Choosing an antimicrobial agent to treat an infection is far more complicated than matching a drug to a known or suspected pathogen. Generally, the systematic approach for selection of antimicrobials includes four steps:
1. Confirm the presence of infection
- Careful history and physical examination
- Signs and symptoms
- Predisposing factors
2. Identification of the pathogen
- Collection of infected material
- Culture and sensitivity
3. Selection of presumptive therapy considering every infected site
- Host factors
- Drug factors
4. Monitor therapeutic response
- Clinical assessment
- Laboratory tests
- Assessment of therapeutic failure
Infectious diseases generally are acute, and a delay in antimicrobial therapy can result in serious morbidity or even mortality. Thus, empirical antimicrobial therapy selection is always needed. This empirical antimicrobial therapy should be based on information gathered from the patient's history and physical examination and results of Gram stains or of rapidly performed tests on specimens from the infected site. Absolutely, the rapid tests to identify pathogen is crucial. Besides, the identification of pathogen determined the subsequent adjustment of antimicrobial therapy.
Confirm the presence of infection
To confirm the presence of infection, a careful history and physical examination, a series of signs and symptoms, and several predisposing factors should be considered. Infectious disease do not often occur in isolation; rather, they spread through a group exposed from a point source or from one individual to another. Thus a detailed history, including information on travel, behavioral factors, exposures to animals or potentially contaminated environments, and living and occupational conditions, must be elicited. History and backgroud is especially important when the patient is febrile only with no symptoms suggestive of an organ system but only constitutional complaints.
First important sign and symptom for infection is fever. The presence of a temperature greater than the expected 37 ℃ "normal" body temperature is considered a hallmark of infectiious diseases. In a healthy person, the internal thermostat is set between the morining low temperature and the afternoon peak as controlled by the circadian rhythm. Fever is defined as a controlled elevation of body temperature above the normal range. The average axillary temperatures is 36.1 ℃ to 36.4 ℃.
But, fever also can be a manifestation of disease states other than infection, including collagen-vascular disorders, some malignancies, drug-induced fever and so on. Possible mechanisms of drug-induced fever are either a hypersensitivity reaction or development of antigen-antibody complexes that result in the stimulation of macrophages and the release of interleukin (IL-1). Besides, noninfectious etiologies of fever can be referred to as "false-positives" and the absence of fever in a patient with signs and symptoms consistent with an infectious disease can be misunderstood as "false-negatives" conversely. To avoid false-negative of fever, careful questioning of the patient or family is vital to assess the ingestion of any medication that can mask fever and the use of antipyretics (aspirin, acetaminophen, NSAIDs, and corticosteroids) should be discouraged during the treatment of infection unless absolutely necessary. In general, elevated body temperature, unless very high (>40.5 ℃), is not harmful and may be beneficial.
White Blood Cell Count
Second, most infections result in elevated white blood cell counts (leukocytosis) because of the increased production and mobilization of granulocytes (neutrophils, basophils, and eosinophils), lymphocytes, or both to ingest and destroy invading microbes. The generaly accepted range of normal values for WBC counts is between 4,000 and 10,000 cells/mm3. Values above or below this range hold important prognostic and diagnostic value. The increased presence of immature forms of neutrophils (shift to the left) is an indication of an increased bone marrow response to the infection. With infection, peripheral WBC counts can be very high, but they are rarely higher than 30,000 to 40,000 cells/mm3. Low leukocyte counts after the onset of infection indicate an abnormal response and generally are associated with a poor prognosis. Lymphocytosis, even with normal or slightly elevated total WBC counts, generally is associated with tuberculosis and viral or fungal infections.
Third, infection commonly accompanies with classic signs of pain and inflammation, which include swelling, erythema, tenderness, heat, and purulent drainage. Unfortunately, these are only visible if the infection is superficial or in a bone or joint. Thus, the manifestations of inflammation in deep-seated infections (e.g., meningitis, pneumonia, endocarditis, and urinary tract infection) must be ascertained by examining tissues or fluids. Symptoms referable to an organ system must be sought out carefully because not only do they help in establishing the presence of infection, but they also aid in narrowing the list of potential pathogens.
Identification of the pathogen
In the setting of confirmed infection, infected body materials must be sampled, if at all possible or practical, before institution of any antimicrobial therapy for two reasons. First, a Gram stain of the material might detect mycobacteria or actinomycetes. Second, a delay in obtaining infected fluids or tissues until after antimicrobial therapy is started might result in false-negative culture results or alterations in the cellular and chemical composition of infected fluids.
The Gram stain is one of the first identification tests run on a specimen brought to the laboratory. The clinican can judge the suspected infection by the color and morphologic characteristics of the microbe and sebsequently the empirical antibiotic therapy can be determined accordingly. The figure on the left is the basic identification of pathogens via Gram stain and morphologics.
Another way to identify pathogen is cultures of microbe. Isolation of the etiologic agent by culture is the most definitive method available for the diagnosis and eventual treatment of infection, of course, also the susceptibility testing. Although suspicion of a specific pathogen or group of pathogens is helpful to the laboratory for the selection of a specific cultivating medium, the more common procedure for the laboratory is to screen for the presence of any potential pathogen.
To increase the possibility to determine the pathogen(s) through cultures, one must know how to collect and transported specimens appropriately. Every effort should be made to avoid contamination with normal flora and to enshure that the specimen is placed in the appropriate transport medium. Meanwhile, culture specimens should be transported to the laboratory as soon as possible because organisms can perish from prolonged exposure to air or drying.
And transport media may not be ideal for all organisms. Specimens that contain fastidious organisms or anaerobes require special transport media and should be forwarded immediately to the laboratory for processing. Finally, the source of the specimen should be clearly recorded and forwarded along with the culture to the laboratory.
Although many benefits with culture, however, detection of microorganisms in the bloodstream (blood culture) is difficult due to the inherently low yield of organisms diluted by blood, humoral factors with bactericidal activity, and the potential of antimicrobial pretreatment affecting organism growth. Despite this, blood culture should be obtained when necessary, such as in chemotherapy offered pateints with sharp elevations in temperature. Of not that under this condition, the blood culture collection should coincide with the sharp rise in temperature.
Once Gram stain and/or culture results are available (not only positive but negative results), clinican must understand and know how to interpreting these results. This incudes whether the organism recovered is true pathogen, a contaminant, or a part of the normal flora. The latter consideration is especially problematic with cultures obtained from skin, oropharynx, nose, ears, eyes, throat, and perineum since these surfaces are heavily colonized with a wide variety of bacteria, some of which can be pathogenic in certain settings.
Importantly, cultures of specimens from purportedly infected sites that are obtained by sampling from or through one of these contaminated areas might contain significant numbers of the normal flora. So other clues like history, signs and symptoms, other labortary tests, etc, should be considered integrately to help confirm infection and rule out colonization. Also, caution must be used in the evaluation of positive culture results from normally sterile sites such as blood, cerebrospinal fluid, or joint fluid since the recovery of bacteria normally found on the skin in large quantities from one of these sites can be a result of contamination of the specimen rather than a true infection.
Selection of presumptive therapy
To select rational antimicrobial therapy for a given clinical situation, a variety of factors must be considered. These include the severity and acuity of the disease, host factors, factors related to the drugs used, and the necessity for using multiple agents. In addition, there are generally accepted drugs of choice for the treatment of most pathogens.
Before the institution of presumptive antimicrobial therapy, clinician must try to define the most likely infecting organisms according to a careful history and physical examination. Once the site and the possible pathogen has been supposed, the selection of presumptive therapy should be based on factors including local antimicrobial susceptibility data publish by the relative institution/ward, the host factors, the drug factors, the possibility to use combination antibiotic therapy.
The local antimicrobial susceptibility data is the local information about the common pathogens and their susceptibilities to antibiotics within the local institution. Each institution should publish an annual summary of antibiotic susceptibilities (we call antibiogram) for organisms cultured from patients. Antibiogram contain both the number of nonduplicate isolates for common species and the percentage susceptible to the antibiotics tested.
The figure at the right side is an example of antibiogram from UCSF medical center on 2012.
Several host factors should be considered when evaluating a patient for antimicrobial therapy. The most important factors are drug allergies, age, pregnancy, genetic or metabolic abnormalities, renal and hepatic function, concomitant drug therapy, and concomitant disease states.
Allergy precludes the use of the allergic antibiotic(s). It is because that the immediate or accelerated reactions caused by the allergic antibiotic(s) can cause fatal results. Examples are penicillin and cephalosporins.
With different ages, the etiologic pathogen(s) can be quite different. For example, in bacterial meningitis, the pathogens differ as the patient grows from the neonatal period through infancy and childhood into adulthood. Also, with different ages, the liver and/or renal function varies, which leads to different drug pharmacokinetic properties. For instance, persons older than 65 years of age have a decline in the number of functioning nephrons that, in turn, results in decreased renal function and resultant decreased drug clearance for drugs excreted primarily by renal route. And for neonate, the bilirubin excretion is decreased and the kernicterus can happen.
During pregnancy, not only is the fetus at risk for drug teratogenicity, but also the pharmacokinetic disposition of certain drugs can be altered. Generally, the marked increased intravascular volume, and glomerular filtration rate will result in decreased antimicrobial concentrations.
Inherited or accquired metabolic abnormalities will influence the therapy of infecious diseases in many ways. I think the basic rationale for this is the pharmacogenetics. For example, patients with severe deficiency of G-6PD (glucose-6–phosphate dehydrogenase) can develop significant hemolysis when exposed to sulfonamides, nitrofurantoin, nalidixic acid, antimalarials, and dapsone.
Patients with diminished renal or hepatic function or both will accumulate certain drugs unless dosage is adjusted. This is easy to understand that the excretion or clearance of these drugs are diminish with decompensated renal and/or liver functions.
Concomitant drugs would influence the selection of presumptive antibiotic therapy. This is belong to DDIs (drug to drug interactions).
Finally, concomitant disease states can influence the selection of therapy. Cetain diseases will predispose patients to a particular infectious disease or will alter the type of infecting organism. For example, patients with diabetes mellitus and the resulting peripheral vascular disease often develop infections of the lower extremity soft tissue. Besides, patients with immunosuppressive diseases are highly predisposed to infections, and the types of causative or pathogenic organisms can be vastly different from what would be expected in normal hosts.
The first factor is the pharmacokinetic and pharmacodynamic properties (PK-PD/time-dependent, concentration-dependent) of the antibiotic for selecting. Generally, antibiotics are divided into concentration-dependent and time-dependent. For concentration-dependent antibiotics there is an important relationship between AUC:MIC ratio, or peak concentration:MIC ratio and the clinical therapy outcome. For time-dependent antibiotics there is a relationship between the time the concentration above MIC and the clinical outcome.
Second, the tissue penetration is another drug factor we should consider. However, the importance of tissue penetration varies with site of infection. Body fluids where drug concentration data are clinically relevant include CSF, urine, synovial fluid, and peritoneal fluid. Apart from these areas, more attention should be paid to clinical efficacy, antimicrobial spectrum, toxicity, and cost than to comparative data on penetration into a given body site.
Third, the route of administration for an antimicrobial depends on the site of infection. For febrile neutropenia or deep-seated infections parenteral theapy is the correct choice. Severe pneumonia often is treated initially with intravenous antibiotics and switched to oral therapy as clinical improvement is evident. Patients treated in the ambulatory setting for upper respiratory tract infections, lower respiratory tract infections, skin and soft tissue infections, uncomplicated urinary tract infections, and selected sexually transmitted diseases can usually receive oral therapy.
Drug toxicity is an important factor we should pay attention. Antibiotics can have CNS toxicities, hepatotoxicities, nephrotoxicity, ototoxicity, hematoxicities, and so on.
Combination antimicrobial therapy
The purpose to use combination antimicrobial therapy is: 1.broadening the spectrum of coverage; 2.synergism; and 3.preventing resistance. For instance, in mixed infections where multiple organisms are likely to be present (e.g., complicated intraabdominal infection), it is necessary to boarden the coverage of antimicrobial therapy. The other clinical situation in which an increased spectrum of activity is desirable is with nosocomial infections.
The data supporting superior efficacy of synergistic over nonsynergistic combinations are week. But for some conditions, such as P aeruginosa or Enterococcus species infection, it would appear that synergistic combinations produce better results.
The third purpse of combination antimicrobial therapy is to prevent resistance. However, the only circumstance where this has been clearly effective is in the treatment of tuberculosis.
Monitoring therapeutic response
After antimicrobial therapy has been instituted, the patient must be monitored carefully for a therapeutic response. Culture and sensitivity reports from specimens sent to the microbiology laboratory must be reviewed and the therapy changed accordingly. Use of agents with the narrowest spectrum of activity against identified pathogens is recommended. If anaerobes are suspected, even if they are not identified, anaerobic therapy should be continued.
Patient monitoring should include many of the same parameters used to diagnose the infection such as the WBC count, temperature, patient's complaints for pain, shortness of breath, cough etc. Appetite should improve. But one must note that the radiologic improvement can lag behind clinical improvement.
Serum or other fluid level of antimicrobials can be useful in ensuring clinical outcome, preventing toxicity or both. There are only a few antimicrobials that require serum concentration monitoring and then only in selected situations. These include the aminoglycosides, vancomycin, flucytosine, and chloramphenicol.
As patients improve clinically, the route of administration should be reevaluated. Streamlining therapy from parenteral to oral has become an accepted practice for many infections. When switching from intravenous to oral route is considered, criteria that should be present to justify a switch include 1.overall clinical improvement; 2.lack of fever for 8 to 24 hours; 3.decreased WBC count; and 4.a functioning gastrointestinal tract.
Failure of Antimicrobial Therapy
A variety of factors may be responsible for an apparent lack of response to therapy. Patients who fail to respond over 2 to 3 days require a thorough reevaluation. It is possible that the disease is not infectious or is nonbacterial in origin, or there is an undetected pathogen in a polymicrobial infection. But others including drug selection, the host factors, or the pathogen. Laboratory error in identification, susceptibility testing, or both is a rare casue of antimicrobial failure.
Update on Nov 23rd 2016
Principles of Anti-Infective Therapy
Choice of the Proper Antimicrobial Agent
To choice the most appropriate antimicrobial agent(s), the clinician should follow those steps.
Step 1 Identification of the Infecting Organism
- Gram-stain preparation
- Immunologic methods for antigen detection, such as enzyme-linked immunosorbent assay (ELISA) or latex agglutination
- Molecular techniques, such as PCR
- Bacteriologic statistics (the statistically reasonable guess)
Step 2 Determination of Antimicrobial Susceptibility of Infecting Organisms
Whenever there is reasonable doubt about the susceptibility of a given organism that is thought to be pathogenic, tests of antimicrobial susceptibility should be performed.
There are very few examples of organism-antibiotic combinations for which susceptibility can be predicted with a sufficiently high degree of certainty that susceptibility testing would be unnecessary in the setting of a severe infection.
It is important to consider geographic differences in patterns of susceptibility of organisms when choosing antimicrobial agents. In many cases, there may be variations in susceptibility patterns between hospitals and the community, between neighboring hospitals, or even among units within a single hospital.
Step 3 Consideration of Factors Specific to the Patient
1.History of previous adverse reactions to antimicrobial agents
2.Age related factors
- Antibiotics absorption variation caused by the change of stomach pH as age grows
- Decreased renal function as age grows
- Underdeveloped liver function in neonates
- Some adverse drug reactions related to children (e.g., tetracyclines to developing bone and tooth, quinolones to cartilage)
- Some adverse drug reactions caused by specific disease states or by impairment of physiologic processes associated with aging
- Some adverse drug reactions just independently related to older age
3.Genetic or metabolic abnormalities
The presence of genetic or metabolic abnormalities may also have a significant effect on the toxicity of a given antimicrobial agent. The presence of metabolic disorders, such as diabetes mellitus, may also pose problems in antimicrobial therapy.
Examples of genetic abnormalities and drug toxicity
- In a small proportion of individuals treated with the antiretroviral drug abacavir, a severe hypersensitivity reaction can occur, consisting of fever, rash, and abdominal and respiratory symptoms. The presence of a human leukocyte antigen allele, HLA-B*5701, has been found to be highly associated with immunologically confirmed cases of abacavir hypersensitivity reaction.
- A number of antimicrobial agents have been shown to be capable of provoking hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Examples of metabolic abnormalities and drug toxicity
- Certain agents, such as the sulfonamides, can potentiate the hypoglycemic activity of sulfonylurea hypoglycemic agents.
- Agents of the fluoroquinolone class have been associated with dysglycemic reactions, both hypoglycemia and hyperglycemia. Individuals with baseline glucose abnormalities and those receiving treatment for diabetes may be particularly at risk. The dextrose load infused with intraveous antibiotics dissolved in dextrose-containing vehicles may be sufficient to produce hyperglycemia and glucosuria in diabetic patients.
4.Renal and hepatic funciton
The ability of the patient to metabolize or excrete antimicrobial agents is one of the most important host factors to consider, espeically when high serum or tissue concentrations of the administered drugs are potentially toxic. From a practical point of view, this means that the clinician must assess the patient's renal and hepatic function carefully beause these organs serve as the major, and in most cases the only, routes of excretion and inactivation of antimicrobials.
5.Site of infection (more precisely, site of the "receptor")
Topics about site of infection and how these factors would affect the efficacy of antibiotics are many. The essential idea is that the concentration of antibiotic agent at the site of "receptor" (generally, the target componment of the pathogenic organism) is the one of the critical determinats of clinical efficacy.
- Critical factor – local antibiotic concentrations and therapeutic efficacy
For antimicrobial therapy to be effective, an adequate concentration of the drug (unbound drug) must be delivered to the site of infection (the anatomic location). In most cases, this means that the local concentration of the antimicrobial agent should at least equal the MIC of the infecting organism. However, in many cases, although concentrations representing multiples of the MIC are generally believed more like to be efficacious, such local concentrations may be difficult or impossible to achieve (due to intolerance or toxicities). Of note, there is evidence that subinhibitory concentrations of drugs may produce antimicrobial effects that aid the host defenses against infections. Postulate rationales explain the clinical observation that, on occasion, doses of antimicrobials that produce seemingly inadequate serum levels may still result in clinical cure. In spite of such observations, most infectious disease clinicians feel that optimal therapy requires concentrations of antimicrobials that are above the MIC at the site of infection.
The ability of an antibiotic to penetrate to the site of infection with an appropriate pharmacodynamic profile is a major determinant in the successful therapy. The ability of an antibiotic to pass through membranes by nonionic diffusion is related to its lipid solubility. Thus, lipid-soluble agents are all more efficient in penetrating membranes than are the more highly ionized compounds.
- Serum concentration and its limitation
Serum concentrations of antimicrobial agents are, in principle, relatively easy to determine. Nevertheless, monitoring of serum concentrations is routinely performed only for a limited number of antimicrobials. Recent data suggest that therpaeutic drug monitoring may have an increasing role in the management of fungal infections. However, except in cases of bacteremia, antimicrobial efficacy is more likely determined by the tissue concentration than by the blood level. Some agents such as spiramycin, certain macrolides such as azithromycin, and tigecycline can be effective in some infections, despite an inability to achieve serum levels above the MIC of certain organisms. This may be explained by their ability to achieve intracellular and tissue concentrations that far exceed those obtained in serum.
- Serum protein binding
Although much careful investigation has been done on protein binding, the precise clinical significance of this phenomenon remains to be determined. For example, it has been shown that only the unbound form of a given antimicrobial agent is active in vitro (and presumably also in vivo) against infecting organisms. However, because protein binding can be rapidly reversible, the activity of even highly protein-bound agents may not be limited absolutely by protein binding. The penetration of antimicrobial agents into interstitial fluid and lymph is related to protein binding because only the free form of the agent is able to pass through the capillary wall (except the sinusoidal capillary). Penetration of antibitoics into fibrin clots, which may be analogous to the penetraton of the drugs to reach the site of infection in patients with bacterial endocarditis, is likewise related to the amount of unbound antibiotic in the surrounding fluid. Nvertheless, it is often difficult to correlate therapeutic outcome with in vitro susceptibility (MIC) and protein binding alone. Several technical factors also contribute to problems with such correlations because the protein binding measured in vitro may vary with the concentration of antibiotic tested and with other variables, such as medium composition, pH, and temperature.
- Pharmacokinetic profile over susceptibility versus clinical efficacy
In recent years, there has been growing appreciation that the (pharmacokinetic) profile of antimicrobial concentrations over time relative to susceptibility of the pathogen is critically important to the effectiveness of antimicrobial therapy. For example, the effectiveness of 𝛽-lactam antibiotics can be best correlated with attainment of unbound (free) drug concentrations greater than the MIC of the pathogen for a certain proportion of the dosing interval; that is, the effectiveness is dependent on time interval of free-drug concentrations greater than the MIC. In contrast, the effectiveness of fluoroquinolones correlates better with the ratio of the free-drug AUC to the MIC of the organism. Thus, for the perspective of pharmacokinetics the effectiveness of an antimicrobial agent depends on a number of factors, including organism susceptibility, drug class (time-dependent or concentration-dependent).
- Inactivation of antibiotics
Even the achievement of "therapeutic concentrations" of antimicrobial agents at the site of infection may not be sufficient for cure because a number of local factors may influence the activity of antimicrobial agents. An important example is the binding and inactivation of daptomycin by pulmonary surfactant. Aminoglycosides and the polymyxins are bound to and inactivated by purulent material. This is one of many reasons why surgical drainage is imperative when treating abscesses with agents such as these. Another example is that penicillin G is inactivated by 𝛽-lactamase.
- Inability to reach the "receptor"
Local decreases in oxygen tension, such as occur in abscesses and intraperitoneal infections, may also have an effect on the activity of certain antimicrobial agents. The aminoglycosides, for example, are inactive against anaerobes and may also be less effective against facultative organisms under anaerobic conditions because oxygen is required for the transport of these agents into the bacterial cell.
- Chemical factors
Local alterations in pH, such as occur in abscesses and especially in the urine, may have an important effect on the activity of a number of antimicrobial agents. Methenamine and nitrofurantoin are more active at an acid pH, whereas alkalinization enhances the activity of erythromycin, azithromycin, clarithromycin, lincomycin, clindamycin, and the aminoglycosides. Indeed, the aminoglycosides show a marked loss of activity at a low pH.
- Foreign bodies
The presence of foreign bodies also has a profound effect on the activity of antimicrobial agents. Thus, it is sometimes necessary to remove foreign material to cure an infection of a prosthetic heart valve and almost always necessary to remove, or at least to debride carefully, prosthetic devices for cure of joint implant infections. The mechanism by which foreign bodies potentiate infection is not clear, but they probably cause localized impairment of host defense mechanisms. In addition, the foreign body often serves as a nidus on which organisms can adhere and produce extracellular substances, such as glycocalyx or biofilm, which may interfere with phagocytosis. Although it was originally thought that biofilm produces a barrier to penetration of antimicrobials, this is clearly not the case. The ineffectiveness of antibiotics against bacteria in biofilm is the result of alterations in the metabolic state of these organisms that renders them relatively resistant to the action of antibiotics.
- Antibiotics' alteration of host defenses
Antimicrobial agents themselves have the potential to alter host defenses. Clinically achievable concentrations of many different agents have been shown to diminish leukocyte chemotaxis, lymphocyte transformation, monocyte transformation, delayed hypersensitivity, antibody production, phagocytosis, and the microbicidal action of polymorphonuclear leukocytes. It is not clear, however, whether any of these effects (largely demonstrated by in vitro studies) are of clinical significance. Nonetheless, the possibility that antimicrobial agents can cause immunosuppression exists, and this fact should discourage the indiscriminate use of antibiotics, especially in patients who are already immunosuppressed because of their underlying disease or concomitant drug therapy.
Antimicrobial agents, such as 𝛽-lactams, that cause rapid lysis of bacteria may also release endotoxins or cell wall components that have potentially deleterious local or systemic effects, or both, in the host. The local inflammatory consequences of such activity have been clearly defined in experimental models of bacterial meningitis (which forms the basis for the use of dexamethasone in bacterial meningitis), but their significance in other settings, cush as gram-negative sepsis, remains to be determined. The use of antibiotics early in the course of intestinal infection with E. coli O157:H7 was found to be a risk factor for the subsequent development of hemolytic-uremic syndrome, consistent with findings that antibiotics may stimulate production of Shiga toxin from these organisms in vitro.