Strategies to minimize antibiotic resistance and maximize efficiency
One of the main problems of antibiotic administration programs is the choice of empirical antibiotic treatment for inpatient sepsis. Although the definition of sepsis is still evolving, antibiotic programmes should optimize treatment while minimizing resistance.
Currently, the recommended treatment for septic shock is the use of empirical broad-spectrum antibiotics, preferably within the first hour after the recognition of septic shock.
It is difficult for a septic patient to make the right antibiotic choice to attack the most likely pathogen associated with the site of infection and minimize resistance.
The maximum effectiveness of antibiotics depends on pharmacokinetics and pharmacodynamics. Potential resistance to antibiotics, which is an integral characteristic of antibiotics, is independent of the class of antibiotics.
Within each class of antibiotics there are agents with low and high resistance potential. Pharmacokinetic and pharmacodynamic considerations optimize performance, as selecting an antibiotic with low resistance potential minimizes the potential for resistance.
In hospitals where endemic gram-negative bacillar microorganisms are resistant to antibiotics, antibiotic use is limited and it is very important to carefully select the initial antimicrobial mode for a septic patient.
The mechanisms of action and inactivation/resistance do not explain why antibiotics in a class have high or low resistance potential. Even with large amounts or prolonged use, antibiotics with low resistance potential have little or no resistance, such as ceftriaxone.
Of third-generation cephalosporins, only ceftazidime, an antibiotic with high resistance potential, is associated with resistance to Pseudomonas aeruginosa, even in modest use.
In contrast, other third-generation cephalosporins have a low resistance potential and minimal resistance potential, even when used extensively over long periods of time. In addition to the inherent antibiotic resistance, the same dose of antibiotics is partly related to the emergence of resistance.
In vitro sensitivity tests for in vivo efficacy
Antibiotic resistance is a complex concept. There is no international agreement on standard cut-off points that defines which pathogens are resistant and sensitive to certain agents. The sensitivity test is based on serum concentrations that can be achieved with normal doses of recommended antibiotics.
Sensitivity tests are used for growing organisms, and for this reason these tests are not carried out for fast-growing organisms. The sensitivity of isolates cultivated from browns requires interpretation and extrapolation.
In vitro sensitivity testing suggests that an antibiotic is used in the usual dose to treat blood flow infection, and that local conditions at the actual site of infection are similar to those in the blood.
The chemical composition of the sensitive media also affects the results. In some organisms, in vitro sensitivity tests do not predict clinical effectiveness in vivo.
In a clinical setting, local acidosis, poor perfusion, local hypoxia and cellular disorders in the cavity of the abscess may significantly reduce the activity of some antibiotics, such as aminoglycosides.
Because of the difficulty in penetrating target tissues, the physician should extrapolate achievable serum concentrations to probable concentrations in target tissues.
Without such extrapolation, when faced with the report that the body is sensitive, an immune clinician may conclude that the isolate is sensitive to antibiotics anywhere in the body, regardless of local factors and the concentrations that the antibiotic reaches locally.
In general, if the body is considered sensitive, it is generally dependent on the body and the serum concentrations that are clinically achieved.
However, there are important non-blooded sites of infection that are difficult to penetrate and require pharmacokinetic assessment of antibiotic concentrations in the tissue/infection site under study.
In most cases, the antibiogram reports sensitivity or stability, but in some cases, such as penicillin and streptococcus pneumonia, 3 different cut points are reported: sensitive, intermediate and stable. These cut points also differ for S. pneumonia, isolated from cerebrospinal fluid, and for S. pneumonia, isolated from other different sites.
The cefepima also has 3 cutting points for aeruginosa. In such cases, the question is whether intermediate susceptibility is considered as sensitive or resistant. In general, if the serum concentration achievable with normal or high dosage exceeds the minimum inhibitory concentration (MIC) of the intermediate or even moderately resistant organism (at the site of infection), then isolates should be considered as sensitive rather than resistant.
This point is important, because many physicians consider the results of susceptibility to be absolute and do not take into account differences in antibiotic concentrations in the absence or presence of inflammation/infection at different sites of the body, e.g., cerebrospinal fluid, bone, prostate or urine.
Clinically relevant types of resistance
Resistance can be classified by the mechanism or type of resistance, but it does not explain the important differences in the resistance potential of different classes of antibiotics. Antibiotic resistance can be considered as intrinsic or acquired and can also be classified within a class or as cross-resistance between classes.
Inherent antibiotic resistance is the natural resistance of certain organisms, e.g. Enterococci are intrinsically resistant to cephalosporins, aeruginosa shows inherent resistance to nafacillin, and so on.
High resistance cannot be overcome by increasing the dose of antibiotics
The opposite of natural resistance is acquired resistance, which refers to organisms that were previously sensitive to various antibiotics but have become resistant. Acquired resistance can be absolute or relative, high or low level.
High resistance cannot be overcome by increasing the dose of antibiotics, i.e. resistance is independent of serum concentrations. In the event of a high level of resistance, an alternative antibiotic must be selected that is effective against the organism.
Similarly, acquired high-level resistance, e.g. aeruginosa infection with acquired high-level resistance that has been treated with an MIC >4000 mg/ml should be treated with another class of antibiotic to which the organism is sensitive.
Acquired resistance provides the clinician with the opportunity to apply the principles of pharmacokinetics to treat infections at different sites in the body. These estimates are based on pharmacokinetic principles but data are limited or unavailable to achieve individualized treatment.
Resistance can also be considered within a class of antibiotics. For example, ciprofloxacin-resistant Pseudomonas aeruginosa may also be resistant to levofloxacin. This is a commonly recognized clinical reality, but there are important exceptions, such as aminoglycosides.
For example, it is not uncommon for Pseudomonas aeruginosa to be resistant to gentamicin and tobramycin, but sensitive to amikacin. Gentamicin and tobramycin have 6 loci in their structure that make them sensitive to aminoglycoside-inactivating enzymes that mediate clinical resistance.
In contrast, amikacin has only one such loci. For this reason, amikacin is the aminoglycoside most likely to act against gentamicin- and tobramycin-resistant Pseudomonas aeruginosa.
In contrast, cross-resistance refers to resistance to antibiotics of different classes. For reasons that are not entirely clear, one antibiotic can induce resistance in another class of antibiotic, with ≥1 organisms manifesting themselves by increased MICs.
These problems are often related to permeability mutants or the presence of non-specific efflux pumps that expel multiple classes of antibiotics out of the cell.
For example, the use of ciprofloxacin for Pseudomonas aeruginosa can induce entrained MIC, which affects other anti-pseudomonal drugs within the same class, e.g. levofloxacin, as well as other classes of antibiotics, (imipenem ceftazidime).
The same applies to other anti-pseudomonal antibiotics with a high resistance potential. If imipenem is the main hospital carbapenem, then IMC with carry-over can be seen with other carbapenems, such as meropenem and doripenem, as well as other classes of anti-pseudomonal antibiotics, such as ciprofloxacin, levofloxacin, gentamicin and ceftazidime.
For this reason, if an institution has a resistance problem with a particular organism, such as Pseudomonas aeruginosa, a single form replacement of a high-potential antibiotic with a low-potential antibiotic will not solve the problem.
For better control of a Pseudomonas aeruginosa resistance problem, all anti-pseudomonal antibiotics on the form should be of the low resistance potential variety.
Antibiotics can be classified into those with a high potential for resistance or a low potential for resistance. Historically, an antibiotic with low resistance potential can be defined as one that has a low propensity to develop resistance, regardless of the volume and duration of use, for example, doxycycline, minocycline, amikacin or cefepim.
In contrast, antibiotics with a high resistance potential are likely to be associated with resistance problems, even with a limited volume of use. It is not known why, within each class of antibiotics, there are some with high resistance potential. And others with low resistance potential. Some members of each class of antibiotics have not caused resistance, while others have.
The third-generation cephalosporin ceftriaxone is an example of an antibiotic with low resistance potential that, even after decades of high volume use, shows very little clinically significant resistance or Another third-generation cephalosporin, ceftazidime, is the only antibiotic with high resistance potential that is associated with resistant Pseudomonas aeruginosa.
Among the fluoroquinolones, ciprofloxacin is the quinolone with high resistance potential, while levofloxacin and moxifloxacin are antibiotics with low resistance potential.
The message for clinicians is clear: for any infection, the way to prevent resistance is to use preferably the antibiotics with low resistance potential.
Almost always, within the same class of antibiotics there are other alternatives that provide similar or better activity against the pathogen than antibiotics with high resistance potential.
Although pharmacodynamic considerations may minimize the resistance potential of antibiotics with high resistance potential, the best approach is to prefer antibiotics with low resistance potential.
Resistance may develop if the clinical setting is incorrect, for example, when treating an abscess even with an antibiotic of low resistance potential, because within the abscess, the concentrations achieved are low and may predispose to resistance.
Pathogens that are intermittently active, living in a biofilm covering the surface of a foreign body, create an ideal environment for the emergence of resistance. In situations where there is impaired blood flow or problems of poor tissue penetration, resistance can occur with any antibiotic, but is certainly more common with antibiotics with high resistance potential.
An additional effort to limit resistance is to apply treatment for as short a time as the infection allows. Longer courses are not more effective and may predispose to resistance.
Inherent resistance potential of selected antibiotics
Antibiotic dosing to optimize efficacy and minimize resistance
The pharmacodynamic aspects of the drug must be considered, which is related to its concentration and distribution in serum and body fluids, as a function of time. Serum concentrations are related to peak serum concentrations, serum half-life, protein findings, and renal and hepatic function.
Tissue penetration characteristics of antibiotics are determined by pharmacokinetic parameters such as peak serum concentration, protein binding and volume of distribution. Clinical improvement should be reassessed on day 3. If there is clinical improvement, therapy is completed with the same drug that was being used.
In the treatment of infection, pharmacodynamics refers to the bacterial destruction caused by antibiotics and is described either by demonstrating concentration-dependent destruction, time-dependent destruction, or a combination of both.
The kinetics of concentration-dependent bacterial killing refers to the fact that bacterial killing increases when antibiotic concentrations exceed the MIC, and is expressed as the concentration of antibiotic (Cmax) in serum, relative to a given MIC.
Antibiotics showing concentration-dependent concentrations, such as aminoglycosides, daptomycin and metronidazole, often show a post-antibiotic effect, indicating that the resurgence of the pathogen is delayed by several hours after adequate levels of antibiotics in the blood have disappeared.
Antibiotics showing a time-dependent killing kinetics are those in which an increase in serum levels does not cause increased bacterial death until 4-5 times the MIC of the organism, and is expressed as the time-dependent drug concentration remaining above the MIC during the dosing period.
Other antibiotics (e.g., fluoroquinolones) express a better destruction kinetic that is described by the pharmacodynamic parameter known as the area under the concentration time curve over a 24-hour period.
Interestingly, some antibiotics show both time-dependent and concentration-dependent kinetics of destruction, e.g. Doxycycline and vancomycin. Even among antibiotics demonstrating a time-dependent killing function there is no drawback to using high doses of antimicrobial treatment.
In general, bacteriostatic antibiotics show a time-dependent kinetic of destruction, while bactericidal antibiotics show a concentration-dependent kinetic of destruction, but some antibiotics exhibit both types of destructive kinetics.
Doxycycline, for example, which shows a time-dependent kinetic of destruction, when used in high concentrations is bactericidal against some pathogens, and therefore shows a concentration-dependent kinetic of destruction.
Penicillins, monobactams and carbapenems show time-dependent kinetics of destruction, but are bactericidal.
Quinolones mainly show concentration-dependent destruction kinetics, but they also show some time-dependent destruction kinetics.
On the other hand, the use of vancomycin may increase the thickness of the staphylococcal cell wall, which decreases the permeability of vancomycin in the body, as well as that of other antibiotics. This permeability-mediated resistance is manifested either by an increase in the MICs of vancomycin or by those of other gram-positive organisms.
Patients with osteomyelitis can be treated for months without adverse effects and with optimal results, with high doses of vancomycin. Because current vancomycin formulations are essentially non-nephrotoxic, high doses of vancomycin are preferred.
Administration of vancomycin at high doses, e.g., 60 mg/kg per 24 hours or 2 g per 12 hours, is a reasonable strategy in adults with normal kidney function, because it can optimize efficacy and minimize resistance. As with other antibiotics, low doses of vancomycin have been associated with the development of resistance.
The ß-lactams show a time-dependent destruction kinetics; optimal bacterial death occurs when antibiotic concentrations are approximately 5 times the MIC of the organism.
Above 5 times the MIC of the organism there is no additional bacterial death. While serum concentrations remain above the MIC, inhibition of sensitive organisms is achieved for more than 75% of the dosing interval.
ß-lactams are bactericidal and, although they have a minimal post-antibiotic effect on Gram-positive bacteria, this effect is not seen in Gram-negative organisms.
Because ß-lactams have a time-dependent destruction kinetics, some researchers have recommended more frequent dosing or continuous infusion, in order to maintain an effective concentration throughout the dosing.
In most hospitals, the preferred strategy is to increase the duration of dosing or shorten the dosing interval. A higher dose also results in higher serum concentrations during most of the dosing period.
Therefore, a high dose and extended dosing duration (2-3 hours) is an optimal way to administer ß-lactam antibiotics, particularly in the intensive care setting, to maximize effectiveness and minimize the potential for resistance.
For tissue penetration, higher serum levels are preferable, with antibiotics whose kinetics are time dependent, e.g. ß-lactams. Higher doses mean higher levels in the tissue, because tissue penetration is a percentage of the maximum serum concentration; with time- and concentration-dependent antibiotics, the higher the serum concentration, the higher the levels in the target tissues.
Carbapenems structurally resemble ß-lactams and have pharmacodynamic characteristics similar to other ß-lactams, but differ in their allergy potential. Serum carbapenem concentrations should exceed 5 times the MIC and be maintained for at least 40% of the dosing interval, in contrast to penicillins (~60%) and cephalosporins (~75%).
The resistance potential of carbapenems seems to be related not only to pharmacodynamic parameters but also to the inherent resistance potential of the antibiotic; for example, imipenem has a high resistance potential while meropenem and doripenem have a low resistance potential. With these antibiotics, the best strategy also seems to be to use them in high doses in order to optimise effectiveness, and not only to take into account pharmacodynamic parameters.
Daptomycin, which is a bactericide against gram-positive organisms, shows concentration-dependent destruction kinetics and has a prolonged post-antibiotic effect (>6 hours). As with other antibiotics, daptomycin shows dual pharmacodynamic characteristics.
The recommended dosing regimens for daptomycin are related to the site of infection, i.e., 4 mg/kg per 24 hours for skin and soft tissue infections or, 6 mg/kg per 24 hours for bacteremias. For relatively resistant organisms, high doses of daptomycin, 10 to 12 mg/kg per 24 hours, have been successfully used.
As with other antibiotics, low doses predispose to resistance. Daptomycin is almost half as active against Group D Streptococci as it is against Staphylococcus. Not surprisingly, the usual dose can result in both vancomycin-resistant and vancomycin-sensitive Enterococci.
Linezolide shows a time-dependent destruction kinetics and is bacteriostatic against Staphylococcus and Enterococci, but is bactericidal against non-group D streptococci. It has been successfully used in the treatment of acute bacterial endocarditis, for which bactericidal antibiotics are theoretically preferred.
In the case of acute bacterial endocarditis due to Staphylococcus aureus, the result is comparable to that of therapy with bactericidal anti-staphylococcal antibiotics. Prolonged treatment with linezolide has been shown to be associated with resistance, as has been the case with daptomycin.
Because tigecycline is a derivative of tetracycline, it is considered to exhibit time-dependent destruction kinetics, but its optimal dosage regime has not yet been determined. To achieve therapeutic serum concentrations, this antibiotic requires a loading dose, as it has a high volume of distribution (8 l/kg).
Because it is generally well tolerated, it may be that for relatively resistant Gram-negative organisms, a higher loading dose than usual (100 mg) is required, e.g. 200-400 mg. The recommended maintenance dose of tigecycline is 50 mg per 12 hours.
Because its half-life is so long (42 hours), there is no point in giving it c/12 hours. From the pharmacokinetic point of view, after the initial loading, the maintenance dose (half of the loading dose) should be administered c/24 hours and not in divided doses.
The concern about possible therapeutic failures of tigecycline that appears in the literature relates to the treatment of innate tigecycline-resistant organisms, e.g. Pseudomonas aeruginosa, or to sub-dosing.
The main concepts expressed so far are:
- Using antibiotics in high doses, with low resistance potential and the shortest possible duration that achieves clinical results.
- To eliminate the infection. The first dose of antibiotic is critical and care must be taken to reach an adequate level in blood and tissues, which inhibits the infecting microorganism and limits the potential for resistance.
- Use supportive measures when necessary, i.e. drainage of abscesses, unclogging or removal of infected devices.
- Use the highest dose of an antibiotic without toxicity, with which resistance is relatively likely.
- Avoid the temptation to initiate treatment for cultivated isolates from colonized sites. Colonising organisms are more difficult to eradicate than those from infections, and treatment of colonisation is usually prolonged. This is a common source of in vivo development of antibiotic resistance by already relatively resistant organisms.
- Antibiotic therapy should not be used to treat fever and leukocytosis that are unexplained or result from pseudoinfectious conditions.
- Unnecessary therapy is costly and may result in potential drug side effects, C. difficile or increased antimicrobial resistance.
- When selecting an empirical antibiotic for the patient with sepsis, clinicians should consider the spectrum (appropriate for the site of infection), degree of activity against the pathogen found at the site (having demonstrated clinical effectiveness), and the potential for resistance.
- When possible, select an antibiotic with low resistance potential, the correct spectrum and a high degree of activity against the pathogen.
- Make every effort to optimize dosage, after considering the pharmacokinetic/pharmacodynamic relationship (use the highest, non-toxic, well-tolerated dose and for the shortest duration that will eradicate the infection.