MINIMUM INHIBITIVE AND BACTERICIDAL CONCENTRATION OF ANTIBIOTICS

Pandolfi F. Minimum inhibitive and bactericidal concentration of antibiotics. International Journal of Infection. 2022;6(3):72-75

F. Pandolfi^*

Department of Internal Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS – Universita Cattolica del Sacro Cuore, Roma, Italy.

*Correspondence to:
Prof. Franco Pandolfi,
Department of Internal Medicine,
Fondazione Policlinico Universitario A. Gemelli IRCCS,
Universita Cattolica del Sacro Cuore,
Roma, Italy.
e-mail: pandolfi@rm.unicatt.it

Received: 16 June, 2022 Accepted: 14 September, 2022

ISSN 1972-6945 [online] Copyright 2022 © by Biolife-publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of an antibiotic are two important parameters. The MIC is the lowest concentration of antibiotic that can completely inhibit bacterial growth after 18-24 hours at 37 °C in vitro, while the MBC represents the lowest concentration of antibiotic that can reduce the initial bacterial population by 99.99% after 24 hours of incubation. However, for bactericidal antibiotics such as beta-lactams and fluoroquinolones, the MIC and MBC are comparable. To evaluate the sensitivity of a bacterial species to the antibiotic, the MIC50 and MIC90 must be taken into account. The maximum plasma concentration (Cmax) of an antibiotic in 24 hours is the concentration reached at the end of absorption of the drug, which is a function of the dose, the route of administration, and the galenical form, while the minimum plasma concentration (Cmin) is the minimum concentration reached at the end of the dosing interval, before the next dose of the drug. The therapeutic efficacy of an antibiotic depends on the relationship between pharmacokinetic and pharmacodynamic (PK/PD) parameters. In choosing an antibiotic, the dose, the therapeutic efficacy of the drug, the pharmacologically active plasma concentration, and the post-antibiotic effect (PAE) are very important. Plasma concentration is directly proportional to the therapeutic efficacy. All these considerations have therapeutic value and are also useful for preventing bacterial resistance.

KEYWORDS: Antibiotic, minimum inhibitory concentration, minimum bactericidal concentration, pharmacodynamic, bacterial sensitivity  

INTRODUCTION

The efficacy of an antibiotic can be evaluated through two pharmacodynamic parameters: the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) (1). The chemosensitivity of a microorganism to the antibiotic is estimated in vitro by determining the MIC which represents the lowest concentration of antibiotic capable of completely inhibiting bacterial growth after 18-24 hours of incubation at 37°C (2). The distinction of antibiotics into bactericides and bacteriostatics instead exploits the determination of the MBC which represents the lowest concentration of antibiotic capable of reducing the initial bacterial population by 99.99% after 24 hours of incubation at 37°C (3).

A bactericidal antibiotic lowers the bacterial population by 1000 times compared to that of the initial inoculum (4). For bactericidal antibiotics, such as beta-lactams and fluoroquinolones, the MICs and MBCs are comparable (5). The MICs therefore provide a good approximation of the bactericidal activity of the antibiotic (6). However, in the same bacterial species, not all strains have the same sensitivity, so the evaluation of the sensitivity of a bacterial species towards an antibiotic must be based on MIC50 and MIC90, which respectively represent the sensitivity of 50% and 90% of the population of the bacterial species under examination towards that antibiotic (7).  The MIC90s are considered the more reliable benchmark of the two (8).

DISCUSSION

The clinical efficacy of an antibiotic is correlated not only to the level of chemosensitivity of the microorganism but also to the following pharmacokinetic parameters: the patient’s exposure to the drug, which is determined by its maximum plasma concentration (Cmax), area under the curve in 24 hours (AUC24), minimum plasma concentration (Cmin), and bioavailability and plasma elimination half-life (9,10).

The Cmax represents the peak concentration reached at the end of the absorption of the drug, and is a function of the dose, the route of administration, and the galenical form (11). Sodium or potassium penicillin G reaches the highest serum peaks only with intermittent and discontinuous perfusions, while third generation cephalosporins always reach high plasma peaks because they are strongly bound to plasma proteins (12).  For macrolides, serum peaks increase with repeated intakes, reaching levels in the equilibrium phase that are even double those obtained with the first intake. From the comparison of Tmax values (time necessary to reach Cmax) in third generation cephalosporins administered intramuscularly and in some oral antibiotics, there is a substantial similarity, and therefore, oral administration is preferable.  AUC24 indicates the extent of systemic exposure to the drug that is indirectly proportional to clearance and Cmin is the minimum concentration reached at the end of the dosing interval, before the next dose of the drug (13).

Bioavailability indicates the percentage share of drug that is absorbed and reaches the systemic circulation in an unchanged form after administration by a route other than the intravenous one (14). The oral bioavailability of beta-lactams is almost zero as they are highly water-soluble antibiotics that cannot passively diffuse through the membranes of the gastrointestinal tract and disappear quickly in the gastric acid environment. Penicillin G is only used parenterally (15). Among beta-lactams, however, amoxicillin and clavulanic acid are exceptions as, although they are highly hydrophilic, they resist the gastric acid environment and are absorbed from the gastrointestinal tract via specific transporters (16). Several authors have stated that the kinetics of amoxicillin and clavulanic acid administered orally and parenterally are almost comparable. Fluoroquinolones and linezolid are moderately lipophilic but have an oral bioavailability greater than 80-90%, while macrolides are strongly dipophilic and, therefore, are easily absorbed (17).

The plasma elimination half-life of a drug is equivalent to the time necessary for its plasma concentration to reach t/2 and is equal to 4/5 of the t/2 itself (18). This parameter is indirectly related to the clearance of the drug and, therefore, to its mode of elimination (19). Hydrophilic beta-lactam antibiotics are eliminated via the kidneys by glomerular filtration and active secretion, while lipophilic antibiotics such as fluoroquinolones and macrolides are predominantly eliminated via the liver by oxidation-reduction or conjugation (20). Penicillin has a short plasma elimination half-life of <1.5 h, and third-generation cephalosporins have a medium or long half-life depending on the molecular characteristics. For example, ceftriaxone has a very long half-life of >7 h, macrolides have a variable half-life, such as erythromycin with 2-3 hours, while azithromycin has a half-life of 15-20 hours (21).

Therapeutic efficacy: pharmacokinetics and pharmacodynamics

The therapeutic efficacy of an antibiotic is related to the relationship between pharmacokinetic parameters and pharmacodynamic parameters (PK/PD) (22). First, antibiotics must be distinguished based on their antibacterial mode of action into two classes: time-dependent and concentration-dependent (23). Time-dependent antibiotics, including beta-lactams and macrolides, have a correlated action in vivo and t>MIC (the time during which concentrations remain above the MIC of the pathogen) (24). To guarantee the therapeutic efficacy of the drug, the pharmacologically active plasma concentration must be maintained for most of the 50/70% dosing range. Thus, increasing the dose has little effect on the bactericidal action, provided that the concentration is already above the threshold and effectiveness. This condition is achieved through a multi-fractionation of the daily dose which also takes into account the plasma elimination half-life of the drug.

Another parameter that must be considered when choosing the most effective antibiotic is the post-antibiotic effect (PAE) (25). Most time-dependent antibiotics have no PAE effect, and so, the elimination of bacterial growth after the disappearance of the antibiotic is zero (24). The administration of these antibiotics in particular requires careful fractionation of the dose. Some antibiotics with time-dependent action, such as azithromycin, are distinguished from others by a prolonged PAE against many bacterial species. For these drugs, the therapeutic efficacy correlates more with the ratio between the daily plasma exposure to the antibiotic and the MIC than t>MIC and AUC>MIC (26).

According to some authors, the AUC/MIC to be maintained for azithromycin, frequently used in the treatment of atypical pneumonia and pertussis, must be 20-30 h (27). For this reason, azithromycin is used in single daily administrations rather than in multiple administrations, unlike other time-dependent antibiotics. However, since 2007, azithromycin has not been widely used for streptococcal infections that cause the most common bacterial pneumonia, as it is resistant (less in Europe than in the United States) (28).

For concentration-dependent antibiotics including fluoroquinolones and aminoglycosides, the indicator of efficacy is Cmax > MIC, the ratio between the maximum plasma concentration and the MIC (23). As the plasma concentration of these antibiotics increases, the therapeutic efficacy also progressively increases, and the Cmax/MIC must be greater than or equal to 10 to achieve eradication of the infection and resolution of the clinical picture in at least 80% of cases (29). The drugs belonging to this class also have a prolonged post-antibiotic effect, and for this reason and the intrinsic concentration-dependent action, they are administered once a day (30). It is estimated that fluoroquinolones used as second-choice antibiotics in community-acquired pneumonia must have an AUC/MIC ratio greater than 25-35 hours in infections caused by Gram positives and greater than 125 hours in those caused by Gram negatives to ensure safe clinical efficacy.  The parameters listed above not only have a high clinical value but also an epidemiological value, as they allow to prevent the selection of resistant strains during antibiotic therapy.

CONCLUSIONS

MIC and MBC are important parameters to obtain effective antibiotic therapy. In antibiotics such as beta-lactams and fluoroquinolones, these two parameters are comparable. The plasma concentration of the antibiotic is related to the absorption of the drug, depending on the dose and route of administration. The observations on these topics reported here are vital considerations for targeted and effective therapy.

Conflict of interest

The author declares that they have no conflict of interest.

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