General Principles of Antimicrobial Therapy

Determining that Antimicrobial Treatment is Indicated

In determining the indication of antimicrobial treatment, obtaining an accurate diagnosis is the first and most crucial step. It goes without saying that only bacterial infections require antimicrobial treatment. Nevertheless, (unconfirmed) viral infections are a frequent cause of antibiotic misuse, sometimes because these infections present in a similar fashion. There is a limited arsenal of antiviral drugs; for the most common viral infectious diseases (i.e., respiratory tract infections and gastroenteritis), there are no etiologic treatment options.

A high suspicion or even proof of a bacterial infection does not necessarily mean that antimicrobials are indicated. Some bacterial infections are self-limiting; antimicrobials only modestly shorten the duration of symptoms and do not reduce the complication rate. Examples include infectious diarrhea, external otitis, acute rhinosinusitis, and pharyngotonsillitis. Guidelines do not recommend systemic antimicrobial treatment for these diseases because the side effects for the patient and the risk of induction of antimicrobial resistance for the public do not justify the limited effect on clinical course. Exceptions are made for immunodeficient patients. For example, enterocolitis caused by the intracellular pathogen Salmonella is associated with bacteremia in patients with cellular immunodeficiency and requires treatment. Similarly, severely ill patients, such as those with bacillary dysentery presumptively due to Shigella or prolonged fever in rhinosinusitis, should be treated with antimicrobials. Importantly, in certain bacterial infections, other measures than antimicrobials, such as abscess drainage or removal or debridement of foreign material, are more important for cure than antimicrobial treatment.

Withholding or delaying antimicrobial treatment in patients without a certain diagnosis but in whom infection is part of the differential diagnosis can be a justifiable strategy. Obtaining a clinical diagnosis and—in case of an infection—a microbiologic diagnosis is important for management, as later attempts at identifying an etiologic agent can be obscured by administration of antimicrobials. Severity of illness and an increased risk of a complicated course are two important considerations that favor prompt initiation of antimicrobial treatment. This is discussed in more detail in the section “Timing of Administration.”

The different steps of designing an antibiotic regimen are summarized in Table 4.1 . Selecting an empirical regimen (i.e., treatment directed against expected pathogens) is based on a clinical “educated guess” and is more complex than targeted treatment in which the pathogen and susceptibility are known.

Activity Against (Expected) Pathogens

Tailoring the Antimicrobial Selection to the Site of Infection

Only if the antimicrobial agent reaches sufficient concentration at the site of infection can it kill an in vitro susceptible microorganism. The central nervous system is the prototypic organ that is difficult to reach. Endothelial cells within the microvasculature and the choroid plexus epithelial cells shield the central nervous system from the systemic circulation. Most large hydrophilic drugs reach low concentrations in the cerebrospinal fluid and brain tissue. This explains why the clinical breakpoint of Streptococcus pneumoniae for penicillin is lower for isolates cultured from cerebrospinal fluid than from other samples. The blood–brain barrier limits the therapeutic arsenal and sometimes necessitates the administration of higher doses of systemic antimicrobials or the intraventricular administration of antimicrobials. Meningeal inflammation, however, makes the blood–brain barrier more penetrable to many antimicrobials. Similarly, the posterior eye segment (blood–retinal barrier) is also poorly penetrated by most antimicrobials ( Table 4.2 ). From a pharmacokinetic perspective, the urinary tract consists of three parts: the prostate, the urine (or bladder), and the kidney. The kidney is well perfused, and concentrations similar to plasma concentration are reached. Limited renal excretion of antimicrobial agents can lead to subtherapeutic concentrations in urine, whereas other agents are concentrated in the urine. Nitrofurantoin is the example of an antimicrobial with high urinary concentrations, which is therefore extremely suited to treat cystitis. Its low plasma—and thus renal tissue—concentration, however, precludes its use for complicated urinary tract infections. Penetration into the prostate is relatively poor for most antimicrobials. If susceptibility of the pathogen allows, preference is given to quinolones or cotrimoxazole.

Besides physiologic barriers for antimicrobial penetration, infection itself induces histologic changes that interfere with antimicrobial penetration. Biofilms are typically formed on foreign material and create three-dimensional structures of microorganisms enclosed by polysaccharides. This organization decreases both antimicrobial penetration and an effective immune response. The effect of cell wall–active agents is further diminished because biofilm-associated microorganisms are in a stationary growth phase. Rifampicin and quinolones are the prototypic antibiotics that that have well-established biofilm activity. Of note, many foreign body infections require surgery next to antimicrobial treatment to eradicate the pathogens. The infected platelet–fibrin deposition that forms the vegetation in infective endocarditis, for example, shows a heterogeneous diffusion of antibiotics within the vegetation that might differ between drugs. To achieve high concentrations, guidelines recommend treating infective endocarditis with high doses of intravenous antimicrobials, as in other deep-seated infections. The fibrous capsule of a mature abscess decreases permeation of the antibiotic, although most antimicrobials reach concentrations above the minimum inhibitory concentration (MIC) in small abscesses.

After reaching sufficient concentrations, retaining activity is crucial for antimicrobials to exert their effect. Antimicrobial activity can be affected by several local factors. An acidic pH increases MICs of aminoglycosides, which, together with low oxygen tension and drug-binding debris, is held responsible for their insufficient effectivity in sterilizing pus collections. Cotrimoxazole also loses its effect in pus. Another example is lung surfactant, which abolishes the antimicrobial effect of daptomycin.

Selection of resistant microorganisms can only occur if the antibiotic reaches the colonizing microorganisms. If absorption is limited, topical antimicrobial treatment only influences microorganisms at the site of application and is therefore to be chosen over systemic treatment if possible. Examples are uncomplicated cases of blepharitis, conjunctivitis, external otitis, dermatomycosis, and impetigo.

Selecting an Appropriately Narrow Spectrum

Although all bacteria need to acquire one or more resistance mechanisms—either by chromosomal mutations or by acquiring genetic elements from the environment—to become phenotypically resistant, it is the exposure to antibiotics that gives resistant subpopulations a survival benefit and the potential to proliferate and disseminate ( Fig. 4.2 ). This is particularly relevant for the human microbiome, estimated at trillions of bacteria. The narrower the spectrum of the antimicrobial, the less selection pressure and the lower likelihood of the emergence of resistance. In empiric treatment, this means that the chosen regimen should only cover the expected pathogens, anticipating their susceptibility profile. In targeted treatment, this implicates that the agents with the narrowest possible spectrum should be chosen. The benefit of avoiding antimicrobials with too broad of a spectrum lies in the future, both for the individual patient and the population (excretion of antimicrobials in the environment and dissemination of resistant bacteria).