Introduction
Antimicrobials differ intrinsically from other drugs. Antimicrobials do not aim to affect biologic processes in the patient, but instead inhibit or kill invading pathogens and commensal microorganisms. The properties of these microorganisms are crucial when choosing an antimicrobial regimen, as are the patient and drug characteristics. The pyramid of infectious diseases is a useful learning tool and illustrates the multiple interactions between the host, pathogen(s), commensals, and antimicrobial drug that should influence drug selection ( Fig. 4.1 ).
Prescribing antimicrobial therapy is a uniform part of the clinical tasks of all physicians and nonphysician prescribers. At any given moment, 30% to 40% of the patients admitted to the hospital are prescribed systemic antimicrobial drugs, either as prophylaxis or as therapy. Many aspects need to be considered before an appropriate choice can be made, but important decisions need to be made in the following days as well. For example, what to do with a patient whose clinical situation deteriorates? Or how to streamline therapy once culture results become available? Or when those remain negative? Local guidelines support the prescriber but will never be able to cover all clinical scenarios. This chapter provides an overview of the general principles of antimicrobial therapy to help the prescriber use antimicrobials appropriately.
Selecting an Antimicrobial Regimen
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.
| The agent(s) should be active against the (expected) pathogen |
| The agent(s) should reach sufficient concentration and retain its activity at the site of infection |
| The agent(s) should have an appropriately narrow spectrum |
| The agent(s) should be suited for the preferred route of administration |
| The agent(s) should have the least toxicity (including allergic reactions) compared with equally effective drugs |
| The agent(s) should have the least costs compared with equally effective drugs |
Activity Against (Expected) Pathogens
Empiric Antimicrobial Treatment
Once the decision has been made to initiate antimicrobial treatment, the next step is to choose the agent or combination of agents with activity against the purported pathogens. In case of empiric treatment (i.e., treatment given before the etiologic agent is known), this choice should be made on the integration of the relative frequency of the etiologic agent combined with its expected susceptibility. The probability that a certain antimicrobial has activity against the expected pathogens derives from the formula that adds up the incidence of the specific pathogens multiplied by the susceptibility percentage for these antimicrobials for all major pathogens. Local surveillance data on antimicrobial resistance are informative for making this determination. Risk factors for antimicrobial resistance, such as prior antibiotic use, known colonization (check prior culture results!), and exposure (e.g., hospital admission, recent travel, or antibiotic use) should be considered.
It is nearly impossible—and undesirable, as it will lead to an unjustified increase in broad-spectrum treatment—to cover all possible pathogens. The severity of illness determines which percentage of inappropriate coverage is acceptable, although clear cut-off values do not exist. It is obvious, however, that the consequences of inappropriate initial empiric treatment are far worse in the case of septic shock than in acute cystitis. Evidence-based guidelines for empirical treatment do take this principle into account. In community-acquired pneumonia, for example, the pneumonia severity index (PSI) and the CURB-65 score are commonly used to guide empirical treatment, not because of their ability to predict etiology, but because an increase in score is associated with increased mortality. Coverage of “atypical pathogens” is only indicated in patients with severe pneumonia or intensive care admission.
Targeted Antimicrobial Treatment
If microbiologic results are available, targeted treatment is given, and the choice of a specific agent is based on the criteria discussed in the following paragraphs. However, as discussed in previous chapters, a positive test result should lead to a moment of reflection: Is this isolate indeed the (only) pathogen? Is the specimen sent to the microbiologic laboratory representative? Could it be contaminated? And if one concludes that the isolated pathogen is relevant, one should consider the pathogenesis and consider if the infection could be polymicrobial. For example, anaerobic bacteria are more difficult and longer to culture and do play a role in infections that have an intestinal (e.g., fecal peritonitis or liver abscess) or odontogenic origin (e.g., lung abscess or brain abscess). This implies that the antimicrobial treatment of these conditions should include anaerobic coverage even if anaerobes have not been isolated.
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.
| Difficult-to-Reach Site | Cause |
|---|---|
| Absess | Biofilm |
| Implant | Blood–brain barrier a |
| Brain/meninges | Epithelial barrier |
| Cysts | Blood–retinal barrier a |
| Eye | Blood–prostate barrier a |
| Prostate | Fibrin mass |
| Intravascular thrombus | Fibrin mass |
| Cardiac vegetation | Fibrous capsule |
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).
Other Aspects Influencing Choice of Regimen
Antimicrobial Combinations
Single-agent antimicrobial therapy often suffices, but combining two or more antimicrobials can be considered for three reasons: (1) to extend the spectrum, (2) to achieve synergy, and (3) to prevent the emergence of resistance. Extending the spectrum by combining antimicrobial agents may be necessary in cases where there is no single sufficiently broad-spectrum antimicrobial to cover the expected pathogens. Synergy implies that the effect of the combination is greater than the sum of the activities of individual agents. Synergistic combinations can be clinically indicated in serious infections for which rapid killing is required, such as endocarditis and other intravascular infections. Synergy identified in vitro may not always translate into clinical benefit. The addition of gentamicin to an antistaphylococcal penicillin is synergistic against some strains of Staphylococcus aureus and leads to a faster clearance of bacteria from the bloodstream in S. aureus endocarditis but does not improve patient survival. To the contrary, it increases the incidence of nephrotoxicity. On the other hand, a synergistic combination of a beta-lactam antibiotic and gentamicin or ceftriaxone results in a bactericidal effect and is essential for the treatment of enterococcal endocarditis. Similarly, the addition of gentamicin to penicillin can shorten the course of antimicrobial therapy in endocarditis due to viridans streptococci. The opposite of synergy is antagonism, where the addition of a second agent results in a decreased effect of the combination compared with the independent activity of the individual agents. This phenomenon has been clearly demonstrated in the combination of tetracyclines and penicillin in pneumococcal meningitis, but clinical reports on clinically significant antagonism are otherwise rare.
The emergence of resistance during treatment results either from selection of preexisting resistant clones (see Fig. 4.2 ) or de novo development of resistance. Provided that the resistance mechanism differs for two (or more) antimicrobial agents, the likelihood that a mutant pathogen displays both resistance mechanisms is much lower than the odds of encountering a strain that is resistant to either one. Size of the infecting population, killing rate, mutation frequency, and biologic fitness costs determine whether resistance emerging during monotherapy is occurring and if combination therapy is indicated. HIV and tuberculosis are the prototypical diseases for which combination therapy is the standard treatment.
Bactericidal Versus Bacteriostatic Therapy
Various microbiologic techniques are available to classify antimicrobial agents as bactericidal or bacteriostatic. Bactericidal agents kill microorganisms, whereas bacteriostatic agents prevent growth and as such would require an intact systemic or local immune system to effectively clear the pathogens. Aminoglycosides, beta-lactams, fluoroquinolones, glycopeptides, lipopeptides, and nitroimidazoles are considered bactericidal; tetracyclines, lincosamides, macrolides, and sulfonamides are bacteriostatic. This categorization, however, is arbitrary because a particular agent has inconsistent bactericidal or bacteriostatic effects against all bacteria. Moreover, this distinction lacks clinical relevance because most infections can be treated with similar efficacy with both groups. However, meningitis, endocarditis, and neutropenia are clinical situations in which bactericidal antimicrobial agents are preferred because in these clinical scenarios with reduced (local) phagocytic capacity, the intrinsic activity of the drug is thought to be the main determinant of clinical success.
Side Effects of Antimicrobial Treatment
The preferred antimicrobial should have the least toxic profile compared with equally effective antimicrobials. Frequent specific side effects are discussed in Chapter 5 . Side effects, preferred route of administration, and costs determine the final choice of the antimicrobial and are relative. One is willing to accept (the risk of) more side effects if a certain antimicrobial results in better patient outcomes, particularly in a severely ill patient with no alternative options.
A specific group of side effects are allergic reactions, which are hypersensitivity reactions, that is, signs or symptoms provoked by exposure to a stimulus at a dose tolerated by normal persons, with a demonstrated immunologic reaction. Immediate type (occurring <6 hours) and nonimmediate type (occurring >6 hours, but often starting after 2 to 5 days) are distinguished and differ in their pathogenesis and severity. Immediate-type reactions are usually immunoglobulin E (IgE)–mediated and cause urticaria, angioedema, and sometimes anaphylaxis. Non–immediate-type reactions usually result in a maculopapular rash and are T-cell mediated. Rarely, severe cutaneous other-type IV allergic reactions occur. Around 10% of hospitalized patients report antibiotic allergies, mostly to beta-lactam antibiotics. However, only maximally 10% of the patients will have a real allergy. Allergy delabeling by taking a thorough history and eventually skin testing are increasingly being recognized as important aspects of antimicrobial stewardship programs (ASPs) to decrease the negative consequences of inexistent allergy. Incorrect allergy labeling of beta-lactams leads to the use of more broad-spectrum and less effective alternatives and is associated with more side effects, more health care–associated infections, and longer hospital stays. Cross allergies do exist, but occur less frequently than previously thought. Only 2% of the patients with a penicillin allergy show cross-reactivity to cephalosporins.
Timing of Administration
As a general rule, obtaining cultures from the blood and other expected sites of infection should precede the administration of antimicrobials, as prior antimicrobial therapy compromises the yield of microbiology tests, the results of which are necessary to guide antimicrobial treatment decisions in the days following initiation. The clinical condition of most patients with an infection allows clinical assessment and obtaining cultures before the administration of an antimicrobial. Common sense dictates that the more compromised the clinical situation of the patient, the shorter the door-to-needle time should be. For example, once a diagnosis of sepsis is made, administration of antibiotics should not be delayed.
A febrile episode without a syndromic diagnosis often creates a dilemma whether or not to start antimicrobial treatment. In practice, a febrile patient frequently evokes an antimicrobial prescription, despite the fact that fever or other signs of inflammation are not always caused by an infection requiring antimicrobials. The crux is to identify those patients whose outcome will be worse without early administration of antibiotics. Patients with organ failure, as in sepsis, without any doubt belong to this group. Patients who are prone to rapid deterioration, like patients with significant comorbidity or immunosuppression, should lead to a low threshold to initiate antibiotic treatment, although assessment should be made case by case. Otherwise, antibiotic treatment can be safely withheld or delayed while collecting and waiting for microbiologic data, such as in the patient without signs of life-threatening organ dysfunction and no clear focus of infection. Frequent reassessment may be necessary, on the one hand, to obtain a specific diagnosis and, on the other hand, to monitor for changes in vital parameters.
Dosing
As previously discussed, the selection of an antimicrobial regimen is guided by whether or not sufficient concentrations are reached at the site of infection. But what determines the concentration at the site of infection? And what is a sufficient concentration? This is the field of pharmacokinetics and pharmacodynamics. Pharmacokinetics describes how the patient affects the antimicrobial drug. In other words, it describes the fate of the drug in the patient. Four key processes are recognized: absorption, distribution, metabolism, and excretion. Pharmacodynamics describes the effect of an antimicrobial agent on a pathogen.
Time- and Concentration-Dependent Antimicrobials
Agents are classified either as concentration-dependent killing agents or as time-dependent killing agents. The efficacy of drugs that exhibit time-dependent killing (beta-lactam antibiotics) depends on the time that the free (unbound) concentration exceeds the MIC ( f T > MIC). Frequent dosing, extended infusions, or continuous infusions are used for time-dependent killing agents with short elimination half-lives, because this dosing strategy increases the time the concentration is above the MIC.
Concentration-dependent agents exhibit effect once their concentration is above the MIC, but their efficacy increases with further increase of the peak concentration ( Fig. 4.3 ). For these agents, a suppressive effect persists for a varying period after the concentration is below the MIC, the so-called postantibiotic effect. Efficacy of concentration-dependent agents is predicted by the ratio of the maximum plasma concentrations (peak) to the minimum inhibitory concentration (C max /MIC) and the ratio of the area under the curve (AUC) of plasma concentrations to MIC (AUC/MIC). These two parameters are correlated, because the AUC increases when C max increases. The total daily dose determines the AUC and thus the efficacy of concentration-dependent killing agents. The elimination half-life and the duration of the postantibiotic effect determine the dosing interval. Once-daily dosing of aminoglycosides leads to lower/undetectable trough levels, which reduces their nephrotoxicity.
