what term describes antibiotic therapy tailored to treat an identified organism?
Mayo Clin Proc. 2011 Feb; 86(2): 156–167.
General Principles of Antimicrobial Therapy
Abstruse
Antimicrobial agents are some of the almost widely, and oftentimes injudiciously, used therapeutic drugs worldwide. Important considerations when prescribing antimicrobial therapy include obtaining an accurate diagnosis of infection; understanding the difference between empiric and definitive therapy; identifying opportunities to switch to narrow-spectrum, cost-effective oral agents for the shortest duration necessary; agreement drug characteristics that are peculiar to antimicrobial agents (such equally pharmacodynamics and efficacy at the site of infection); accounting for host characteristics that influence antimicrobial activeness; and in plough, recognizing the adverse effects of antimicrobial agents on the host. It is also important to understand the importance of antimicrobial stewardship, to know when to consult infectious disease specialists for guidance, and to exist able to identify situations when antimicrobial therapy is not needed. By following these general principles, all practicing physicians should exist able to use antimicrobial agents in a responsible way that benefits both the individual patient and the community.
The terms antimicrobial, antibiotic, and anti-infective encompass a wide multifariousness of pharmaceutical agents that include antibacterial, antifungal, antiviral, and antiparasitic drugs. Of these, antibacterial agents are past far the most ordinarily used and thus are the focus of this article, although similar principles apply to the other agents as well. Evidence-based practice guidelines from the Infectious Diseases Guild of America1 tin help direct advisable therapy for specific infectious disease syndromes as well as for infections caused past specific microorganisms. These guidelines should be applied in the context of host characteristics, response to therapy, and price of therapy. This commodity discusses many such factors that should guide appropriate use of antimicrobial therapy.
SELECTING AND INITIATING AN Antibody REGIMEN
Obtaining an Accurate Communicable diseases Diagnosis
An infectious disease diagnosis is reached by determining the site of infection, defining the host (eg, immunocompromised, diabetic, of avant-garde historic period), and establishing, when possible, a microbiological diagnosis. It is critical to isolate the specific pathogen in many serious, life-threatening infections, especially for situations that are likely to require prolonged therapy (eg, endocarditis, septic arthritis, disk space infection, and meningitis). Similarly, when a patient does not benefit from antimicrobial therapy called on the basis of clinical presentation, additional investigations are needed to decide the etiologic agent or exclude noninfectious diagnoses. To optimize an accurate microbiological diagnosis, clinicians should ensure that diagnostic specimens are properly obtained and promptly submitted to the microbiology laboratory, preferably before the institution of antimicrobial therapy. Infectious disease diagnoses also ofttimes rely on a detailed exposure history, every bit in the example of a patient with nonresolving pneumonia who has resided in or traveled to the southwestern Usa where coccidioidomycosis is endemic. Although the microbiological diagnosis is ideally based on information such as bacterial or fungal culture or serologic testing, ofttimes the "most likely" microbiological etiology can exist inferred from the clinical presentation. For example, cellulitis is most frequently assumed to be acquired past streptococci or staphylococci, and antibacterial treatment tin can be administered in the absence of a positive culture. Similarly, customs-acquired pneumonia that does not warrant hospitalization can also be treated empirically—with a macrolide or fluoroquinolone antibody—without performing specific diagnostic testing.two Finally, noninfectious atmospheric condition should be considered in the differential diagnosis for infections, especially when the diagnosis is not articulate-cutting.
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Timing of Initiation of Antimicrobial Therapy
The timing of initial therapy should be guided past the urgency of the situation. In critically ill patients, such as those in septic shock, febrile neutropenic patients, and patients with bacterial meningitis, empiric therapy should be initiated immediately after or concurrently with drove of diagnostic specimens. In more stable clinical circumstances, antimicrobial therapy should exist deliberately withheld until advisable specimens take been nerveless and submitted to the microbiology laboratory. Important examples of this principle are subacute bacterial endocarditis and vertebral osteomyelitis/diskitis. Patients with these infections are oftentimes ill for a period of several days to weeks before presentation, and assistants of antibiotic therapy should be delayed until multiple sets of claret cultures (in the case of endocarditis) or disk infinite aspirate and/or bone biopsy specimens (for osteomyelitis/diskitis) accept been obtained. Premature initiation of antimicrobial therapy in these circumstances can suppress bacterial growth and preclude the opportunity to establish a microbiological diagnosis, which is disquisitional in the direction of these patients, who require several weeks to months of directed antimicrobial therapy to attain cure.
Empiric vs Definitive Antimicrobial Therapy
Because microbiological results do non become bachelor for 24 to 72 hours, initial therapy for infection is often empiric and guided past the clinical presentation. It has been shown that inadequate therapy for infections in critically ill, hospitalized patients is associated with poor outcomes, including greater morbidity and bloodshed also as increased length of stay.3,4 Therefore, a common approach is to use broad-spectrum antimicrobial agents as initial empiric therapy (sometimes with a combination of antimicrobial agents; for further information on these combination regimens, run into "Use of Antimicrobial Combinations") with the intent to cover multiple possible pathogens ordinarily associated with the specific clinical syndrome. This is true for both community- and hospital-acquired infections. For example, in an otherwise healthy immature adult with suspected bacterial meningitis who is seen in the emergency department, the nearly probable pathogens would exist Streptococcus pneumoniae and Neisseria meningitidis, and thus a combination of a third-generation cephalosporin (ceftriaxone) plus vancomycin would be recommended as empiric therapy.v Hospital-caused infections are often related to the presence of invasive devices and procedures that issue in loss of the normal barriers to infection, as is the instance with intravascular catheter–associated bacteremia, ventilator-associated pneumonia, and catheter-associated urinary tract infections (UTIs). They are ordinarily acquired by drug-resistant organisms, both gram-positive (eg, methicillin-resistant Staphylococcus aureus [MRSA]) and gram-negative (eg, Pseudomonas aeruginosa) bacteria, which are often owned in hospitals considering of the selection pressure from antimicrobial employ. In selecting empiric antimicrobial therapy for such infections, clinicians should consider the post-obit: (1) the site of infection and the organisms nearly probable to exist colonizing that site (eg, intravascular catheter–associated bacteremia is oftentimes a issue of colonization and infection acquired by staphylococci present on the pare); (two) prior knowledge of leaner known to colonize a given patient (eg, a screening nasal swab [currently conducted routinely by many hospitals before admitting patients to the intensive care unit] may signal that the patient is colonized with MRSA); and (three) the local bacterial resistance patterns or antibiograms that are available for important pathogens at virtually hospitals.half-dozen
Once microbiology results have helped to identify the etiologic pathogen and/or antimicrobial susceptibility data are available, every effort should be fabricated to narrow the antibiotic spectrum. This is a critically important component of antibiotic therapy because it tin reduce cost and toxicity and prevent the emergence of antimicrobial resistance in the community. Antimicrobial agents with a narrower spectrum should be directed at the most probable pathogens for the elapsing of therapy for infections such as community-acquired pneumonia or cellulitis in the ambulatory setting because specific microbiological tests are not typically performed.
Interpretation of Antimicrobial Susceptibility Testing Results
When a pathogenic microorganism is identified in clinical cultures, the next footstep performed in well-nigh microbiology laboratories is antimicrobial susceptibility testing (AST). Antimicrobial susceptibility testing measures the ability of a specific organism to grow in the presence of a particular drug in vitro and is performed using guidelines established by the Clinical and Laboratory Standards Plant,seven a nonprofit global arrangement that develops laboratory procedure standards through extensive testing and clinical correlation. The goal of AST is to predict the clinical success or failure of the antibody being tested against a particular organism. Data are reported in the grade of minimum inhibitory concentration (MIC), which is the everyman concentration of an antibody that inhibits visible growth of a microorganism, and are interpreted by the laboratory as "susceptible," "resistant," or "intermediate," according to Clinical and Laboratory Standards Establish criteria. A report of "susceptible" indicates that the isolate is probable to be inhibited past the ordinarily achievable concentration of a item antimicrobial agent when the recommended dosage is used for the particular site of infection. For this reason, MICs of different agents for a particular organism are not directly comparable. For case, MICs of 1 (susceptible) for ciprofloxacin and 2 (susceptible) for ceftriaxone confronting Escherichia coli exercise not imply that ciprofloxacin is twice as active as ceftriaxone. Instead, it indicates that concentrations accomplished by giving recommended doses of both drugs are likely to be active against the organism. Although AST results are generally quite useful in narrowing the antibody regimen, AST has some limitations that should be kept in heed. First, it is important for both clinicians and laboratory personnel to exist aware of the site of infection. For case, an isolate of S aureus could be reported as susceptible to cefazolin in vitro; nevertheless, if this particular isolate was obtained from the cerebrospinal fluid (CSF), cefazolin would non be an optimal therapeutic selection considering it does not attain therapeutic concentrations in the CSF. Clinical laboratories may provide unlike AST interpretations for dissimilar sites of infection (eg, meningitis and nonmeningitis AST results for Southward pneumoniae). In add-on, some organisms bear enzymes that, when expressed in vivo, can inactivate antimicrobial agents to which the organism shows in vitro susceptibility. Although their presence is not immediately apparent from AST results, certain AST "patterns" can provide a inkling to their beingness. For example, extended-spectrum β-lactamases (ESBLs) in Enterobacteriaceae are enzymes that mediate resistance to nearly all β-lactam agents except carbapenems (eg, meropenem or imipenem). Extended-spectrum β-lactamases can be difficult to detect considering they have unlike levels of in vitro activity against various cephalosporins. In clinical practice, susceptibility to cephamycins (cefoxitin, cefotetan) only resistance to a tertiary-generation cephalosporin (eg, cefpodoxime, cefotaxime, ceftriaxone, ceftazidime) or aztreonam should warning 1 to the possibility of ESBL production. The production of ESBL should also exist suspected when treatment with β-lactams fails despite credible in vitro susceptibility. This should pb to additional testing, which usually involves growing the bacteria in the presence of a third-generation cephalosporin alone and in combination with clavulanic acid (a β-lactamase inhibitor); enhanced bacterial inhibition with the add-on of clavulanic acid indicates ESBL. When detected by the laboratory, these bacteria should be considered resistant to all β-lactam agents except the carbapenem class.
In general, it is expert practise to communicate directly with the microbiology laboratory when antimicrobial susceptibility patterns appear unusual. Information technology is also useful to exist enlightened of the limitations of AST at the local laboratory, particularly in smaller hospitals (eg, testing of relatively newer agents [such as daptomycin for gram-positive cocci] might not be routinely performed or reported but could exist bachelor on request).
Bactericidal vs Bacteriostatic Therapy
A commonly used distinction among antibacterial agents is that of bactericidal vs bacteriostatic agents. Bactericidal drugs, which cause death and disruption of the bacterial prison cell, include drugs that primarily act on the cell wall (eg, β-lactams), cell membrane (eg, daptomycin), or bacterial Deoxyribonucleic acid (eg, fluoroquinolones). Bacteriostatic agents inhibit bacterial replication without killing the organism. Almost bacteriostatic drugs, including sulfonamides, tetracyclines, and macrolides, act past inhibiting poly peptide synthesis. The distinction is not absolute, and some agents that are bactericidal against certain organisms may simply be bacteriostatic against others and vice versa. In nearly cases, this distinction is not meaning in vivo; still, bactericidal agents are preferred in the instance of serious infections such as endocarditis and meningitis to achieve rapid cure.
Use of Antimicrobial Combinations
Although unmarried-amanuensis antimicrobial therapy is generally preferred, a combination of 2 or more antimicrobial agents is recommended in a few scenarios.
When Agents Exhibit Synergistic Action Against a Microorganism. Synergy between antimicrobial agents means that, when studied in vitro, the combined effect of the agents is greater than the sum of their independent activities when measured separately.viii For example, the combination of certain β-lactams and aminoglycosides exhibits synergistic activity against a variety of gram-positive and gram-negative leanerix and is used in the treatment of serious infections, for which rapid killing is essential (eg, treatment of endocarditis caused by Enterococcus species with a combination of penicillin and gentamicin). In this setting, the addition of gentamicin to penicillin has been shown to exist bactericidal, whereas penicillin alone is but bacteriostatic and gentamicin alone has no significant activity. For sure streptococci, similar synergistic combinations that result in more rapid clearance of the infecting microorganism can also be used to shorten the course of antimicrobial therapy (eg, for endocarditis due to viridans group streptococci, a combination of penicillin or ceftriaxone with gentamicin for 2 weeks can be equally effective as penicillin or ceftriaxone lone for 4 weeks).10,11
When Critically Ill Patients Require Empiric Therapy Before Microbiological Etiology and/or Antimicrobial Susceptibility Tin can Be Adamant. As already discussed, antibiotic combinations are used in empiric therapy for health care–associated infections that are frequently caused past leaner resistant to multiple antibiotics. Combination therapy is used in this setting to ensure that at to the lowest degree 1 of the administered antimicrobial agents will be agile against the suspected organism(s). For example, when a patient who has been hospitalized for several weeks develops septic daze and blood cultures are reported to be growing gram-negative bacilli, information technology would exist appropriate to provide initial therapy with 2 agents that have action against gram-negative bacilli, particularly P aeruginosa, which is both a common nosocomial pathogen and frequently resistant to multiple agents—in this case, a combination of an antipseudomonal β-lactam with a fluoroquinolone or aminoglycoside could exist used.
To Extend the Antimicrobial Spectrum Across That Accomplished by Use of a Single Agent for Treatment of Polymicrobial Infections. When infections are idea to exist caused by more than i organism, a combination regimen may exist preferred because it would extend the antimicrobial spectrum across that accomplished by a unmarried agent. For example, most intra-abdominal infections are usually caused past multiple organisms with a diversity of gram-positive cocci, gram-negative bacilli, and anaerobes. Antimicrobial combinations, such equally a 3rd-generation cephalosporin or a fluoroquinolone plus metronidazole, can exist used as a potential treatment option in these cases and tin sometimes be more cost-effective than a comparable single agent (eg, a carbapenem).
To Foreclose Emergence of Resistance. The emergence of resistant mutants in a bacterial population is more often than not the consequence of selective pressure level from antimicrobial therapy. Provided that the mechanisms of resistance to 2 antimicrobial agents are dissimilar, the risk of a mutant strain being resistant to both antimicrobial agents is much lower than the take a chance of it being resistant to either ane. In other words, use of combination therapy would provide a better chance that at least one drug will be effective, thereby preventing the resistant mutant population from emerging as the ascendant strain and causing therapeutic failure. This is why combination drug therapy is used every bit the standard for treatment of infections such as tuberculosis and the human immunodeficiency virus (HIV) when treatment elapsing is likely to exist prolonged, resistance tin emerge relatively easily, and therapeutic agents are limited.
Host Factors to Be Considered in Selection of Antimicrobial Agents
Although information technology is helpful for clinicians to gain familiarity with a few specific antimicrobial agents, a "one size fits all" approach is non appropriate in antimicrobial option, and several host factors must exist taken into account. Published guidelines on appropriate dose adjustments for individual antimicrobial agents are available from a variety of sources.12,13
Renal and Hepatic Role. Considering the kidney and the liver are the primary organs responsible for elimination of drugs from the body, information technology is important to determine how well they are operation during antimicrobial administration. In most cases, one is concerned with dose reduction to prevent accumulation and toxicity in patients with reduced renal or hepatic function. However, sometimes doses might need to be increased to avoid underdosing young healthy patients with rapid renal elimination or those with rapid hepatic metabolism due to enzyme induction past concomitant use of drugs such as rifampin or phenytoin.
Age. Patients at both extremes of age handle drugs differently, primarily due to differences in torso size and kidney function. Virtually pediatric drug dosing is guided by weight. In geriatric patients, the serum creatinine level solitary is not completely reflective of kidney function, and the creatinine clearance should be estimated by factoring in age and weight for these patients.
Genetic Variation. Genetic susceptibility to the adverse effects of antimicrobial agents, which has been demonstrated for several antimicrobial agents, is occasionally significant plenty to warrant testing for such variability earlier administration of certain drugs.8 For example, the antiretroviral drug abacavir, which has become part of the standard combination treatment for HIV infection, is associated with a well-described and potentially fatal hypersensitivity reaction that can manifest with whatever combination of fever, rash, intestinal pain, and respiratory distress. The take chances of experiencing this reaction has been shown to be significantly higher in patients with the man leukocyte antigen allele HLA-B*5701,14 and current HIV handling guidelines recommend routine screening for the presence of this genetic susceptibility in patients before prescribing this drug. Some other example is that of glucose-6-phosphate dehydrogenase (G6PD) deficiency, which can outcome in hemolysis in individuals when exposed to certain antimicrobial agents, such every bit dapsone, primaquine, and nitrofurantoin. These drugs should exist avoided in those known to be deficient in G6PD, and it is appropriate to test for this predisposition in patients who might have a higher risk of G6PD deficiency (eg, African Americans) before prescribing these agents. Many antimicrobial agents are handled past the hepatic cytochrome P450 system, and although variation in expression of these enzymes occurs, insufficient information are available to recommend routine clinical testing to guide antimicrobial dosing.
Pregnancy and Lactation. Special considerations for the use of antimicrobial agents in pregnancy relate to both the mother and the fetus. In the case of the mother, increases in plasma volume and renal blood period, especially past the tertiary trimester, can consequence in more rapid clearance and lower serum levels of pharmaceutical agents, including antimicrobial agents. However, information to back up the clinical relevance of this change are sparse, and higher antimicrobial doses are not routinely recommended in the third trimester of pregnancy. Some experts recommend an increased dose of several protease inhibitors for the management of HIV infection in pregnancy. In the case of the developing fetus, many antimicrobial agents can be either teratogenic or otherwise toxic to the fetus. Penicillins, cephalosporins, and macrolides have historically been the most commonly used antimicrobial agents considered safe in pregnancy, and a recent multicenter study of more than xiii,000 women with pregnancies affected past birth defects constitute no association between adverse outcomes and these item antimicrobial agents.15 In dissimilarity, agents such as sulfonamides and nitrofurantoin, which were not previously considered harmful in early pregnancy, were found to exist associated with several nascency defects in this written report. Other drugs, such as tetracyclines and chloramphenicol, take well-described fetal or neonatal adverse effects and should be avoided. In general, however, homo studies on the condom of many antimicrobial agents in pregnancy and lactation are express, and antimicrobial agents should exist prescribed with caution.
History of Allergy or Intolerance. A history of antimicrobial allergy or intolerance should be routinely obtained in the evaluation and management of infection (for a fuller give-and-take, see "Adverse Effects").
History of Recent Antimicrobial Use. Eliciting a history of exposure to antimicrobial agents in the recent past (approximately 3 months) can also aid in selection of antimicrobial therapy. Considering the causative microorganism for a current episode of infection emerged nether the selective pressure of a recently used antimicrobial amanuensis, it is probable to exist resistant to that drug and/or drug class, and an alternative agent should be used.
Oral vs Intravenous Therapy
Patients hospitalized with infections are often treated with intravenous antimicrobial therapy because their access is often prompted by the severity of their infection. However, patients with mild to moderate infections who require hospitalization for other reasons (eg, dehydration, hurting command, cardiac arrhythmias) and have normal gastrointestinal function are candidates for handling with well-captivated oral antimicrobial agents (eg, treatment of pyelonephritis and community-acquired pneumonia with oral fluoroquinolones). Furthermore, patients initially treated with parenteral therapy can be safely switched to oral antibiotics when they go clinically stable. When using oral therapy for invasive infections (such as pneumonia, pyelonephritis, or abscesses), clinicians are advised to select an agent that has excellent absorption and bioavailability (ie, the pct of the oral dose that is available unchanged in the serum). Examples of antibiotics with excellent bioavailability are fluoroquinolones, linezolid, trimethoprim-sulfamethoxazole, and metronidazole. For more serious infections, such every bit infective endocarditis and key nervous organization infections (eg, meningitis), in which high serum or CSF drug concentrations are desired, a switch to oral therapy is less reliable and non generally recommended.10
Pharmacodynamic Characteristics
Along with host factors, the pharmacodynamic properties of antimicrobial agents may also exist of import in establishing a dosing regimen. Specifically, this relates to the concept of fourth dimension-dependent vs concentration-dependent killing.11 Drugs that exhibit time-dependent activity (β-lactams and vancomycin) have relatively slow bactericidal activeness; therefore, information technology is important that the serum concentration exceeds the MIC for the duration of the dosing interval, either via continuous infusion or frequent dosing. In dissimilarity, drugs that exhibit concentration-dependent killing (aminoglycosides, fluoroquinolones, metronidazole, and daptomycin) take enhanced bactericidal activeness every bit the serum concentration is increased. With these agents, the "peak" serum concentration, and not the frequency of the dosing interval, is more than closely associated with efficacy. To illustrate the impact of this distinction on dosing options, we can accept the example of a 70-yr-sometime adult female with a creatinine clearance estimated to be 30 mL/min who is existence treated with ciprofloxacin for pyelonephritis caused by E coli. Antimicrobial dosing guidelines suggest that a dose of either 250 mg orally every 12 hours or 500 mg every 24 hours is an acceptable modification for her reduced kidney function. However, given that ciprofloxacin exhibits concentration-dependent killing, pick of the latter dosing schedule would be more appropriate.16 In contrast, if the same patient were beingness treated with intravenous ampicillin, for which the time above the MIC is more than closely related to efficacy, a dose of 1 g every 4 hours would be preferable to two g every 8 hours.
Efficacy at the Site of Infection
In add-on to possessing in vitro antimicrobial activity and achieving adequate serum levels, the efficacy of antimicrobial agents depends on their capacity to accomplish a concentration equal to or greater than the MIC at the site of infection and modification of activity at certain sites. Antimicrobial concentrations attained at some sites (eg, ocular fluid, CSF, abscess cavity, prostate, and bone) are often much lower than serum levels. For case, offset- and 2nd-generation cephalosporins and macrolides practise not cross the blood-brain barrier and are non recommended for central nervous organization infections. Fluoroquinolones achieve high concentrations in the prostate and are preferred oral agents for the handling of prostatitis.17 Daptomycin, an fantabulous bactericidal agent against gram-positive bacteria, is not useful for handling of pneumonia (eg, pneumococcal pneumonia) considering information technology is inactivated by lung surfactant.18 Many antibiotics (eg, aminoglycosides) are less active in the low-oxygen, low-pH, and high-protein environment of abscesses, and drainage of abscesses to heighten antimicrobial efficacy is recommended when possible.8 Agents in the same course can differ from one another; for case, moxifloxacin does not reach significant urinary concentrations considering of its low renal excretion and is therefore not suitable for treatment of UTIs; in contrast, both levofloxacin and ciprofloxacin are fantabulous choices for UTIs caused past susceptible bacteria. The presence of strange bodies at the site of infection also affects antimicrobial activity (see "Antimicrobial Therapy for Foreign Body–Associated Infections").
Pick of Antimicrobial Agents for Outpatient Parenteral Antimicrobial Therapy
To decrease cost, and with the help of advances both in antimicrobial agents and in technology to assist antimicrobial administration, prolonged treatment of serious infections with intravenous or parenteral antimicrobial agents has increasingly shifted away from the hospital to the outpatient setting, and guidelines to assist with delivery of high-quality outpatient parenteral antimicrobial therapy (OPAT) have been developed.nineteen Therapy can be provided via one of several types of indwelling central venous access catheters (a peripherally inserted central catheter is most frequently used) and can be delivered at an infusion center, by a dwelling house-visiting nurse, by self-administration, or in a nursing domicile.6 In add-on to the full general principles for choice of antimicrobial agents that take already been discussed, OPAT requires some further considerations. Get-go, other things being equal, an amanuensis that requires less frequent administration is preferred. For example, for the treatment of osteomyelitis or other serious infections caused by methicillin- or oxacillin-sensitive South aureus, cefazolin is frequently used in favor of nafcillin or oxacillin because it allows assistants every 8 hours. Its apply makes handling outside the hospital setting much more viable than the assistants every four hours required for the other drugs. Agents with once- or twice-daily dosing have gained popularity for OPAT and include ceftriaxone, ertapenem, vancomycin, and daptomycin. An alternative for nigh β-lactams, which crave frequent dosing, is use of a continuous infusion pump; however, such a device can frequently be cost-prohibitive. Second, the agent must possess chemical stability and should last for about 24 hours afterward mixing to allow plenty time for delivery and administration. As an important illustration of the principle, the use of intravenous ampicillin for OPAT via cocky-administration or continuous infusion is often precluded because of a short (approximately 8-hour) stability menstruation at room temperature. Ampicillin or penicillin (in combination with an aminoglycoside) is the drug of choice for endocarditis acquired by penicillin-sensitive enterococci; therefore, OPAT for this blazon of infection usually necessitates either nursing home stay or investment in a continuous infusion device (for penicillin only). 3rd, agents with minimal toxicity or predictable toxicity acquiescent to monitoring are preferred as OPAT is generally used in the context of longer-term antimicrobial therapy. Finally, when possible, provided adherence can exist expected, consideration should exist given to using oral agents (as discussed in "Oral vs Intravenous Therapy") in the outpatient setting.
Apply of Therapeutic Drug Monitoring
Monitoring serum concentrations for drugs is most useful for medications that accept a fairly narrow therapeutic index, which is the ratio of the toxic to the therapeutic dose. Fortunately, about antimicrobial agents accept a wide therapeutic index,20 allowing standard doses to be used, with predictable modifications on the basis of age, weight, and renal and hepatic function. However, sure antimicrobial agents require monitoring of serum levels considering the therapeutic window is narrow. This could exist due primarily to toxicity at loftier levels (eg, aminoglycosides)21 or therapeutic failure at low drug levels (eg, vancomycin)22,23 simply is usually a combination of both (eg, voriconazole).24 In some cases, the apply of serum drug level monitoring is supported by its beneficial effect on clinical outcomes (eg, voriconazole in the treatment of invasive fungal infections).24
CONSIDERATIONS FOR CONTINUING ANTIBIOTIC THERAPY
Duration of Antimicrobial Therapy
The duration of therapy for many infections has long been based on anecdotal data and good opinion. In view of the deleterious effects of prolonged courses of antimicrobial agents, including the potential for agin reactions, problems with adherence, selection of antibiotic-resistant organisms, and loftier cost, a number of studies accept tried to define the optimal elapsing of therapy, with an accent on shorter courses of therapy. For example, bear witness supports limiting treatment of uncomplicated UTI in women to 3 days,25 community-caused pneumonia to 5 days,26 and ventilator-associated pneumonia to eight days.27 However, when administering abbreviated treatment courses, it is of import for clinicians to ensure that their patients fit the profile of the study population and advisedly monitor high-risk patients for improvement. For example, in the study of brusk-course treatment for ventilator-associated pneumonia,27 the 8-day course was non sufficient for the treatment of infections due to P aeruginosa or in immunocompromised patients. In other situations, a longer duration of therapy is clearly warranted (eg, 4-half dozen weeks for endocarditis, osteomyelitis, and intra-abdominal abscesses, and weeks to months for invasive fungal infections) to reach cure and foreclose relapse. In many such infections, treatment duration has to be carefully individualized on the basis of clinical and radiologic response and may require the guidance of an expert in infectious diseases.
Cess of Response to Treatment
Response to treatment of an infection can exist assessed using both clinical and microbiological parameters. Clinical parameters of improvement include symptoms and signs (eg, a decrease in fever, tachycardia, or confusion), laboratory values (eg, decreasing leukocyte count), and radiologic findings (eg, decrease in the size of an abscess). Although radiologic criteria are commonly used in assessing response to infectious disease therapy, radiologic improvement can frequently lag backside clinical improvement, and routine radiographic follow-upwardly of all infections is not always necessary. For example, in a study of clinical and radiographic follow-upwards of patients with community-acquired pneumonia,28 clinical cure was observed in 93% of patients after 10 days of follow-up, whereas radiographic resolution was noted in only 31% of patients. In fact, several weeks or even months may be required before breast radiography or computed tomography shows consummate resolution of an infiltrate.
Bacteremia is the nearly common scenario in which microbiological response is closely assessed considering clearance of the bloodstream is as of import every bit clinical improvement. Persistent bacteremia can frequently be the only inkling to the presence of an inadequately treated source or to the being or development of endovascular infection (such as endocarditis or an intravascular device infection). Persistent bacteremia tin can also be associated with the emergence of antimicrobial resistance and should always be investigated.29
Adverse Effects
Although the term antimicrobial allergy is often used synonymously with adverse reaction or adverse issue, allergic reactions constitute merely one subset of adverse reactions to antimicrobial agents (encounter the Table for a useful classification of antimicrobial adverse effects).
Tabular array.
Classification of the Adverse Effects of Antimicrobial Drugs
Allergic or hypersensitivity reactions can be either immediate (IgE-mediated) or delayed and usually manifest as a rash; anaphylaxis is the almost severe manifestation of IgE-mediated allergy. In a recent national written report of the prevalence of adverse drug furnishings, antibiotics were implicated in 19% of all emergency department visits for drug-related adverse events, and 79% of all antibiotic-associated adverse events were classified as allergic reactions.30 Although a history of serious allergic reaction should be carefully documented to avert inadvertent administration of the aforementioned drug or another drug in the same form, cocky-report of antibiotic allergies tin can exist quite unreliable—it has been shown that simply x% to 20% of patients reporting a history of penicillin allergy were truly allergic when assessed past pare testing.31 Historical details should be elicited to help distinguish allergic from nonallergic reactions and IgE-mediated from delayed reactions because failure to do so tin result in unnecessary avoidance of the most effective, narrow-spectrum, and cost-effective antimicrobial agent (eg, use of vancomycin in identify of a β-lactam). Although no unmarried exam or clinical finding leads to a diagnosis of antibiotic allergy, a negative skin test (best described for penicillin) tin can reliably exclude the possibility of developing an IgE-mediated reaction (such as anaphylaxis) and assistance optimize antibiotic use.32-34 Both clinicians and patients should understand that a negative skin test does not mean that a patient is non at risk for developing a non–IgE-mediated delayed allergic reaction, simply that in many circumstances the benefit of receiving a more appropriate antibiotic would outweigh the take chances of a less significant allergic reaction. If an ongoing reaction is attributed to an antimicrobial drug allergy, this usually requires discontinuation of the offending agent. Related drugs (eg, cephalosporins in patients with a history of penicillin allergy) can be used under conscientious observation, provided that the reaction is not severe or the pare examination is negative. In some cases, if the offending amanuensis is the simply or highly preferred agent, desensitization may be necessary. Desensitization involves administration of the drug in progressively increasing doses given by oral cavity; protocols are available for certain agents, such as β-lactams and sulfonamides, and should exist guided by experts in allergic diseases.
Nonallergic drug toxicity is usually, but not always, associated with higher doses and/or prolonged utilize and is peculiarly noted in patients with poor kidney or liver part that results in impaired clearance. Examples include nephrotoxicity with aminoglycosides, neurotoxicity of penicillins, and peripheral neuropathy with prolonged use of metronidazole; these potential adverse effects need to be discussed with patients before initiation of therapy. For patients receiving prolonged systemic antimicrobial therapy, periodic clinical and laboratory monitoring is likewise recommended,19 especially for those drugs that cause predictable toxicity with increasing duration of use (eg, monitoring consummate blood cell count, including white blood cell differential, with β-lactams, trimethoprim-sulfamethoxazole, and linezolid; creatine kinase level with daptomycin; and creatinine level with aminoglycoside and β-lactams). In add-on, drug doses should be adapted in response to changes in creatinine level to avoid toxicity and reach optimal serum concentrations.
Many antimicrobial agents interact with other drugs to increase or decrease their serum levels and furnishings. This is frequently the instance with antimicrobial agents that are metabolized by and/or affect the cytochrome P450 enzyme organization (eg, rifampin is a powerful inducer, whereas macrolides and azole antifungal agents are inhibitors of cytochrome P450 enzymes). Clinicians should always remain alert to the possibility of such interactions of antimicrobial agents with other drugs, and it is advisable to review a patient's medication listing when prescribing antimicrobial agents. Certain drug combinations can also crusade additive toxicity, as exemplified by the concomitant use of amphotericin and gentamicin, which can significantly increase the risk of nephrotoxicity.
SPECIAL SITUATIONS IN Communicable diseases THERAPY
Antimicrobial Therapy for Foreign Body–Associated Infections
Prosthetic implants and devices are increasingly being used in modern medical handling. An unfortunate consequence of this increased utilize is the emergence of infections associated with the placement of such devices, involving both temporary (eg, urinary catheter, cardinal venous catheter) and permanent (eg, prosthetic joint, artificial eye valve) implants. One of the of import characteristics of device-related infection is the germination of biofilms, which have been described as "a structured customs of bacterial cells enclosed in a self-produced polymeric matrix and adherent to an inert or living surface."35 Bacteria growing in biofilms have been shown to be relatively protected from the effects of antimicrobial therapy, probably every bit a issue of alteration of their metabolic state.36 Primary care physicians should exist aware of this because prolonged antibody treatment for these infections can be ineffective, associated with adverse effects, and issue in the emergence of resistant strains of organisms.37 Certain agents (eg, rifampin38 and fluoroquinolones39) have better activity against staphylococci in biofilms and are recommended in the management of infections of prosthetic valves10 and jointsforty caused by these organisms. All the same, because of the difficulty of eradicating infections with antimicrobial therapy alone, removal of the implant is often necessary for cure. As an alternative, for patients unable to tolerate implant removal, long-term suppressive antimicrobial therapy is sometimes used, with variable success. It is advisable to involve an infectious diseases proficient in the direction of infections associated with implanted foreign bodies.
Use of Antimicrobial Agents as Safety or Suppressive Therapy
In an ideal scenario for use of an antimicrobial agent as safe treatment, the infection would occur predictably in a certain setting and would exist well known to exist associated with a specific organism or organisms, and an constructive antimicrobial agent would be available with no or limited long-term toxicity and with little likelihood of leading to the emergence of resistance.vi Not surprisingly, such scenarios are relatively rare. Notwithstanding, antimicrobial prophylaxis is appropriate in some instances, a give-and-take of which follows.
Presurgical Antimicrobial Prophylaxis. Antimicrobial prophylaxis is used to reduce the incidence of postoperative surgical site infections. Patients undergoing procedures associated with high infection rates, those involving implantation of prosthetic material, and those in which the consequences of infection are serious should receive perioperative antibiotics. The antibody(s) should comprehend the most probable organisms and be present in the tissues when the initial incision is made, and adequate serum concentrations should be maintained during the process. A unmarried dose of a cephalosporin (such every bit cefazolin) administered within 1 60 minutes before the initial incision is appropriate for near surgical procedures; this practice targets the most likely organisms (ie, peel flora), while fugitive unnecessary wide-spectrum antimicrobial therapy. Duration of prophylaxis for surgical site infection should not exceed 24 hours in nigh cases.41
Antimicrobial Prophylaxis in Immunocompromised Patients. Immunocompromised patients, particularly those with HIV infection/AIDS, those who are undergoing chemotherapy for cancer, or those who are receiving immunosuppressive therapy after organ transplant, are at increased run a risk of infection. These infections are acquired by predictable organisms at an increased frequency and/or associated with loftier mortality (eg, invasive aspergillosis associated with prolonged neutropenia, Pneumocystis pneumonia in the setting of dumb cell-mediated immunity [eg, AIDS, organ transplant]). In these specific settings, evidence supports the use of prolonged antimicrobial prophylaxis until immune markers are restored (eg, trimethoprim-sulfamethoxazole to preclude Pneumocystis pneumonia42).
Antimicrobial Prophylaxis to Prevent Transmission of Communicable Pathogens to Susceptible Contacts. Antimicrobial agents tin can exist prescribed prophylactically to prevent transmission of pathogens to susceptible contacts; for example, antiviral agents can be used to limit the spread of influenza in nursing abode residents, ciprofloxacin can be given to close contacts of a patient with meningitis caused by N meningitidis, and macrolides tin be prescribed to reduce transmission of pertussis.
Antimicrobial Prophylaxis Before Dental and Other Invasive Procedures in Patients Susceptible to Bacterial Endocarditis. It should be noted that guidelines recommending antimicrobial prophylaxis in this setting have recently been updated and limit such employ to only a few very loftier-risk scenarios—prosthetic valves, prior endocarditis, or congenital heart disease before surgical correction.43
Traumatic Injuries With a High Probability of Infectious Complications. Certain types of injuries pose a particularly loftier risk of infection because of disruption of normal barriers and/or delivery of a high inoculum of pathogenic organisms (eg, antibody prophylaxis has been shown to be of some do good and is recommended for certain types of animal bites44 and subsequently penetrating brain injury45). An case of inappropriate antimicrobial "prophylaxis" is prolonged antimicrobial utilise in those with open but non infected wounds, including surgical wounds. No consensus has yet been reached on the use of antimicrobial prophylaxis in another settings, such equally before invasive procedures in patients with prosthetic joints.
Nonantimicrobial Therapy for Infections
Antimicrobial therapy is commonly, only not always, the most important therapy for infectious diseases. The all-time-recognized example of nonantimicrobial therapy in the treatment of infections is the utilize of operative drainage or débridement. This procedure is useful when the organism burden is very high or in the management of abscesses, for which the penetration and activity of antimicrobial agents are often inadequate. Other therapies used in the handling of infectious diseases involve modulating the host inflammatory response to infection. Systemic corticosteroids, thought to deed past decreasing the deleterious effects of the host inflammatory response, have been plant beneficial when used in conjunction with antimicrobial therapy for the treatment of bacterial meningitis,46 tuberculous meningitis,47 and Pneumocystis pneumonia in patients with AIDS.48 Temporary discontinuation or dose reduction of immunosuppressive agents is often required for successful treatment of infections, such equally cytomegalovirus disease in organ transplant recipients or patients with rheumatologic disorders. Similarly, granulocyte colony–stimulating cistron is sometimes administered to patients with prolonged neutropenia who develop invasive infections with filamentous fungi. Intravenous immunoglobulin therapy, which acts to neutralize toxin produced by the bacteria, tin can be used in add-on to surgical débridement and antimicrobial therapy in the treatment of necrotizing fasciitis acquired by group A streptococci.49 Probiotics (such as Lactobacillus and Saccharomyces species) are occasionally used in the management of colitis acquired by Clostridium difficile, with the promise of restoring the normal flora that has been altered by antimicrobial administration.50 Some of these interventions lack a stiff evidence base but are often recommended by experts on the footing of clinical experience.
JUDICIOUS Employ OF ANTIMICROBIAL AGENTS
Cost Considerations in Antibody Option and Antimicrobial Stewardship
The "cost" of an antimicrobial agent is dependent on many factors in addition to the buy cost of a particular agent and may include administration costs, prolonged hospitalization every bit a event of adverse furnishings, the cost of serum concentration monitoring, and clinical efficacy. I strategy that can significantly reduce cost is the switch from intravenous to oral therapy. Oral therapy is generally less expensive, potentially associated with fewer adverse effects, and can result in considerable cost savings by facilitating earlier dismissal and a shortened hospital stay.51 Fifty-fifty if the purchase price of an oral amanuensis is greater than its parenteral equivalent, the reduction in hospital stay tin can consequence in meaning price savings. This has been demonstrated for oral linezolid when compared with intravenous vancomycin for the handling of complicated skin and soft tissue infections caused past MRSA.52,53
Toll considerations in the selection and continuation of advisable antimicrobial therapy in acute intendance hospitals are part of a broader activity that is referred to as antimicrobial stewardship. Antimicrobial stewardship programs are aimed at "optimizing antimicrobial choice, dosing, route, and duration of therapy to maximize clinical cure or prevention of infection while limiting the unintended consequences, such every bit the emergence of resistance, adverse drug events, and cost."54 These programs are unremarkably coordinated past a team of infectious disease doc(s) and pharmacist(south) and are oftentimes computer-based. Some components recommended for these programs include the post-obit: prospective audit and feedback of antimicrobial prescriptions to clinicians, formulary restriction, education, apply of clinical order sets and guidelines, de-escalation of therapy, and intravenous to oral antimicrobial conversion when appropriate.54 Clinicians should make it a priority to get aware of such programs in their institutions.
Preventing Emergence of Antibiotic Resistance
The widespread—and often inappropriate—utilise of antimicrobial agents is the single most important cause of the emergence of drug resistance, both in the customs and hospital settings. Prior antibody exposure has been shown to exist the most frequent risk cistron for the development of community-caused respiratory infections caused by drug-resistant South pneumoniae.55 This is non surprising considering acute upper respiratory illnesses account for the highest proportion of convalescent antibiotic prescriptions,56 with nigh beingness dispensed in situations in which antibiotics were not fifty-fifty indicated.57 Clearly, the emergence of antimicrobial resistance tin can be prevented or delayed through judicious prescribing, which can be characterized as follows: abstention of antibiotic treatment for community-acquired, more often than not viral, upper respiratory tract infections; use of narrow-spectrum antibiotics when possible; and use of antibiotics for the shortest duration that is constructive for the handling of a particular clinical syndrome. In the past few years, interest has been increasing in the development of rapid and accurate diagnostic tests for detection of viral respiratory pathogens with the ability to distinguish between viral and bacterial infections, such as measurement of procalcitonin levels and nucleic acid tests. Although not yet widely bachelor in clinical do, these tests have the potential to curtail the employ of antibacterial agents for clinical syndromes that are clearly acquired by viruses.
Common Misuses of Antibiotics
In some settings, the employ of antibiotics is conspicuously inappropriate. A discussion follows of some of the typical scenarios in which they are contraindicated.vi
Prolonged Empiric Antimicrobial Treatment Without Clear Evidence of Infection. One of the nearly mutual mistakes in antimicrobial utilise is continuing to add or switch antibiotics when a patient does not appear to be responding to therapy, even though at that place is no articulate prove of an communicable diseases. Many noninfectious, inflammatory, or neoplastic syndromes can present with symptoms and signs that mimic infectious diseases. Examples include adult-onset All the same affliction and other connective tissue disorders that can present with loftier fever; drug-induced fever; the fever associated with pulmonary embolism; lymphoma; and Wegener granulomatosis, which can present with fever, cavitary pulmonary nodules, and recurrent sinusitis.
Treatment of a Positive Clinical Civilisation in the Absence of Disease. Colonization with potentially pathogenic organisms without any associated manifestation of affliction occurs frequently in certain populations (eg, colonization of the urinary tract in women of advanced historic period or in the presence of an indwelling urinary catheter, colonization of endotracheal tubes in mechanically ventilated patients, and colonization of chronic wounds). Appropriate management in these situations involves obtaining cultures from these sites only when indicated and avoiding treatment of a "positive" culture result when symptoms and signs of active infection are absent (eg, asymptomatic bacteriuria).
Failure to Narrow Antimicrobial Therapy When a Causative Organism Is Identified. Equally already discussed, initial therapy is often empiric and relies on broad-spectrum agents until culture or other tests help determine the microbiological etiology. One time civilization and susceptibility data are available, an antibiotic with the narrowest possible spectrum should be selected for continuation of therapy. Often, yet, this does not occur, specially if the patient has improved while receiving empiric therapy, and the md is uncomfortable about changing therapy in the face of clinical improvement.
Prolonged Prophylactic Therapy. As already discussed, infection can be prevented in sure situations by the safety use of antimicrobial agents (eg, presurgical prophylaxis). Yet, in most cases, guidelines back up the use of a single, preoperative dose of an antimicrobial amanuensis. Prolonged "prophylaxis" simply sets the stage for the emergence of antimicrobial resistance. For example, the common practice of prolonging antimicrobial therapy until the removal of surgical drains is not evidence based.
Excessive Use of Sure Antimicrobial Agents. The frequent utilise of certain agents (or classes of antimicrobial agents) in a hospital or other health care setting can upshot in selection of organisms that are resistant to that item antibiotic. For example, the increased utilize of fluoroquinolones during the past decade is thought to be, in part, responsible for the epidemic of a fluoroquinolone-resistant strain of C difficile,58 the most mutual crusade of nosocomial infectious diarrhea. More recently, an increase in levofloxacin use every bit initial therapy for UTI as a result of policy change at a single institution was found to accept led to a rapid increment in fluoroquinolone resistance among outpatient urinary E coli isolates at that institution.59 For this reason, those involved in antimicrobial stewardship should avoid the excessive prescribing of a single class of antibiotic.
CONCLUSION
Appropriate use of antimicrobial agents involves obtaining an accurate diagnosis, determining the need for and timing of antimicrobial therapy, understanding how dosing affects the antimicrobial activities of dissimilar agents, tailoring treatment to host characteristics, using the narrowest spectrum and shortest elapsing of therapy, and switching to oral agents equally soon as possible. In add-on, nonantimicrobial interventions, such as abscess drainage, are every bit or more than important in some cases and should be pursued diligently in comprehensive communicable diseases direction.
Supplementary Material
Notes
This activity was designated for ane AMA PRA Category 1 Credit(s).™
The contributions to the Symposium on Antimicrobial Therapy are now a CME activeness. For CME credit, run into the link on our Web site at mayoclinicproceedings.com.
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