An “empiric” antimicrobial regimen is begun before the offending organism is identified and sometimes before the documentation of the presence of infection, whereas a “definitive” regimen is instituted when the causative organism is known.
Confirming the presence of infection
Fever is defined as a controlled elevation of body temperature above the expected 37°C (98.6°F) (measured orally) and is a manifestation of many disease states other than infection.
Many drugs have been identified as causes of fever. Drug-induced fever is defined as persistent fever in the absence of infection or other underlying condition. The fever must coincide temporally with the administration of the offending agent and disappear promptly upon its withdrawal, after which the temperature remains normal.
Signs and symptoms
White Blood Cell Count
Most infections result in elevated white blood cell (WBC) counts (leukocytosis) because of the mobilization of granulocytes and/or lymphocytes to destroy invading microbes. Normal values for WBC counts are between 4000 and 10,000 cells/mm3.
Bacterial infections are associated with elevated granulocyte counts (neutrophils and basophils), often with increased numbers of immature forms (band neutrophils) seen in peripheral blood smears (left-shift). With infection, peripheral leukocyte counts may be high, but they are rarely higher than 30,000 to 10,000 cells/mm3 (4 × 109 and 10 × 109/L). Low neutrophil counts (neutropenia) after the onset of infection indicate an abnormal response and are generally associated with a poor prognosis for bacterial infection.
Relative lymphocytosis, even with normal or slightly elevated total WBC counts, is generally associated with tuberculosis and viral or fungal infections. Many types of infections, however, may be accompanied by a completely normal WBC count and differential.
Pain and Inflammation
Pain and inflammation may accompany infection and are sometimes manifested by swelling, erythema, tenderness, and purulent drainage. Unfortunately, these signs may be apparent only if the infection is superficial or in a bone or joint.
The manifestations of inflammation with deep-seated infections such as meningitis, pneumonia, endocarditis, and urinary tract infection must be ascertained by examining tissues or fluids. For example, the presence of polymorphonuclear leukocytes (neutrophils) in spinal fluid, lung secretions (sputum), and urine is highly suggestive of bacterial infection.
Identification of the pathogen
Infected body materials must be sampled, if at all possible or practical, before the institution of antimicrobial therapy. A Gram stain of the material may reveal bacteria, or an acid-fast stain may detect mycobacteria or actinomycetes. A delay in obtaining infected fluids or tissues until after therapy is started may result in false-negative culture results or alterations in the cellular and chemical composition of infected fluids.
Blood cultures should be performed in the acutely ill, febrile patient. Less accessible fluids or tissues are obtained when needed to assess localized signs or symptoms (e.g., spinal fluid in meningitis and joint fluid in arthritis). Abscesses and cellulitic areas should also be aspirated.
Caution must be used in the evaluation of positive culture results from normally sterile sites (e.g., blood, cerebrospinal fluid [CSF], and joint fluid). The recovery of bacteria normally found on the skin in large quantities (e.g., coagulase-negative staphylococci and diphtheroids) from one of these sites may be a result of contamination of the specimen rather than a true infection.
Selection of presumptive therapy
A variety of factors must be considered to select rational antimicrobial therapy, including the severity and acuity of the disease, host factors, factors related to the drugs used, and the necessity for use of multiple agents.
The drugs of choice for the treatment of most pathogens are compiled from a variety of sources and are intended as guidelines rather than specific rules for antimicrobial use
When antimicrobial regimens are selected, local susceptibility data should be considered whenever possible rather than information published by other institutions or national compilations.
When a patient for initial or empiric therapy is evaluated, the following factors should be considered:
• Allergy or history of adverse drug reactions.
• Age of patient.
• Metabolic or genetic variation.
• Renal and hepatic function: Patients with diminished renal and/or hepatic function will accumulate certain drugs unless the dosage is adjusted.
• Concomitant drug therapy: Any concomitant therapy the patient is receiving may influence the selection of drug therapy, the dose, and monitoring.
• Concomitant disease states.
Integration of both pharmacokinetic and pharmacodynamic properties of an agent is important when choosing antimicrobial therapy to ensure efficacy and prevent resistance. Antibiotics may demonstrate concentration-dependent (aminoglycosides and fluoroquinolones) or time-dependent (β-lactams) bactericidal effects.
The importance of tissue penetration varies with the site of infection. The central nervous system (CNS) is one body site where the importance of antimicrobial penetration is relatively well defined, and correlations with clinical outcomes are established. Drugs that do not reach significant concentrations in CSF should either be avoided or instilled directly when treating meningitis.
Apart from the bloodstream, other body fluids in which drug concentration data are clinically relevant are urine, synovial fluid, and peritoneal fluid.
Pharmacokinetic parameters such as area under the concentration-time curve (AUC) and maximal plasma concentration can be predictive of treatment outcome when specific ratios of AUC or maximal plasma concentration to the minimum inhibitory concentration (MIC) are achieved. For some agents, the ratio of AUC to MIC, peak-to-MIC ratio, or the time that the drug concentration is above the MIC may predict efficacy.
The most important pharmacodynamic relationship for antimicrobials that display time-dependent bactericidal effects (such as penicillins and cephalosporins) is the duration that drug concentrations exceed the MIC.
Combination of antimicrobial therapy
Combinations of antimicrobials are generally used to broaden the spectrum of coverage for empiric therapy, achieve synergistic activity against the infecting organism, and prevent the emergence of resistance.
Increasing the coverage of antimicrobial therapy is generally necessary in mixed infections in which multiple organisms are likely to be present, such as intraabdominal and female pelvic infections in which a variety of aerobic and anaerobic bacteria may produce disease. Another clinical situation in which increased spectrum of activity is desirable is with nosocomial infection.
Disadvantages of Combination Therapy
Although there are potentially beneficial effects from combining drugs, there are also potential disadvantages, including increased cost, greater risk of drug toxicity, and super infection with even more resistant bacteria.
Some combinations of antimicrobials are potentially antagonistic. For example, agents that are capable of inducing β-lactamase production in bacteria (e.g., cefoxitin) may antagonize the effects of enzyme-labile drugs such as penicillins or imipenem.
Failure of antimicrobial therapy
A variety of factors may be responsible for the apparent lack of response to therapy. It is possible that the disease is not infectious or non bacterial in origin, or there is an undetected pathogen. Other factors include those directly related to drug selection, the host, or the pathogen. Laboratory error in identification and/or susceptibility testing errors are rare.
Failures Caused by Drug Selection
Factors directly related to the drug selection include an inappropriate selection of drug, dosage, or route of administration. Malabsorption of a drug product due to GI disease (eg, short-bowel syndrome) or a drug interaction (eg, complexation of fluoroquinolones with multivalent cations resulting in reduced absorption) may lead to potentially subtherapeutic serum concentrations.
Accelerated drug elimination is also a possible reason for failure and may occur in patients with cystic fibrosis or during pregnancy, when more rapid clearance or larger volumes of distribution may result in low serum concentrations, particularly for aminoglycosides.
A common cause of failure of therapy is poor penetration into the site of infection. This is especially true for the so-called privileged sites, such as the CNS, the eye, and the prostate gland.
Failures Caused by Host Factors
Patients who are immunosuppressed (eg, granulocytopenia from chemotherapy and acquired immunodeficiency syndrome) may respond poorly to therapy because their own defenses are inadequate to eradicate the infection despite seemingly adequate drug regimens.
Other host factors are related to the necessity for surgical drainage of abscesses or removal of foreign bodies and/or necrotic tissue. If these situations are not corrected, they result in persistent infection and, occasionally, bacteremia, despite adequate antimicrobial therapy.
Failures Caused by Microorganisms
Factors related to the pathogen include the development of drug resistance during therapy. Primary resistance refers to the intrinsic resistance of the pathogens producing the infection. However, acquisition of resistance during treatment has become a major problem as well.
The increase in resistance among pathogenic organisms is believed to be due, in large part, to continued overuse of antimicrobials in the community, as well as in hospitals, and the increasing prevalence of immunosuppressed patients receiving long-term suppressive antimicrobials for the prevention of infections.