Principles of Diagnosis of lnfec­tious Diseases and Antimicrobial Therapy

There are certain aspects which deserve special consideration when treating patients with antimicrobial agents.

Need for representative specimen collection before starting therapy

lt is important to obtain adequate and representative specimens from all potentially infected sites prior to the initiation of antimicrobial therapy. Appropriate antimicrobial therapy is based on definitive identification of pathogenic organisms, which usually requires culture. Once antimicrobial therapy hos been started, cultures often are ren­dered sterile, even though viable organisms may remain in the host. lt is also important to avoid or minimize contamination by surface contaminants and commensals when collecting specimens.

 lnitial empirical choice

(i.e. informed guess) based on the most likely pathogens and susceptibilities

ln most coses. it may be impossible to determine the exact nature of the infecting organisms before institution of antimicrobial therapy. lnitial therapy must therefore be empirical - to make o rational choice from the many currently available antimicrobial agents, the clinician must be able to predict or "guess" infecting microorganism(s) and the antimicrobial susceptibility thereof. ln these coses. the use of "bacteriological statistics" i.e. an awareness of those microorganisms most likely to cause infection in o given clinical setting, in conjunction with the local antibiotic resistance patterns, may be particularly helpful in choosing an empiric antimicrobial agent.

Subsequent need to adjust antimicrobial therapy in light of the laboratory results

Since different organisms vary in their susceptibility to antimicrobial agents, it is imperative that we have some means for determining the antimicrobial susceptibility of the infecting organism(s). Once the pathogen hos been isolated, it can be subjected to susceptibility testing.

The commonly used disc-diffusion method is relatively simple to perform and is the most widely employed method. lt provides semi quantitative or qualitative data about the susceptibility of o given organism too given agent. The qualitative assessment of susceptibility is generally categorized as sensitive or resistant; however, some laboratories also report an intermediate category.

Quantitative data are also provided by methods that incorporate serial dilutions of antimicrobials in agar-containing or broth culture media. The lowest concentration of the antimicrobial agent which inhibits visible growth after an 18 - 24 hour incubation period is known as the minimal inhibitory concentration (MIC). The minimal bactericidal concentration (MBC) is determined in broth dilution tests by subculturing samples without visible growth; this is based on 99.9% killing after 18 to 24 hours of incubation.

Testing the ability of the cultured pathogen to grow or not at a critical concentration (chosen to distinguish between sensitive and resistant bacteria), is a modification known as "breakpoint" testing. A recently described modification of the classical MIC test. the E-test, uses diffusion of a continuous concentration gradient of an antimicrobial agent from a plastic strip into an agar medium to yield quantitative measurements of antimicrobial susceptibility.

Monitoring Therapeutic response

ln many patients, it is possible to monitor the therapeutic response on clinical grounds alone. Thus the subsidence of fever, the return of well-being, and the disappearance of both local and systemic signs of infection in the patient, all signify an appropriate response. No further formal monitoring is necessary in most cases.

An apparent failure to respond clinically may be due to either ineffectiveness of antimicrobial agent(s) (due to resistance or inappropriate route of administration) or to other reasons e.g. a localized infection that requires surgical drainage, or a superinfection etc. Careful reassessment is recommended when considering changes of antimicrobial therapy.

ln certain situations, measurement of antimicrobial activity may be useful in predicting clinical response, e.g. determination of serum bactericidal activity (Schlichter test) in cases of infective endocarditis.

Assays for drugs with narrow Therapeutic: toxic ratio

For antibiotics such as the aminoglycosides and vancomycin, the measurement of their concentrations in serum/plasma or other body fluids is often useful to avoid excessive levels which are associated with toxicity, yet ensure that adequate (therapeutic) levels are achieved.

Pharmacokinetic properties of antibiotics

Knowledge of the pharmacodynamic and kinetic properties of antibiotics is impera­tive in choosing the correct antibiotic and correct dose.

ln order for antibiotics to exert their bactericidal or bacteriostatic activity, a few impor­tant principles pertain:

• Microbiological activity- antibiotic must bind to a specific binding site (e.g. ribo­some or penicillin binding protein).

Concentration of the antibiotic at the site of the infection is important (the higher the concentration the more binding sites are occupied on/in the bacterial cells).

The antibiotics also have to remain on these binding sites for a sufficient period of ti me.

Minimum inhibitory concentration (MIC): This concentration represents the mini­mum amount of drug with which the bacteria have to come into contact, in order for the antibiotic to work.

Clinically speaking, 2 distinct groups of antibiotics are recognized:

Time dependant killing: (penicillins, cephalosporins, macrolides / azalides) The time that the antibiotic exceeds the MIC is crucial in predicting clinical outcome and cure. Concentrations of members of this group of antibiotics are required to be above the MIC for at least 50% of the dosing interval. lf the bacterium is more resistant, the MIC is higher with subsequent reduction in time that the antibiotic concentration exceeds the MIC and therefore higher dosages of the drug may be required.

Concentration dependant antibiotics: (quinolones, aminoglycosides). The more the antibiotic concentration exceeds the MIC, the more killing will take place (irrespective and independent of the time the concentration exceeds the MIC). For this group of antibiotics o ratio of concentration: MIC 10 is required. This implies that o dose regi­men should be chosen which results in o serum or tissue concentration of at least l O times the MIC. Failure to achieve this concentration at the site of infection will lead to clinical and bacteriological failure, and is likely to induce resistance to the entire class of antibiotic.