concentrations (post-antibiotic effects), which may provide persistent antimicrobial effects and facilitate host removal of bacteria. Persistent effects have been demonstrated for penicillins, cephalosporins, macrolides, tetracyclines, aminoglycosides, and several other antibacterial agents. Susceptibility testing also does not take into account the impact of the time course of drug concentrations on antimicrobial efficacy.

Appropriate Selection of Antimicrobial Agents

Among the factors to be considered are the causative microorganism(s), results of sensitivity tests, pathogenicity of organisms, pathologic lesions, acuteness of infection, pharmacokinetics of the drug(s) indicated, expense, potential drug toxicity, organic dysfunctions (especially kidney and liver function), and possible interactions with drugs administered concurrently.

The integration of pharmacokinetics and pharmacodynamics should facilitate the selection of both drug and dosing regimen. Concentration-dependent drugs should be compared based on the ratio of C_max of each drug and the MIC or MIC₉₀ of the infecting (or assumed infecting) organism. For time-dependent drugs, comparisons are made in the time that elapses as plasma drug concentrations decline from the C_max to the MIC of the infecting organisms.

Correct Dosage and Route of Administration

The dosage selected should result in adequate therapeutic concentrations at the site(s) of infection for sufficient time without causing side effects or toxicity. For concentration-dependent drugs, higher dosages that assure the peak drug concentration is 10–12 times the MIC of the infecting organism are more likely to enhance therapeutic success than are shorter intervals. For β-lactam and other time-dependent drugs, therapeutic success appears to be greater if the concentration remains above the MIC for about 50% to 75% of the dosing interval, and efficacy is likely to be improved more by decreasing the interval than by increasing the dose. The advocated dosage schedules should be carefully followed for at least 7 days (although response should be apparent in 3–4 days for most infections), or longer if needed, to ensure elimination of the pathogen and to prevent relapse, reinfection, or development of antimicrobial resistance.

Ancillary Treatment, Nutritional Support, and Nursing Care

Supportive treatment, optimal nutrition, and general nursing care are often critical for successful management of infectious disease. Ancillary treatment might include the use of anti-inflammatory agents, antidiarrheal preparations, expectorants, bronchodilators, inotropic agents, urinary acidifiers and alkalinizers, immunopotentiators, and fluid and electrolyte replacement. Attention should be given to caloric and nutrient intake, especially of protein and vitamins. These nutrients play a cardinal role in immune responsiveness.

Combination Therapy

Treatment with antimicrobial combinations may be necessary in certain cases. The administration of 2 or more agents may be beneficial in the following situations: 1) to treat mixed bacterial infections in which the organisms are not susceptible to a common agent, 2) to achieve synergistic antimicrobial activity against particularly resistant strains (eg, Pseudomonas aeruginosa), 3) to overcome bacterial tolerance, 4) to prevent the emergence of drug resistance, 5) to minimize toxicity, or 6) to prevent inactivation of an antibiotic by enzymes produced by other bacteria that are present.

Additive or synergistic effects are seen when antibacterial agents are used in combination, but antagonism may also emerge, sometimes with serious consequences. Generally, bacteriostatic agents act in an additive fashion with one another, whereas bactericidal agents are often synergistic when combined. However, the effects of several bactericidal antibiotics are substantially impaired by simultaneous use of drugs that impair microbial growth or “bacteriostatic” drugs (eg, most ribosomal inhibitors). This is a general guideline only; many exceptions are known, and confounding factors also play a role. Classification of antimicrobials as bactericidal or bacteriostatic can also be misleading because “bactericidal” drugs can be rendered bacteriostatic if sufficient drug concentrations are not achieved at the site of infection. However, in general, the following common antimicrobials at MIC concentrations are likely to be bactericidal: penicillins, cephalosporins, aminoglycosides, trimethoprim/sulfonamides, nitrofurans, metronidazole, and quinolones. The following antimicrobials at usual concentrations are generally bacteriostatic: tetracyclines, chloramphenicol, macrolides, lincosamides, spectinomycin, and the sulfonamides.

Ideally, antimicrobial selection should be based on mechanisms of action that are different and on spectra of activity that are complementary. β-Lactams are often selected because their action is unique and not only complements other drugs but also facilitates movement of other drugs through the damaged cell wall into the microbe. Examples of combination therapy for mixed infections include the use of clindamycin, metronidazole, or the semisynthetic penicillins for their anaerobic coverage in combination with aminoglycosides for their gram-negative efficacy. Synergism against certain bacterial pathogens frequently can be achieved with combinations of penicillins or cephalosporins and aminoglycosides. The combined use of trimethoprim with selected sulfonamides or clavulanic acid with other β-lactams are other examples of synergistic effects.

Preventing the development of resistance with combination antimicrobial therapy is best exemplified by the use of carbenicillin or amikacin together with gentamicin or tobramycin for the treatment of Pseudomonas infections.

Bacterial enzymatic inactivation of β-lactam antibiotics, such as the penicillins and cephalosporins, can be decreased by concurrent administration of a β-lactamase inhibitor, such as clavulanic acid or sulbactam.