Antibiotic pharmacodynamics for clinicians: a summary of the basics; why MICs cannot tell you everything you need to know – minimum inhibitory concentration
Keith M. Olsen
ABSTRACT
For an antimicrobial agent to be effective, it must reach the site of infection in sufficient concentration and duration to inhibit pathogen growth. While the minimum inhibitory concentration (MIC) reflects an organism’s in vitro susceptibility to an antibiotic, it does not predict drug concentration at the site of infection. Certain classes of antibiotics are more effective in killing pathogens as their peak serum concentration above the MIC is increased (concentration-dependent killing), while others are more effective the longer the antibiotic concentration remains above the pathogen’s MIC (time-dependent killing). The fluoroquinolones and aminoglycosides exhibit concentration-dependent killing. Penicillins, carbapenems, cephalosporins, and macrolides–with the exception of azithromycin–display time-dependent killing. In the treatment of pulmonary infections, an antibiotic must cross the blood-bronchoalveolar barrier and enter the epithelial lining fluid. Antibiotics that accomplish this include azithromycin, clarithromycin, and the fluoroquinolones. (J Respir Dis. 2002;23(11):561-568)
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The different antibiotic classes vary markedly in their pharmacodynamic profiles. An understanding of pharmacodynamic principles allows you to make the best decisions about dosing strategies to produce the lowest toxicity and the best clinical efficacy. While the antibiotic pharmacodynamic profile is an important consideration, specific patient characteristics must be taken into account when selecting the optimum antimicrobial therapy.
In this article, we will review the basic pharmacodynamic principles. We will focus on the antibiotics that are used to treat patients with pulmonary infections, including [ss]-lactams, macrolides, fluoroquinolones, and aminoglycosides, and on how pharmacodynamics can be applied to treatment.
THE BASICS
For an antimicrobial agent to be effective, it must reach the site of infection in sufficient concentration and duration to inhibit pathogen growth. Since the introduction of the short-half-life antibiotic aqueous penicillin G 60 years ago, the traditional approach to predicting in vivo efficacy of antimicrobial agents has been to compare the peak antimicrobial serum concentration with the minimum concentration of the antibiotic that inhibits growth of the pathogen. This minimum inhibitory concentration (MIC) usually is measured in a test tube or on an agar plate.
For decades, the principle of dosing antibiotics above the MIC for most of the dosing interval was the prevailing method used to establish dosing intervals. However, as early as the 1940s, Eagle (1) raised important questions about antibiotic pharmacodynamics and optimal dosing schedules; these questions were ignored, for the most part, until the 1970s. Over the past 2 decades, a wealth of in vivo and in vitro evidence has supported different pharmacokinetic parameters and their relationship to the MIC of the infecting pathogen as predictors of clinical outcomes in persons with pneumonia and other infectious diseases.
The activity of antibiotics used to treat infections is a result of 2 separate, but related, components: pharmacokinetics and pharmacodynamics. These concepts are important in selecting antibiotics and optimizing the dose for a specific patient and infection. Pharmacokinetics–the effect the body has on the drug–includes the absorption, distribution, metabolism, and excretion of the drug. These parameters, in addition to the dosing regimen, determine the concentration profile of a drug in serum over a specified time.
Pharmacodynamics is the effect the drug has on the body or, in the case of infection, the effect on the pathogen. While the microbiologic and pharmacokinetic activity profiles are used in the comparison of different antibiotics, our current understanding of antibiotic effectiveness is based on the pharmacodynamic profile, which simultaneously assesses microbiologic activity and pharmacokinetics. (2,3) For antibiotics, this includes both the antimicrobial effect at the site of infection and the toxic effects of the drug during the course of therapy. Studies have shown that antibiotic classes display markedly different pharmacodynamic profiles. (4-7)
The MIC and the minimum bactericidal concentration (MBC) were the first pharmacodynamic parameters used. The end point for the MIC is no visible growth of bacteria, and the end point for the MBC is 99.9% reduction in bacterial inoculum. These 2 parameters are a measure of the organism’s in vitro susceptibility to the antibiotic, and they represent the antibiotic’s intrinsic activity against a particular organism, with the MIC remaining a primary reporting mechanism of antibiotic sensitivity.
Unfortunately, these parameters often are inadequate predictors for infectious outcomes, because they do not take into account the penetration and interaction of the drug at the site of infection. Thus, an antibiotic may demonstrate excellent in vitro activity but, when given to patients, may not achieve adequate drug concentration at the site of infection. For example, a highly protein-bound drug such as ceftriaxone (84% to 96% protein-bound) penetrates lung tissue in adequate concentrations to treat Streptococcus pneumoniae pneumonia but may have insufficient CNS penetration to treat some intermediate or resistant strains of S pneumoniae in meningitis.
Similar problems of ceftriaxone protein binding exist in the treatment of methicillin-sensitive Staphylococcus aureus infections. Despite sensitive MICs, there are ceftriaxone treatment failures with S aureus, partly due to the minimal concentration of the non-protein-bound drug.
The MIC of the infecting pathogen and the drug’s half-life have been used to determine an antibiotic’s dose and interval. If the offending pathogen’s MIC was below a predetermined breakpoint, based on the peak serum level for that antibiotic, the organism was considered susceptible and therapy would be initiated. The MIC still provides a good prediction of the potency of an antibiotic against a given pathogen, but it does not provide any information on the time course of the activity or the activity at the site of infection.
One of the first classes of antibiotics in which pharmacodynamic and pharmacokinetic data were used to determine the dose and the time course of activity were the aminoglycosides. Because of the nephrotoxicity and ototoxicity of these agents, it became common practice to obtain peak and trough levels. These levels were used to try to establish the relationship between concentration, antimicrobial activity, and adverse events. Eventually, antimicrobial efficacy was demonstrated to be related to peak serum levels, and nephrotoxicity was linked to trough levels.
The role of the MIC has been refined further with in vitro models of infections and animal studies. These studies demonstrated that certain classes of antibiotics were more effective in killing pathogens as their peak serum concentration above the MIC was increased (concentration-dependent killing), and other classes of antibiotics were more effective the longer the. antibiotic concentration remained above the offending pathogen’s MIC (time-dependent killing). (2-8)
With concentration-dependent killing, the higher the serum drug concentration, the greater the extent and rate of killing. Examples of antimicrobial agents that exhibit concentration-dependent killing include the fluoroquinolones, the aminoglycosides, and metronidazole (Table 1). (2)
Two pharmacokinetic ratios that are considered good predictors of clinical, microbiologic, and in vitro response are the peak serum concentration divided by the MIC (peak/MIC) of the organism and the area under the serum concentration versus the time curve (AUC) divided by the MIC (AUC/MIC) (Figure 1). If the peak/MIC ratio is 8 to 10 or more, the bactericidal activity of concentration-dependent antibiotics appears to be maximized.
Knowing that an antibiotic is concentration-dependent is important when selecting a dose and adjusting the dosages. For example, if a patient has end-organ dysfunction that requires adjustment of the dosing regimen, the dosing interval, rather than the dose, should be changed initially for any concentration-dependent antibiotic. The dose should be maintained to reach the target antibiotic concentration necessary for maximum efficacy This concept led to rigorous dosing and monitoring of aminoglycosides and to single or once-daily dosing methods.
Antimicrobial agents that exhibit time-dependent killing demonstrate little difference in rate and extent of killing once the concentration is 2 to 4 times above the MIC; the rate of killing is constant and is not affected by further increases in antimicrobial concentrations. The length of time the antibiotic concentration remains above the MIC affects killing, which is described by the ratio: time greater than MIC (T > MIC). Thus, the goal of therapy with these agents is to maintain the concentration above the MIC for as long as possible during the dosing interval.
Antibiotics that exhibit time-dependent killing include [beta]-lactams, macrolides (with the exception of azithromycin), and clindamycin. (2,8) The dosage adjustments for these agents differ from concentration-dependent agents. Generally, intervals should be maintained to keep the concentration above the MIC for the longest duration of time possible, because little is gained by increasing peak concentrations if T > MIC is inadequate.
Other pharmacodynamic principles are not as well understood but play important roles in antimicrobial activity. For example, some antibiotics retain a persistent bacterial inhibitory effect even after concentration at the site of infection falls below the MIC. This is called the postantibiotic effect (PAE) and refers to the continued suppression of bacterial growth after exposure to an antimicrobial agent.
Most antibiotics have a PAE on common gram-positive cocci, but only those agents that inhibit protein synthesis or nucleic acid synthesis have a prolonged PAE for gram-negative organisms. One exception is the carbapenems (ertapenem, imipenem, meropenem), which exhibit a prolonged PAE against gram-negative bacteria.
Another persistent effect of some antibiotics is the postantibiotic sub-MIC effect, whereby agents slow the growth of and produce morphologic changes in bacteria at sub-MIC levels that can even further enhance the PAE. Some classes of antibiotics exert a postantibiotic leukocyte effect. This occurs when the antibiotic renders the bacteria more susceptible to phagocytosis or intracellular killing after exposure. (2,8)
ANTIBIOTIC CLASSES
[ss]-Lactams
These antibiotics, including penicillins, carbapenems, and cephalosporins, follow time-dependent pharmacodynamics. The major pharmacodynamic parameter that correlates with clinical efficacy is T > MIC. The percentage of time that the serum concentration must remain above the MIC varies, depending on both the infecting organism and the antibiotic.
Generally, animal studies and in vitro models of respiratory infection have shown that antibiotic concentrations do not need to exceed the MIC for the entire dosing interval. In studies of animals infected with S pneumoniae and treated with either a cephalosporin or penicillin, the mortality rate was nearly 100% if serum concentrations were less than the MIC for 20% or less of the dosing interval; the survival rate increased to 90% to 100% when the concentration was above the MIC for more than 40% to 50% of the dosing interval. (2) Some have suggested using continuous intravenous infusions to maintain serum antibiotic concentrations above the MIC. Despite the potential advantages, only a few small clinical trials have documented success of this dosing method. (9,10)
Bacteriologic cure in patients with otitis media has also been used to demonstrate the relationship between T > MIC and efficacy. A variety of [ss]-lactams have been shown to have success against S pneumoniae and Haemophilus influenzae when the time above the MIC is greater than 40%. This duration is associated with an 85% to 100% cure of these infections. (2)
Table 2 lists a number of common [ss]-lactam dosing regimens and the expected time above the MIC in the average patient in the treatment of infection with both penicillin-intermediate and penicillin-resistant S pneumoniae. A comparison can be made of antibiotic regimens that have acceptable T > MIC profiles against these common respiratory pathogens. The treatment options for patients infected with penicillin-resistant S pneumoniae have been limited by the emergence of resistance and T > MIC ratios that are less than 40% for many of the [ss]-lactam antibiotics. Similar data have been reported for gram-negative community-acquired respiratory pathogens such as H influenzae and Moraxella catarrhalis. (11)
When administering [ss]-lactam antibiotics, increasing the dose usually results in marginal improvement to the T > MIC parameter, and the higher dose often increases the rate of adverse events. Generally, we recommend maintaining shorter dosing intervals rather than increasing the dose. Exceptions are extended-release antibiotics that maximize the T > MIC parameter by prolonged serum concentrations, allowing longer dosing intervals.
Macrolides
With the exception of azithromycin, the macrolide antibiotics display time-dependent killing. Because of a prolonged half-life (about 60 hours), azithromycin is best described by the pharmacodynamic parameter AUC/MIC. Before the existence of antibiotic-resistant S pneumoniae strains, serum concentrations of both azithromycin and clarithromycin exceeded the MICs for 88% to 100% of the dosing interval. With antibiotic-resistant S pneumoniae strains, often it is difficult to maintain serum concentrations above the MIC for more than 25% of a dosing interval.
H influenzae, a pathogen that is intrinsically less susceptible to macrolides than S pneumoniae, has shown results similar to those for S pneumoniae. In clinical trials involving patients with pneumonia and acute bacterial exacerbations of chronic bronchitis, despite the higher pathogen MICs associated with serum drug concentration data, azithromycin and clarithromycin have demonstrated clinical cure rates similar to those of newer fluoroquinolones. (12) This clinical success is partly a result of the macrolides’ unique pulmonary tissue pharmacokinetic properties that enhance efficacy in the treatment of pulmonary infections. (12-14)
Both azithromycin and clarighromycin achieve higher concentrations in alveolar macrophages and lung epithelial lining than in serum (Table 3). When these concentrations are applied to in vitro MICs, results similar to those in in vivo clinical trials are seen and, therefore, these concentrations may be a better predictor of macrolide clinical response. (12)
Because of its prolonged half-life and anion trapping in alveolar macrophages, azithromycin allows shorter treatment durations compared with other antibiotics. An extended-release formulation of clarithromycin increases the T > MIC pharmacodynamic parameter, permitting once-daily dosing in the treatment of susceptible pathogens.
Fluoroquinolones
These agents are concentration-dependent antibiotics. The parameters that best correspond to success with these agents are the peak/MIC and AUC/MIC ratios. Some studies have suggested that for clinical success, a 24-hour AUC/MIC ratio should be higher than 30 for S pneumoniae and higher than 125 for gram-negative bacteria that cause serious infection.
Forrest and colleagues (15) found that a 24-hour AUC/MIC value of 125 or more was associated with a higher likelihood of clinical and microbiologic cure in seriously ill patients with gram-negative infections who were treated with intravenous ciprofloxacin. Patients with an AUC/MIC ratio of more than 125 had a probability of clinical and microbiologic cure of 80% and 82%, respectively. If the AUC/MIC value was less than 125, the probability of clinical and microbiologic cure was 42% and 26%, respectively.
Lacy and associates (16) found that the microbiologic response to fluoroquinolones was associated with the AUC/MIC ratio. This study, examined the effectiveness of levofloxacin, ciprofloxacin, and ampicillin against S pneumoniae in an in vitro model of infection that simulated serum pharmacokinetics. The investigators determined that the critical AUC/MIC ratio associated with bacterial growth was about 30 and that regrowth did not occur when the ratio was higher than 30. This study was important because it demonstrated concentration-dependent bacterial killing with S pneumoniae, the most common cause of community-acquired respiratory infections.
Several reports have shown that the AUC/MIC ratios for gatifloxacin, levofloxacin, and moxifloxacin associated with success against S pneumoniae are about 30. (17, 18) Since few clinical trial data are available comparing one fluoroquinolone with another, pharmacodynamic ratios that are generated from MICs and human pharmacokinetic data may help determine the differences between these antibiotics.
Table 4 lists typical dosages of fluoroquinolones and the calculated AUC/MIC ratio (using free fraction of drug) that can be expected for each agent against common respiratory pathogens. These ratios seem to suggest that new fluoroquinolones offer advantages over older compounds in optimizing the pharmacodynamic ratios associated with microbiologic and clinical success.
The peak/MIC ratio is a second parameter that has been associated with fluoroquinolone clinical success. For example, in a large community-acquired pneumonia trial with levofloxacin, Preston and colleagues (19) demonstrated that a peak/MIC ratio of 12.2 was associated with a favorable microbiologic and clinical outcome and may deter resistance. When administering fluoroquinolones in clinical practice, the treatment goal should be to maximize the dose to provide optimal peak/MIC and AUC/MIC ratios.
Aminoglycosides
The pharmacodynamics of aminoglycosides have been studied widely and display concentration-dependent pharmacokinetics. To reach a clinical success rate of more than 90%, the peak/MIC ratio should be 8 to 10 or more. As with the fluoroquinolones, these high peaks not only correspond to greater efficacy and more rapid bacterial kill but also to reduced emergence of bacterial resistance during therapy.
One effort to maximize the peak/MIC ratio of aminoglycosides is the use of single or once-daily dosing. The agents can be dosed infrequently because of the prolonged PAE that they demonstrate against gram-negative bacteria.
The use of large infrequent doses may help reduce ototoxicity and nephrotoxicity, because aminoglycoside uptake in the endolymph of the ear and in the renal tubular cells is more efficient with lower sustained levels than with high intermittent concentrations. A large open-label study of more than 2100 patients treated with either intravenous tobramycin or gentamicin (7 mg/kg/d) demonstrated favorable efficacy with similar or reduced toxicity. (20) The dosage resulted in peak serum concentrations of approximately 20 mg/L, to achieve the peak/MIC ratio of 10 for infections caused by Pseudomonas aeruginosa.
SITE OF INFECTION
Efficacious antibiotic therapy requires the delivery of the drug to the site of infection. Serum concentrations may not be predictive for all antibiotic concentrations at the site of infection, especially in lung infections. A number of distinct sites are involved in pulmonary infections. In acute exacerbations of chronic bronchitis, bacteria are found in the lumen of the airways, at the mucosal cell surface, and within the bronchial mucosal wall. (12, 14, 18, 20) The bacteria in these infections also are found in the epithelial lining fluid (ELF) and alveolar macrophages.
Before an antibiotic can penetrate the ELF, it must cross the blood-bronchoalveolar barrier (Figure 2). The barrier consists of the relatively permeable capillary endothelium; the capillary basement membrane leading to the interstitium; the alveolar basement membrane; and the alveolar epithelium, which is relatively impermeable because of tight junctions between the cells. (12,19)
Modern endoscopic procedures allow the measurement of antibiotics at various sites within the respiratory tract. Samples of ELF and alveolar macrophages are obtained through bronchoalveolar lavage. The degree of antibiotic concentration within these sites depends on both the physiologic environment of the lung (inflammation, pH at the site) and the characteristics of the drug.
Macrolides have been shown to concentrate in the ELF and in alveolar macrophages. Reported concentrations of clarithromycin and azithromycin in these two sites exceed both concentrations in serum and MICs for common respiratory flora. (13,21,22) In addition, the fluoroquinolones show higher concentrations in the ELF and in alveolar macrophages than in serum. (21-23) [SS]-Lactams do not penetrate cells well-they penetrate the ELF poorly, with levels of only 20% to 50% of serum concentrations and no detectable levels (of most [SS]-lactams) in alveolar macrophages.
The clinical significance of drug concentration in tissue varies and depends on the pharmacodynamic profile of the agent and the site of infection. For time-dependent antibiotics, if the concentration of the antibiotic at the site of infection is above the MIC required to kill bacteria or inhibit their growth for a significant time, clinical success is likely.
For concentration-dependent antibiotics, higher concentrations at the site of infection should correlate with greater success. Intracellular concentration of the drug is especially important if the target is bacteria such as Legionella pneumophila and the atypical respiratory pathogens. Some preliminary data have suggested that intracellular drug concentration is not as important as the specific part of the cell in which the drug accumulates.
[FIGURE 1 OMITTED]
Table 1
Pharmacodynamic ratios that correspond to antibacterial efficacy
Parameter Antibiotics
T > MIC [ss]-Lactarns, such as aztreonam
(monobactam), carbapenems,
cephalosporins, penicillins;
macrolides, such as erythromycin,
clarithromycin; clindamycin
(lincosamide); vancomycin
(glycopeptide)
AUC/MIC Aminoglycosides, azithromycin
(azalide), fluroquinolones,
metronidazole (amebicide)
Peak/MIC Aminoglycosides, fluoroquinolones
T, time; MIC, minimum inhibitory concentration; AUC/MIC; area under the
serum concentration curve vs time curve divided by the MIC; peak/MIC,
peak serum concentration divided by the MIC.
Adapted from Craig WA. Clin Infect Dis. 1998. (2)
Table 2
T > MIC ratios of [ss]-lactam antibiotics for treatment of infection
with penicillin-intermediate and penicillin-resistant Streptococcus
pneumoniae (2,23)
T > MIC (% of interval)
for penicillin-intermediate
Drug Regimen S pneumoniae *
Amoxicillin 13.3 mg/kg tid 80 – 55
Cefaclor 13.3 mg/kg q8h 0
Cefprozil 15 mg/kg q12h 56
Cefuroxime 15 mg/kg q12h 64
Cefpodoxime 5 mg/kg q12h 63
Cefixime 200 mg q24h 0
Loracarbef 15 mg/kg q12h 17
T > MIC (% of interval)
for penicillin-resistant
Drug S pneumoniae +
Amoxicillin 55 – 43
Cefaclor 0
Cefprozil < 40
Cefuroxime [less than or equal to] 30
Cefpodoxime < 40
Cefixime < 40
Loracarbef < 40
T, time; MIC, minimum inhibitory concentration.
* MIC = 0.25 – 1 [micro]g/mL.
+ MIC = 1 – 2 [micro]g/mL.
Table 3
Mean concentrations of macrolides and fluoroquinolones in serum and
pulmonary tissue (13,21,22)
Drug Dosage Serum (mg/L)
Clarithromycin 250 mg bid for 2 days 1.2
Azithromycin Single dose, 500 mg orally;
then 250 qd for 4 days 0.1
Ciprofloxacin 250 mg q12h for 4 days 1.19
Levofloxacin Single dose, 500 mg orally 4.1
Epithelial lining Alveolar
Drug fluid (mg/L) macrophages (mg/L)
Clarithromycin 10.4 86.5
Azithromycin
2.2 23.4
Ciprofloxacin 3.0 13.39
Levofloxacin 10.9 27.7
Table 4
AUC/MIC ratios of fluoroquinolones used for common respiratory pathogens
(24, 25)
Drug Regimen Organism ([MIC.sub.90])
Ciprofloxacin 500 mg q 12h Streptococcus pneumoniae
(0.5 – 2)
Haemophilus influenzae
(0.004 – 0.015)
Levofloxacin 500 mg/d S pneumoniae (0.5 – 2)
H influenzae (0.008 – 0.03)
Gatifloxacin 400 mg/d S pneumoniae (0.12 – 0.5)
H influenzae (0.004 – 0.3)
Moxifloxacin 400 mg/d S pneumoniae (0.06 – 0.25)
H influenzae (0.008 – 0.03)
Drug AUC/[MIC.sub.90] * +
Ciprofloxacin 50 – 13
6320 – 1667
Levofloxacin 101 – 25
6343 – 1700
Gatifloxacin 340 – 82
10,200 – 137
Moxifloxacin 400 – 96
3000 – 800
AUC/MIC, area under the serum concentration curve versus time curve
divided by the minimum inhibitory concentration.
* Calculated using the lowest and highest [MIC.sub.90] reported for each
organism.
+ Determined using free traction of antibiotic.
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Dr Olsen is associate professor of pharmacy practice and Dr Skiermont is a pharmacist at the University of Nebraska Medical Center in Omaha. Dr Campbell is professor of medicine and chief, division of pulmonary and critical care medicine, University of Mississippi School of Medicine, Jackson. Dr Campbell is also a member of the Editorial Board of The Journal of Respiratory Diseases.
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