PHARMACEUTICAL MICROBIOLOGY - V. A. Galynkin - 2015

PART II. ANTIMICROBIAL AGENTS

CHAPTER 12. APPLICATION OF ANTIMICROBIAL DRUGS

12.1 Chemotherapy of Infectious Diseases

The term “chemotherapy” refers to the Treatment of infectious diseases through the systemic administration of Antibiotics or other medicinal products (Table 26). It is based on the selective action of a chemotherapeutic agent that suppresses the Reproduction of a pathogenic microorganism without disrupting the Functions of the host Organism, thereby helping the body's natural defenses cope with the infection.

A chemotherapeutic drug will be effective under the following conditions:

1) when used for the treatment or Prevention of a disease caused by a microorganism susceptible to the given drug;

2) when achieving a concentration in the Tissues sufficient to inhibit the growth of the infecting agent;

3) with a sufficiently long duration of treatment;

4) in the absence of severe adverse reactions.

The therapeutic action of a drug is ensured by the following factors: maintenance of structural stability upon administration into the body, rate of absorption and elimination, and The ability to penetrate into tissues and biological fluids. The Main criteria for evaluating the effectiveness of antimicrobial drugs are the therapeutic index and the achievable serum concentration.

Therapeutic index — the ratio obtained by dividing the minimum toxic dose of a drug by the minimum dose exhibiting antimicrobial activity; a higher value corresponds to greater drug efficacy.

Achievable serum concentration is a value that depends on the patient's body weight, the dose of the drug, the route and schedule of administration, and The rate of its elimination from the body. This indicator does not reflect the concentration of drugs in body tissues, which may significantly exceed the serum concentration.

The factors that must be considered when choosing a chemotherapeutic agent are presented in Table 23, and a more detailed Description of the highlighted factors is provided below.

Class="center">Table 23. Factors to be considered when prescribing a chemotherapeutic drug

12.2 Microbiological Factor

The Nature of the infecting agent and its susceptibility to chemotherapeutic drugs form the basis for their Selection. The possibility of pathogen resistance developing during the course of the infectious disease must also be taken into account. Therefore, under ideal conditions, microbiological analysis should precede the prescription of a therapeutic agent. In practice, however, treatment must in most cases be initiated before antibiotic susceptibility test results are obtained, selecting the medicinal product based on the clinical signs of the disease and subsequently adjusting the antibiotic after determining the susceptibility of the patient's specific microbiota. It is important to remember that infectious material for analysis must be collected prior to THE START OF treatment.

Situations sometimes arise where selecting a medicinal product is difficult because Diseases of the same type may be caused by multiple microorganisms (e.g., septicemia, bacterial Pneumonia) or by microorganisms susceptible to several antibiotics, so the choice of drug must be based on clinical and pharmacological data.

12.3 Pharmacological Factor

Chemotherapeutic drugs are effective only if they are present at the site of infection in a concentration that ensures suppression of the microorganism's growth. Doses and dosing intervals are selected based on careful pharmacological and clinical research and must guarantee that this condition is met. Low doses of the drug and long intervals between its administrations render the treatment ineffective and lead to The Development of microbial resistance.

The duration of treatment is determined by clinical experience. Insufficient duration of treatment can lead to relapses of the disease and the development of its complications.

12.4 Toxicological Factor and Side Effects

In the doses used, chemotherapeutic drugs have low or no toxicity, although some of them cause side effects, such as ototoxicity in Aminoglycosides or photosensitization in Tetracyclines. The main side effect of antibiotics is dysbiosis resulting from the suppression of the normal microbiota, primarily in the intestine. This can result in avitaminosis and secondary infection, such as candidiasis. Therefore, antibacterial antibiotics are often prescribed in combination with antifungals (nystatin) and Vitamins.

In addition, all medicinal products can trigger an Immune Response with the appearance of allergic reactions. The frequency and intensity of such reactions depend both on the type of antibiotic and on the patient's individual sensitivity. A patient who has experienced an allergic reaction to a given antibiotic even once must never be re-prescribed that drug or drugs of the same chemical group, though this does not constitute a contraindication to The Use of drugs from other groups.

12.5 Epidemiological Factor and Resistance

The Emergence of resistant and multi-resistant strains of microorganisms is discussed in Chapter 13. Physicians must stay informed about the latest data on the prevalence of antibiotic-resistant Bacteria in their specific geographical working area. If a doctor knows that 80% of the staphylococcal population in their region is resistant to penicillin, they will not prescribe this antibiotic for a staphylococcal infection unless testing first confirms that the patient's isolated culture is susceptible to penicillin.

The prevalence of Antibiotic Resistance within a given bacterial population is not constant; it fluctuates depending on how widely the antibiotic is used in that region, with the frequency of resistant strains increasing alongside the intensity of antibiotic use.

The frequency of strains with transferable resistance depends on the density of the microbial population. Consequently, the highest rates of resistant and multi-resistant strains are observed in hospitals (nosocomial strains), where antimicrobial drugs are used most heavily and microbial population density reaches its peak.

12.6 Prophylactic Use of Chemotherapeutic Agents

Given the potential for adverse side effects (see above), the prophylactic use of antibiotics is considered appropriate only when the following conditions are met.

1. The presence of conditions where the development of a given disease is genuinely to be expected. Examples include:

a) extensive Burns (infection with Staphylococcus aureus or Pseudomonas aeruginosa);

b) surgical Procedures such as lower limb amputation (anaerobic infection caused by Clostridium perfringens), Heart surgery (endocarditis caused by S. aureus), and dental procedures in patients with prosthetic heart Valves;

c) streptococcal throat infections, Kidney infections, and rheumatoid Arthritis;

d) the presence of meningococci and Haemophilus influenzae in healthy carriers. This list is far from exhaustive, and many other examples could be cited.

2. The correct choice of drug, taking into account the pathogen's susceptibility. Both systemic and local administration are possible (for burns or during surgical procedures).

3. The correct timing of administration to ensure that the antimicrobial drug reaches the site of infection precisely when it is likely to begin. If this timing is difficult to predict, such as the onset of a relapse in rheumatoid arthritis, the drug should be administered over a prolonged period.

12.7 Combined Use of Chemotherapeutic Agents

The simultaneous use of two or more chemotherapeutic agents can be considered appropriate for the following reasons.

1. Reducing the frequency of resistant strains. To achieve this goal, drugs with different Mechanisms of action (having distinct targets within the microbial Cell) should be used; otherwise, Mutations conferring resistance to one drug will also lead to resistance to another drug with a similar MECHANISM OF ACTION.

2. Broadening the antibacterial spectrum when treating mixed infections or severe infections of unknown Etiology. In this case, the drugs must have differing antibacterial spectra so that their combined spectrum is sufficiently broad.

3. Reducing the dose of components in a mixture through a synergistic effect, which may allow for a decrease in the dose of a potentially toxic drug.

4. Enhancing therapeutic efficacy. When antimicrobial drugs are used together, Three types of effects may be observed: synergy, additivity, and antagonism. With synergy, the combined effect of the drugs exceeds the sum of the effects produced by each of them individually. Additivity means that The Effect of the combination equals the sum of the components' effects. In the case of antagonism, one component of the mixture reduces the effectiveness of the other. The BIOCHEMICAL BASIS OF these phenomena can be determined by understanding The Mechanism of action of the antimicrobial agents. For example, the antagonism between penicillin and tetracycline is due to the fact that penicillin acts only on actively growing bacteria. Tetracycline halts growth, keeping the bacteria in a physiological phase where they are insensitive to penicillin.

A typical example of synergy is the combination of two antimetabolites—sulfonamides and trimethoprim—where synergy results from a dual metabolic blockade (see Ch. 10). When synergy is present, the concentration of each drug in the mixture required to inhibit Microbial growth is lower than the growth-inhibiting concentration of each drug used separately. However, it is essential that the pharmacokinetic Properties of the two components ensure that concentrations capable of producing synergy are maintained at the infection site. Furthermore, drug combinations may differ in their toxicity profile compared to the components used individually, and the presence of one drug can affect the pharmacokinetics of another. Therefore, every new combination should be treated as a new medicinal product, and its toxicology and pharmacokinetics must be thoroughly investigated.

12.8 Use of Antibiotics for the Treatment of Infectious Diseases

Based on their spectrum of activity, antibiotics are classified as antibacterial, antifungal, antiprotozoal, and antiviral. This section covers the THERAPEUTIC USE OF antibacterial antibiotics, as treatments for other infectious diseases are discussed in their respective sections (Part I).

There are several generations of antibiotic drugs, which differ in their spectrum of activity, ability to affect resistant microbial strains, and pharmacological properties. Accordingly, they are recommended for specific infectious diseases (Fig. 43, 44, 45).

Most antibiotics exert a bactericidal effect (Table 19), but bacteriostatic antibiotics (such as chloramphenicol, tetracyclines, and macrolides) are also used, because the body's natural defenses help eliminate the pathogen whose reproduction has been suppressed by the chemotherapeutic agent.

12.9 Application of Synthetic Chemotherapeutic Agents.

Synthetic chemotherapeutic agents, much like antibiotics, are characterized by selective action that depends on specific targets within the Cells of the infectious agent. This target Specificity determines the drug's antimicrobial spectrum and therapeutic application (Table 24) [25]. The table lists only the major antibacterial agents; substances with antiviral, antifungal, and antiprotozoal activity are discussed in the respective sections.

Table 24. Application of synthetic antibacterial chemotherapeutic agents

12.10 Use of Antibiotics in Agriculture

In veterinary medicine, antibiotics are employed both for individual treatment and mass animal management.

Individual administration is practiced when treating both small domestic animals (cats, dogs, etc.) and large livestock (cows, horses, sheep, etc.) suffering from infectious diseases (pneumonia, Bronchitis, mastitis, intestinal infections, etc.).

The treatment of small animals follows the same principles as human infectious disease chemotherapy and utilizes the same

pharmaceutical drugs. Large animal treatment likewise relies on human chemotherapy principles; however, if the animal is intended for food production, antibiotics must be withdrawn well in advance of slaughter to prevent residues in the food supply. Most animal diseases are managed using both veterinary-specific antibiotics (grisein, bacitracin) and human medical antibiotics (streptomycin, Penicillins, chloramphenicol, tetracyclines), as well as other chemotherapeutic agents (sulfonamides, nitrofurans).

Prophylactic mass treatment can be administered to all animals within a given farm, whereas mass therapeutic treatment is generally restricted to herds or farms where an infectious outbreak has occurred. In such cases, antibiotics are delivered via feed or drinking Water.

Mass treatment interrupts the infection cycle, eliminates the infection source, and helps combat both active disease and asymptomatic infections.

Antibiotics are widely used as feed additives to accelerate animal growth, an effect linked to their impact on gut microbiota. It is believed that antibiotics suppress toxin production by intestinal bacteria, inhibit the growth of potentially pathogenic bacteria and microorganisms that consume and break down vital dietary components, and stimulate bacteria that synthesize vitamins and other beneficial substances, ultimately altering animal physiology. In Russia, grisein and bacitracin are commonly used as feed additives.

However, the widespread use of antibiotics in animal husbandry can lead to consequences hazardous to Human and Animal health. Bacteriological consequences involve the selection and dissemination of multiresistant microbial strains, while pharmacological consequences stem from the accumulation of antibiotic residues in animal products, which can trigger allergic or other adverse reactions in humans.

Certain antibiotics are utilized for plant protection against diseases caused by phytopathogenic bacteria (streptomycin targeting Erwinia, Xanthomonas, Pseudomonas) and Fungi (cycloheximide, kasugamycin, aureofungin).