03_antibiotica.pdf

# Antibiotics and their mechanisms of action This topic delves into the world of antibiotics, exploring their interaction with bacteria and the human host, methods to predict their efficacy, and their diverse mechanisms of action, while also addressing the critical issue of antibiotic resistance [1](#page=1) [9](#page=9). ### 1.1 Introduction to antibiotics Antibiotics are pharmaceuticals designed to specifically inhibit the multiplication of microorganisms, primarily for the treatment of bacterial infections. Key characteristics include [4](#page=4): * **Selective toxicity:** They are toxic to bacteria but, in principle, not to human cells [4](#page=4). * **Specific molecular target:** They act on a specific molecular site within the microorganism [4](#page=4). * **Spectrum of activity:** Depending on their target, they have a defined spectrum, meaning they are clinically useful against specific classes of bacteria [4](#page=4). * **Impact on normal flora:** Even narrow-spectrum antibiotics can affect the normal flora, leading to side effects and complications [4](#page=4). * **Potent life-saving agents:** Antibiotics are potentially life-saving and must be used judiciously to preserve their future efficacy [4](#page=4). The action of antibiotics relies on a specific interaction with bacteria, unlike disinfectants and sterilizers which cause generalized damage to proteins and metabolism due to their non-selectivity. The first antibacterial agents were explored as chemotherapeutics, with Paul Ehrlich pioneering the principle of selective toxicity using arsenic compounds for syphilis in 1910. Sulfonamides, synthetic molecules, were introduced by Bayer AG in 1935 as the first "antibiotics." Natural antibiotics, such as penicillin discovered by Alexander Fleming, are produced by microorganisms like fungi to compete in their environment. The term "antibiotic" is typically used for antibacterial agents, while "antimycotics" are for fungi, "antivirals" or "virostatica" for viruses, and "antiprotozoary" and "antiparasitic" for protozoa and worms, respectively [4](#page=4) [5](#page=5) [6](#page=6). ### 1.2 Interaction with bacteria and host Effective antibiotic use requires understanding the complex interplay within the patient-bacterium-antibiotic triangle [10](#page=10). #### 1.2.1 The host-germ relationship Understanding the nature and location of an infection is paramount for judicious antibiotic use. This involves identifying the pathogen through diagnostic microbiology, including sensitivity testing. In many instances, intervention with antibiotics is not necessary due to the natural course of infection (e.g., sore throat). In other cases, antibiotics may be insufficient, requiring additional measures like abscess drainage. Specific characteristics of the infection, patient, or pathogen may necessitate deviations from standard antibiotic choices and dosages, impacting the interpretation of laboratory results. The body possesses natural defenses, and infections can resolve spontaneously. However, in severe cases like meningitis or endocarditis, where natural defenses are overwhelmed, appropriate and potent antibiotic therapy is essential [11](#page=11). #### 1.2.2 Antibiotics and the human body The human body's physiology dictates how antibiotics are absorbed, distributed to tissues and fluids, and ultimately metabolized or excreted. This process defines the pharmacokinetic (PK) profile. While designed to target bacteria selectively, antibiotics can also cause undesirable effects, including toxicity and side effects [12](#page=12). #### 1.2.3 Antibiotics and bacteria Antibiotics exert their activity through specific targets on bacteria, a characteristic that defines their spectrum of effectiveness. The nature of exposure, such as high peak concentrations versus prolonged lower concentrations, can also influence their effect. These are known as pharmacodynamic (PD) characteristics. Bacterial sensitivity to antibiotics can be measured in the laboratory. However, in patients, antibiotic concentrations fluctuate due to PK properties, making the prediction of in vivo efficacy dependent on considering both PK and PD characteristics. Insufficient knowledge or incorrect use of these principles can lead to reduced efficacy, treatment failure, and the promotion of antibiotic resistance [13](#page=13). ### 1.3 Predicting efficacy in the patient #### 1.3.1 The dilution and diffusion antibiogram The **dilution antibiogram** is a fundamental laboratory test to determine the intrinsic sensitivity of a bacterial isolate to an antibiotic. Bacteria are grown in a series of cultures containing a serial dilution of the antibiotic. The **Minimum Inhibitory Concentration (MIC)** is defined as the lowest antibiotic concentration that inhibits bacterial growth. Some antibiotics are considered bacteriostatic if the concentration required to kill the bacteria is significantly higher than the MIC [15](#page=15). The **diffusion antibiogram** (also known as the disk diffusion or Kirby-Bauer test) is a derivative technique. Antibiotic-impregnated disks are placed on an agar plate inoculated with bacteria. The antibiotic diffuses from the disk, creating a concentration gradient. Bacterial growth is inhibited in a zone around the disk, and the diameter of this inhibition zone correlates with the bacterium's susceptibility. A larger zone indicates greater sensitivity. The diffusion antibiogram shows a good inverse correlation with the MIC; a high MIC corresponds to a small inhibition zone, and vice versa [16](#page=16) [17](#page=17). An **antibiogram** is a report detailing a bacterium's sensitivity to various antibiotics, typically forming part of a bacteriological investigation. While MIC values or inhibition zones are rarely reported, the interpretation is usually presented as Sensitive (S), Intermediate (I), or Resistant (R). This interpretation relies on the **clinical breakpoint** [17](#page=17). > **Example:** An antibiogram report for *E. coli* might list Amoxicillin as R (Resistant), Cefuroxim as S (Sensitive), and Ofloxacin as S (Sensitive) [18](#page=18). #### 1.3.2 The clinical breakpoint The **clinical breakpoint** represents the in vitro susceptibility level of a species to a particular antibiotic at which the point between clinical utility and non-utility lies. It's crucial to understand that [19](#page=19): * Clinical breakpoints are not necessarily the concentrations achieved at the infection site [19](#page=19). * They are determined from animal studies and clinical trials, and may be subject to revision [19](#page=19). * These values are often based on standard dosing regimens and assumed plasma concentrations are representative of infection site concentrations, which can vary [19](#page=19). * Breakpoints are internationally agreed upon and form the basis for therapeutic guidelines [19](#page=19). #### 1.3.3 PK/PD characteristics of the antibiotic Predicting in vivo activity from a static MIC value is challenging due to the dynamic nature of antibiotic pharmacokinetics. Analysis of animal and human studies has revealed predictable relationships between antibiotic exposure and infection clearance, known as PK/PD characteristics. Three key parameters correlate with efficacy [20](#page=20): 1. Time above MIC (T > MIC) 2. Area Under the Curve (AUC) / MIC ratio 3. Cmax / MIC ratio Animal studies indicate which PK/PD parameter best predicts activity. For beta-lactam antibiotics like ceftazidime, "time above MIC" is the strongest predictor of bacterial elimination. An optimal effect is often achieved when concentrations remain above the MIC for more than 50% of the dosing interval for beta-lactams [21](#page=21) [22](#page=22). ##### 1.3.3.1 Best effect based on "time above the MIC" This category of antibiotics exhibits "time-dependent" killing. A key target is achieving concentrations above the MIC for approximately 50% of the dosing interval. The primary group includes **β-lactams**. Due to their short half-lives, multiple daily administrations or continuous infusion are often employed to maintain concentrations above the MIC. For cephalosporins, maintaining concentrations above the MIC for at least 60% of the time is targeted. Dosing adjustments can alter the breakpoint for susceptibility [22](#page=22) [23](#page=23) [24](#page=24). > **Tip:** Understanding the concept of "intermediate" (I) sensitivity is crucial. It signifies a zone of uncertainty where clinical success is difficult to predict, often due to patient variability and testing method limitations [25](#page=25). ##### 1.3.3.2 Best effect based on Cmax/MIC For this group, higher peak concentrations correlate with better efficacy. The PK/PD target is often a Cmax/MIC ratio greater than 3 or 10. The most important antibiotic class exhibiting this characteristic is **aminoglycosides**. Dosing adjustments focus on achieving high peak concentrations [26](#page=26). ##### 1.3.3.3 Best effect based on AUC/MIC These antibiotics show a mixed PK/PD behavior, with the AUC/MIC ratio providing the best prediction of efficacy. Targets typically involve an AUC/MIC ratio greater than 30 or 100, depending on the bacterial group. Key classes include **glycopeptides, macrolides, tetracyclines, and quinolones**. Dosing adjustments aim for a sufficient total daily dose, rather than high peak concentrations [26](#page=26). > **Tip:** For β-lactams, Time above MIC is the best activity parameter, while for quinolones, AUC/MIC is more predictive [27](#page=27). Continuous infusion of β-lactams can maintain concentrations above the MIC for longer periods compared to intermittent dosing. For aminoglycosides, a single daily dose maximizes peak concentration, improving efficacy and reducing toxicity [28](#page=28). #### 1.3.4 Influence of local conditions and patient-specific factors The predictive value of an antibiogram and recommended dosages is based on normal pharmacokinetics and systemic administration. In situations where antibiotic concentrations are lower in specific tissues (e.g., prostate, abscesses, brain) or in critically ill patients (e.g., ICU, burns), PK may be altered, leading to reduced bacterial elimination and selection of resistant mutants. It is essential for physicians to interpret antibiogram results within the individual patient's context, considering the infective site and the specific patient's condition. Dose adjustments may be necessary for patients with significantly altered pharmacokinetics, and consultation with infectious disease specialists or microbiologists is recommended when in doubt [30](#page=30). ### 1.4 Overview of antibiotics and their mechanisms of action Antibiotics are classified into groups based on their molecular targets within bacteria [31](#page=31). #### 1.4.1 Target 1: Cell wall synthesis Antibiotics targeting cell wall synthesis interfere with various steps of peptidoglycan synthesis [32](#page=32). ##### 1.4.1.1 Glycopeptides * **Prototype:** Vancomycin [33](#page=33). * **Mechanism:** Blocks a step in the incorporation of peptidoglycan precursors [33](#page=33). * **Pharmacokinetics:** Must be administered parenterally due to poor oral absorption, though oral vancomycin is useful for *Clostridioides difficile* diarrhea [33](#page=33). * **Toxicity:** Ototoxic and nephrotoxic; requires careful dosing and serum level monitoring, making it a hospital antibiotic [33](#page=33). * **Spectrum:** Active only against Gram-positive bacteria due to the outer membrane barrier of Gram-negatives [33](#page=33). * **Application:** Crucial for treating resistant Gram-positive infections, such as Methicillin-resistant *Staphylococcus aureus* (MRSA) [33](#page=33). Fosfomycin is a urinary antiseptic that inhibits peptidoglycan synthesis with a broad spectrum and low resistance rates. Nitrofurantoin is another urinary antiseptic that inhibits bacterial metabolism and synthesis, with a broad spectrum but is contraindicated in renal insufficiency [32](#page=32). ##### 1.4.1.2 The β-lactam group These are the most frequently used antibiotics [34](#page=34). * **Mechanism:** Block peptidoglycan synthesis by inhibiting penicillin-binding proteins (PBPs), leading to cell wall disruption and bacterial autolysis. Examples include penicillins, cephalosporins, and carbapenems. Bacteria can evolve β-lactamases to break down these antibiotics. Adding β-lactamase inhibitors (e.g., clavulanic acid) can broaden their spectrum [34](#page=34). * **Pharmacokinetics:** Generally good, with variable penetration into certain sites like the meninges and prostate. Both oral and parenteral forms exist, with newer broad-spectrum agents often only available parenterally [35](#page=35). * **Toxicity:** Generally safe, with allergic reactions (including anaphylactic shock) being the most significant side effect [35](#page=35). * **Spectrum:** Varies by product. No activity against bacteria without cell walls (e.g., Chlamydia, Mycoplasma) [35](#page=35). * **Applications:** Widely used. Preference is given to older, narrow-spectrum β-lactams to minimize resistance selection pressure [35](#page=35). **Overview of β-lactams:** * **Penicillins:** Limited current applications [36](#page=36). * **Broad-spectrum penicillins (e.g., ampicillin, amoxicillin):** Used for many routine applications [36](#page=36). * **Penicillinase-resistant penicillins (e.g., methicillin, oxacillin):** Active against bacteria with penicillinase [36](#page=36). * **Amoxicillin + clavulanic acid:** Protects against penicillinase and other β-lactamases, offering a broader spectrum including *Staphylococcus* [36](#page=36). * **Cephalosporins (1st and 2nd generation):** Spectrum similar to amoxicillin + clavulanic acid, susceptible to certain β-lactamases [36](#page=36). * **Cephalosporins (3rd generation):** Broad spectrum, less susceptible to many β-lactamases but can be degraded by extended-spectrum β-lactamases (ESBLs) [36](#page=36). * **Carbapenems (e.g., meropenem):** Broadest spectrum, often used as a last resort, but susceptible to carbapenemases [36](#page=36). #### 1.4.2 Group 2: Antibiotics acting on protein synthesis This group targets bacterial ribosomes, affecting protein synthesis. They can bind to the 50S or 30S ribosomal subunit or interfere with tRNA-ribosome interactions [37](#page=37). ##### 1.4.2.1 Aminoglycosides (aminosides) * **Prototype:** Gentamicin, amikacin, tobramycin, streptomycin [38](#page=38). * **Mechanism:** Blockade of the 30S ribosomal subunit [38](#page=38). * **Pharmacokinetics:** Administered parenterally due to poor oral absorption. Rapid bactericidal action and a significant post-antibiotic effect. Poor penetration into cerebrospinal fluid and prostate. Long half-life allows for once-daily administration, aligned with their PK/PD characteristics [38](#page=38). * **Toxicity:** Nephrotoxic and ototoxic with a narrow therapeutic margin, requiring serum level monitoring. Contraindicated in pregnant women [38](#page=38). * **Spectrum:** Good activity against staphylococci and most Gram-negatives (no activity against anaerobes or streptococci) [38](#page=38). * **Applications:** Primarily hospital antibiotics, increasingly replaced by less toxic quinolones and newer β-lactams but remain important reserve agents [38](#page=38). ##### 1.4.2.2 Macrolides (and neomacrolides) * **Prototype:** Erythromycin [39](#page=39). * **Mechanism:** Blockade of the 50S ribosomal subunit [39](#page=39). * **Pharmacokinetics:** Bacteriostatic. Good tissue penetration, including intracellularly. Available orally and parenterally [39](#page=39). * **Toxicity:** Generally low [39](#page=39). * **Spectrum:** Active against "simple" Gram-positives and *Neisseria*. Spectrum overlaps with penicillin, but resistance is increasing. Also active against some bacteria not targeted by β-lactams (e.g., *Campylobacter*, *Legionella*) and cell-wall deficient organisms (*Chlamydia*, *Mycoplasma*). Not active against Gram-negative rods or anaerobes [39](#page=39). * **Use:** Alternative to penicillins for allergies, but with 10-20% resistance. Used for respiratory and sexually transmitted infections [39](#page=39). **Neomacrolides (e.g., azithromycin, clarithromycin):** Similar mechanism and spectrum to erythromycin but with improved pharmacokinetics. They are also used for immunomodulatory effects. Their high intracellular activity makes them options for infections caused by intracellular pathogens [40](#page=40). ##### 1.4.2.3 Clindamycin * **Prototype:** Clindamycin [40](#page=40). * **Mechanism, Pharmacokinetics, and Toxicity:** Related and analogous to erythromycin [40](#page=40). * **Spectrum:** Similar to macrolides, but also active against anaerobic bacteria. Resistance is gradually increasing [40](#page=40). * **Use:** Similar to macrolides, but also indicated for abscesses and wound infections involving mixtures of aerobes and anaerobes [40](#page=40). ##### 1.4.2.4 Tetracyclines * **Prototype:** Doxycycline [41](#page=41). * **Mechanism:** Blocks tRNA binding to the ribosome [41](#page=41). * **Pharmacokinetics:** Bacteriostatic. Good tissue penetration, including intracellularly. Available orally and parenterally [41](#page=41). * **Toxicity:** Can precipitate in developing bone and teeth; not recommended for pregnant women after the first trimester or young children. Can cause gastrointestinal upset, photosensitivity, and candidiasis [41](#page=41). * **Spectrum:** Broad-spectrum, active against Gram-positives, Gram-negatives, *Chlamydia*, *Mycoplasmata*, and *Malaria*. Resistance is common among anaerobes [41](#page=41). * **Use:** For *Chlamydia* infections, spirochetal and leptospiral infections (syphilis, Lyme disease). Doxycycline is often preferred for once-daily dosing. Tigecycline is a newer variant with broad activity, used in hospitals [41](#page=41). #### 1.4.3 Group 3: Antibiotics acting on nucleic acid synthesis These antibiotics interfere with the synthesis or function of bacterial DNA. ##### 1.4.3.1 Quinolones (or chinolones) * **Prototypes:** Older: nalidixic acid; newer: ciprofloxacin, levofloxacin, moxifloxacin [42](#page=42). * **Mechanism:** Inhibit bacterial topoisomerase enzymes, which relax DNA supercoiling by creating double-strand breaks necessary for replication and transcription. Quinolones are synthetic [42](#page=42). * **Pharmacology:** Nalidixic acid has limited systemic activity and is mainly used as a urinary antiseptic. Newer quinolones achieve effective tissue concentrations and are used as systemic antibiotics. They achieve high concentrations in most tissues and intracellularly [42](#page=42). * **Toxicity:** Relatively few side effects (gastrointestinal, occasional tendon and muscle inflammation). Contraindicated in pregnancy and breastfeeding due to potential effects on fetal/infant joint cartilage [42](#page=42). * **Spectrum:** Active against many Gram-positives and Gram-negatives, *Chlamydia*, *Mycoplasmata*, and *Legionella*. Newer agents have activity against pneumococci and anaerobes. Resistance is unfortunately increasing [42](#page=42). * **Use:** Widely used for gastrointestinal, urogenital, respiratory, and wound infections due to their spectrum and limited side effects [42](#page=42). ##### 1.4.3.2 Metronidazole * **Prototype:** Metronidazole [43](#page=43). * **Mechanism:** Metronidazole itself is inactive; it is converted to radical metabolites that directly damage bacterial DNA [43](#page=43). * **Pharmacokinetics:** Distributes well to various organs. Available orally and parenterally [43](#page=43). * **Side effects:** Minor, but causes alcohol intolerance [43](#page=43). * **Spectrum:** Most anaerobic bacteria, many protozoa (*Trichomonas*, *Entamoeba*, *Giardia lamblia*), and a few aerobic bacteria like *Helicobacter pylori* [43](#page=43). * **Use:** For protozoal intestinal infections, trichomoniasis, anaerobic infections (often combined with an aerobic-active antibiotic), and specific bacterial infections like *Helicobacter pylori* and bacterial vaginosis [43](#page=43). #### 1.4.4 Group 4: Inhibition of metabolic pathways These antibiotics interfere with essential metabolic processes in bacteria. * **Prototypes:** Trimethoprim and cotrimoxazole [44](#page=44). * **Mechanism:** Act on sequential steps of purine-pyrimidine synthesis. Sulfonamides alone are rarely used; trimethoprim is used for urinary tract infections. Cotrimoxazole, a combination of trimethoprim and a sulfonamide, is most frequently used. These are not "true" antibiotics as they are not derived from microorganisms [44](#page=44). * **Pharmacokinetics:** Oral and parenteral administration [44](#page=44). * **Side effects:** Not frequent but can include increased renal insufficiency and severe skin reactions. Contraindicated in the first trimester of pregnancy [44](#page=44). * **Spectrum:** Originally broad, but frequent resistance has emerged due to extensive use. Not active against anaerobes [44](#page=44). * **Use:** Limited indications for empirical use in outpatient settings. More commonly used after sensitivity is documented. Used for *Pneumocystis jirovecii* (a fungus) and *Toxoplasma gondii* (a protozoon) [44](#page=44). --- # Antibiotic resistance and its management This section outlines the mechanisms of antibiotic resistance in bacteria, its kinetics of development and spread, and strategies for preventing and controlling it, differentiating between resistance mutants and persisters [3](#page=3). ### 2.1 The driving forces of antibiotic resistance The primary driving force for antibiotic resistance is Darwinian evolution, where individuals better adapted genetically to their environment are selected for. In the presence of antibiotics, bacteria with a higher Minimum Inhibitory Concentration (MIC) survive better, as random mutations that increase MIC offer an advantage only in the presence of antibiotics. Increased "antibiotic pressure" and selection pressure have been observed since 1942 due to the increasing quantities of antibiotics in humans and their environment. Furthermore, antibiotics can eliminate the normal flora, reducing colonization resistance and allowing "aliens" (other bacteria) to colonize altered eco-niches. Poor hygiene facilitates the transmission and persistence of resistant bacteria [47](#page=47). ### 2.2 Mechanisms of resistance Bacteria can develop resistance through several mechanisms: #### 2.2.1 Neutralization The bacteria modify the antibiotic into an inactive form, often through hydrolysis or blocking. The most well-known example is $\beta$-lactamase, which breaks down $\beta$-lactams by opening the $\beta$-lactam ring, rendering the antibiotic inactive. $\beta$-lactamases vary significantly in quantity and quality, leading to different levels of clinical resistance for various $\beta$-lactam antibiotics. New, more efficient $\beta$-lactamases are continually emerging. For instance, clavulanic acid can neutralize some $\beta$-lactamases but not others. Extended-spectrum $\beta$-lactamases (ESBLs) have a broad spectrum of degradation, including third-generation cephalosporins. Carbapenems were initially resistant to all known $\beta$-lactamases, but carbapenemases have now appeared. The development and spread of these latter two types of $\beta$-lactamases exemplify the ongoing conflict between humans and bacteria [48](#page=48). #### 2.2.2 Reduced uptake of antibiotics This occurs through modified porins in the bacterial cell wall, or porins may be absent entirely [49](#page=49). #### 2.2.3 Efflux resistance Membrane pumps, which transport molecules like antibiotics out of the bacteria, become more efficient or numerous [49](#page=49). #### 2.2.4 Alternative metabolic pathway (bypass) In response to antibiotic-induced metabolic blockage, bacteria utilize alternative metabolic pathways to maintain their physiological functions. For example, with cotrimoxazole, purine and pyrimidine precursors are synthesized via different enzymes. Methicillin-resistant *Staphylococcus aureus* (MRSA) achieves resistance by employing an alternative PBP. Ribosomal modification in *S. pneumoniae* confers tetracycline resistance [50](#page=50). #### 2.2.5 Combinations Often, resistance results from multiple simultaneous changes, such as a modified target combined with altered permeability, or slight degradation coupled with reduced permeability. Plasmid exchange can lead to a spectacular accumulation of multiple resistance genes, making the bacteria carrying or receiving the plasmid resistant to numerous antibiotic classes. Through transfer, another bacterium can become resistant in a single maneuver, even if it's of a different type or species. This phenomenon means that the use of one antibiotic can maintain or select for resistance to multiple antibiotic types [50](#page=50). ### 2.3 Kinetics of development and spread of resistance The speed at which resistance develops and spreads varies dynamically and can have different genetic bases. Development is often slow and gradual, but resistance eventually becomes robust and can spread rapidly [51](#page=51). #### 2.3.1 Natural resistance Examples of natural resistance include *Klebsiella pneumoniae*'s resistance to ampicillin and fungi (*Candida* sp.)'s resistance to all antibiotics. The consequences of natural resistance are twofold [51](#page=51): 1. Antibiotics can select for these resistant species, leading to their local increase and dominance of the flora. Candidiasis (vaginal, oral) and diarrhea caused by *Clostridioides difficile* are examples of new infections that can occur after antibiotic administration for another infection [51](#page=51). 2. Treatment can increase the number of these relatively resistant bacteria in feces, urine, etc., facilitating their transmission to the environment and other individuals through hygiene errors, leading to hospital-acquired infections [51](#page=51). The normal microflora typically consists of species that have remained sensitive to antibiotics and are decimated by antibiotic use. This reduction in colonization resistance allows exogenous bacteria, whether pathogenic or not, resistant or less resistant, to colonize a niche more easily than they otherwise would [51](#page=51). #### 2.3.2 Reduced colonization resistance This refers to the phenomenon where the elimination of sensitive normal flora by antibiotics allows colonization by more resistant or opportunistic pathogens [51](#page=51). #### 2.3.3 Gradual development, 'step-by-step' This involves a gradual increase in MIC values. An initial mutant exhibits a slightly elevated MIC, and subsequent mutations lead to further increases until the strain becomes clinically resistant, with an MIC exceeding the breakpoint. This mechanism relies on point mutations that are selected for. The distribution of MICs changes, with the population's boundary moving closer to the breakpoint, eventually leading to the first resistant mutants [52](#page=52). #### 2.3.4 Resistance in one step: switching on (or off) Resistance can arise rapidly in a single step, at one site or in one patient. A sensitive strain can transform into a strain with a very high MIC, rendering it untreatable with the antibiotic. These are typically regulatory mutations (up or down) or the acquisition/loss of a factor. Examples include the loss of porins or the activation of efflux pumps. Acquiring resistance genes via horizontal gene transfer, such as through plasmids, also falls into this category [53](#page=53). #### 2.3.5 Concentration and mobilization of resistance genes Genes or parts of genes can be exchanged through bacteriophage transduction and transformation. Plasmids are the most efficient mechanism for exchanging entire genes. Due to selection pressure, large plasmids have evolved that carry numerous genes. These plasmids code for sex pili, inducing "sexual" contact with other strains (conjugation), and transfer a copy of themselves to the other bacterium. These plasmids can acquire various resistance genes, making the bacterium carrying the plasmid resistant to multiple antibiotic types. Through transfer, another bacterium becomes resistant in a single maneuver, even if it's of a different type or species. This phenomenon contributes to the maintenance or selection of resistance to multiple antibiotic types through the use of a single antibiotic. Gene flow can occur between plasmids and chromosomes, and between isolates and species [54](#page=54). #### 2.3.6 Spread of strains Clonal spread involves the exchange of resistant strains between individuals. One can become infected with a resistant bacterium without ever having taken antibiotics themselves. Transmission can occur within households, hospitals, through food, or to animals in the environment. An infected person can relocate to another hospital, region, or country. Food products containing resistant bacteria can be transported intercontinentally, and migratory birds (ducks, gulls) serve as another transport mechanism [55](#page=55). #### 2.3.7 Consequences of resistance for antibiotic choice The prevalence of penicillin-resistant pneumococci in Belgium has shown fluctuations. In 1985, almost all strains (99.6%) were sensitive to penicillin, with a gradual increase in strains with reduced sensitivity reaching about 15% in 2002, 11% in 2017, and 14% in 2022. Meningitis caused by pneumococci can no longer be treated empirically with amoxicillin, although respiratory infections can be, provided sufficient dosage. Around 1998-1999, a small percentage (5%) of strains were fully resistant to penicillin (MIC >2 mg/L), also rendering respiratory infections untreatable with amoxicillin in such cases. This increase was fortunately and temporarily a phenomenon, with only 2.0% recorded in 2022. Spain shows slightly higher resistance rates for pneumococci to penicillin compared to Belgium [56](#page=56). > **Tip:** Understanding the trends in antibiotic resistance for specific pathogens in your region is crucial for making informed treatment decisions. ### 2.4 Persisters and their distinction from resistance mutants #### 2.4.1 Resistance mutants * These are selected for during treatment in a Darwinian manner [57](#page=57). * They represent an irreversible, definitive characteristic of the bacterium, although loss of resistance genes is possible, it's usually a slow process [57](#page=57). * Detected by the laboratory upon new culturing, showing a different MIC (S becomes R) [57](#page=57). #### 2.4.2 Persisters * These represent a temporary, purely phenotypic form of insensitivity (also termed stress mutants, among other names) [57](#page=57). * They are reversible, resulting from phenotypic, physiological adaptation, not mutation [57](#page=57). * Not detected in standard laboratory conditions as the bacteria are studied in 'planktonic form', which differs from in vivo persistence [57](#page=57). * Can be a purely passive phenomenon (metabolically inactive) or involve "active" persistence mechanisms [57](#page=57). * Biofilms and quorum sensing involve more than just a mucus-like layer; the bacteria possess a different physiological arsenal [57](#page=57). * Small-colony variants exhibit slow, intracellular growth [57](#page=57). * Mixed populations where a portion of the bacterial population has a different enzyme arsenal, which might not be immediately useful but becomes vital during a catastrophe that rapidly decimates the main population [57](#page=57). * "Empty artis" antibiotic therapy reduces the chance of persisters forming. The phenomenon of persisters explains why certain antibiotic treatments require weeks to months (e.g., osteomyelitis), even though the bacteria are killed in vitro within hours [57](#page=57). Antibiotics kill bacteria in a logarithmic process. Persisters are cells that are insensitive due to a different metabolic state. They survive and can become metabolically active again [58](#page=58). ### 2.5 How to prevent and curb resistance #### 2.5.1 Preventing resistance * **Avoid unnecessary use:** Resist the pressure of uncertainty, patients, or pharmaceutical companies [59](#page=59). * Antibiotics are ineffective against viral infections (flu, common cold) [59](#page=59). * Patients do not heal better or faster with antibiotics for acute angina, ear infections, bronchitis, or gastroenteritis (except in severe cases or high-risk groups), even if of bacterial origin [59](#page=59). * **Ensure good individual therapy:** * **Dosage:** Prescribe correctly and ensure patient compliance [59](#page=59). * **Duration:** Avoid prolonged use which can select for flora, and avoid short courses that might not eradicate the infection [59](#page=59). * **Antibiotics with low selection pressure:** Opt for the narrowest spectrum, which are also often the cheapest [59](#page=59). * **Address resistance in animals and agriculture:** * Avoid unnecessary antibiotics in agriculture, fish farming, and livestock [59](#page=59). * Do not use water contaminated with animal and human feces for irrigation and spraying in agriculture [59](#page=59). * Maintain general hand and kitchen hygiene [59](#page=59). * **Importance of awareness:** Implement training, sensitization campaigns (including for the public), and collaboration with experts [59](#page=59). #### 2.5.2 Important additional elements * Prevent the transmission of resistant strains (refer to infection prevention lessons) [59](#page=59). * Prevent infections and vaccinate where possible [59](#page=59). --- # Antiviral and other antimicrobial agents This topic provides an overview of antiviral medications (virostatica) and their role in the viral life cycle, touching on prophylactic antimicrobial use and specific antiviral treatments [1](#page=1). ### 3.1 Introduction to antimicrobial agents Antimicrobial agents, including antibiotics and virostatica, are primarily used to treat infections. However, in certain situations, they can be administered preventatively or prophylactically, even in the absence of an existing infection. This prophylactic use requires careful adherence to recommendations and indications to ensure efficiency, prevent side effects, and mitigate the development of resistance [61](#page=61). ### 3.2 Prophylactic use of antimicrobial agents Prophylactic use is indicated when either the risk of infection is very high, or when the consequences of infection, even if not highly probable, are very severe. A distinction can be made between pre-exposure and post-exposure prophylaxis [61](#page=61). #### 3.2.1 Pre-exposure prophylaxis This type of prophylaxis is administered before any contact with a pathogen has occurred. An example is taking medication before traveling to neutralize potential parasites, such as *Plasmodia* (malaria), transmitted by infected mosquitoes [61](#page=61). #### 3.2.2 Post-exposure prophylaxis This is administered after an exposure has already taken place. Examples include taking antiviral drugs after potential exposure to HIV through a needlestick injury or sexual contact with an infected individual [61](#page=61). #### 3.2.3 Examples of prophylactic use **For bacterial infections:** * After suspected sexual contact (e.g., gonorrhea) [62](#page=62). * For contaminated wounds following trauma or animal/human bites [62](#page=62). * In cases of recurrent infections (e.g., urinary tract infections) [62](#page=62). * Following close contact with a patient infected with meningococci [62](#page=62). * For travel to prevent traveler's diarrhea [62](#page=62). * Prophylaxis of postoperative wound infections [62](#page=62). * Endocarditis prophylaxis in patients with heart valve lesions, to prevent bacteremia and subsequent endocarditis after dental extractions or other procedures [62](#page=62). **For parasitic infections:** * Malaria prevention when traveling to endemic areas [62](#page=62). **For viral infections (virostatica):** * Combined antiretroviral therapy (cART) after a needlestick accident or sexual contact with a presumed HIV patient [62](#page=62). **For fungal infections:** * In hematological patients during neutropenia, to prevent infections primarily from airborne *Aspergillus* [62](#page=62). * For recurrent *Candida* vaginitis [62](#page=62). ### 3.3 Antiviral agents (virostatica) and their role in the viral life cycle Antiviral medications, or virostatica, are designed to inhibit viral infection and replication by targeting virus-specific interactions or enzymes, aiming for minimal impact on cellular metabolism and function. Currently, their use is predominantly for severe chronic infections like HIV, HCV, and HBV, often requiring long-term or lifelong oral administration. The effectiveness of treating influenza virus infections with medication is a subject of debate. For other viruses causing severe diseases, medical therapies may not be available, though vaccination might be an alternative [76](#page=76). Similar to antibiotic use, the development of resistance to virostatica is a concern, making judicious use and good patient compliance essential. Resistance can typically be identified by sequencing the viral genome. Interferon alfa, a naturally occurring antiviral, is used less frequently for chronic viral hepatitis due to its side effects and is being replaced by virus-specific antiviral agents for HBV and HCV [76](#page=76). #### 3.3.1 Targeting the viral life cycle Antiviral agents intervene at various stages of the viral life cycle [77](#page=77): * **Attachment inhibitors:** Targeting viral attachment to host cell receptors. Examples include antireceptor antibodies like palivizumab (for RSV) and receptor antagonists like maraviroc (for HIV) [77](#page=77). * **Fusion inhibitors:** Blocking the fusion of the viral envelope with the host cell membrane. An example is enfuvirtide (for HIV) [77](#page=77). * **Uncoating inhibitors:** Preventing the release of the viral genetic material into the host cell. Amantadine (for influenza) is an example [77](#page=77). * **Expression inhibitors:** Interfering with the expression of viral genes. Examples include interferon-induced gene products [77](#page=77). * **Replication (polymerase) inhibitors:** Blocking viral nucleic acid synthesis [77](#page=77). * **Nucleoside/nucleotide analogs:** These mimic natural building blocks of DNA or RNA and cause chain termination when incorporated by viral polymerases. Examples include zidovudine, abacavir, lamivudine (for HIV/HBV), acyclovir (for herpes), tenofovir, sofosbuvir (for HCV), and ribavirine (for HCV/other RNA viruses) [77](#page=77). * **Non-nucleoside analogs:** These inhibit viral polymerases through different mechanisms. Examples include nevirapine and efavirenz (for HIV), as well as foscarnet and cidofovir (for herpes) [77](#page=77). * **Integrase inhibitors:** Blocking the integration of viral DNA into the host genome. Raltegravir (for HIV) is an example [77](#page=77). * **Protease inhibitors:** Preventing the cleavage of viral polyproteins into functional proteins. Examples include ritonavir and darunavir (for HIV), as well as boceprevir and telaprevir (for HCV) [77](#page=77). * **Release inhibitors:** Preventing the release of newly formed virions from infected cells. Oseltamivir and zanamivir (for influenza) are examples [77](#page=77). #### 3.3.2 Anti-herpes agents: acyclovir and valacyclovir Acyclovir is a synthetic nucleoside analog that closely resembles 2'-deoxyguanosine. It is selectively phosphorylated by viral thymidine kinase (in HSV1/2, VZV) or phosphotransferase (in CMV) to acyclovir monophosphate. This initial phosphorylation step is specific to infected cells, as cellular enzymes are less efficient. Further phosphorylation by cellular enzymes yields acyclovir triphosphate, which is then incorporated into viral DNA by viral and cellular polymerases, leading to chain termination and halting both viral and cellular DNA synthesis [78](#page=78) [79](#page=79). **Indications for acyclovir:** * **HSV1 and HSV2:** For topical treatment of herpes labialis and genitalis (requires early initiation). Systemically for severe infections (neonatal, encephalitis, ophthalmic), and for outbreaks of herpes genitalis [78](#page=78). * **VZV:** For herpes zoster (shingles) within 72 hours of the first skin lesions to reduce pain in the weeks following lesion disappearance and the duration of postherpetic neuralgia. Recommended for the elderly and immunocompromised patients. For ophthalmic zoster. For varicella (chickenpox) in high-risk individuals (e.g., immunocompromised, pregnant, or adults with severe presentations) due to the risk of complications like encephalitis and pneumonia [78](#page=78). Valacyclovir is a valylester prodrug of acyclovir, offering improved oral bioavailability [78](#page=78). #### 3.3.3 Antiviral agents for influenza * **Amantadine:** Inhibits viral replication by blocking acid-activated ion channels formed by the M2 protein. It has numerous side effects and is rarely used now [80](#page=80). * **Zanamivir (Relenza) and Oseltamivir (Tamiflu):** These are neuraminidase (NA) inhibitors. Inhibition of NA activity leads to viral aggregation at the cell surface and reduces the release of new virions from infected cells. The effectiveness of these drugs is debated. For instance, the Belgian government had a stock of oseltamivir in 2009, which was later phased out [80](#page=80). #### 3.3.4 Antiviral agents: combined antiretroviral therapy (cART) for HIV The treatment of HIV has seen significant success with antiviral medications, utilizing cocktails of reverse transcriptase and protease inhibitors, along with second-line reserve agents. This therapy requires meticulous, specialized monitoring of side effects, viral load, potential resistance through sequencing, and patient compliance. In most patients, cART can reduce the viral load to undetectable levels, controlling the infection, preventing the progression to AIDS, and reducing sexual transmission. However, a cure is not achieved as the virus integrates into the patient's DNA. A similar therapeutic arsenal is available for HCV, leading to definitive cures [81](#page=81). --- # Practical application of antibiotic therapy This section details the practical considerations and decision-making processes involved in prescribing antibiotic therapy. ### 4.1 Predicting antibiotic efficacy in patients Predicting the in vivo efficacy of an antibiotic requires understanding laboratory results, pharmacokinetic/pharmacodynamic (PK/PD) properties, and individual patient factors [14](#page=14). #### 4.1.1 Laboratory sensitivity testing Laboratory sensitivity tests, such as dilution and diffusion antibiograms, determine a bacterium's susceptibility to an antibiotic under static conditions. The Minimum Inhibitory Concentration (MIC) is the minimum concentration of an antibiotic that inhibits visible bacterial growth. These results are interpreted using clinical breakpoints, classifying isolates as sensitive (S), resistant (R), or intermediate (I) [14](#page=14) [18](#page=18). * **Sensitive (S):** Clinically usable [14](#page=14). * **Resistant (R):** Clinically not usable [14](#page=14). * **Intermediate (I):** Clinically usable only with increased dosages [14](#page=14). **Tip:** While laboratory tests are performed under static conditions, antibiotic concentrations in the body are dynamic, highlighting the importance of PK considerations [14](#page=14). #### 4.1.2 The clinical breakpoint The clinical breakpoint represents the in vitro susceptibility level of a bacterial species to a specific antibiotic at which the tipping point between clinical usability and non-usability lies. It is crucial to understand that clinical breakpoints are not necessarily the antibiotic concentration achieved at the infection site. They are determined based on animal studies supplemented by clinical studies and may be subject to revision. Breakpoints are established for a specific standard dosage (amount and frequency) and assume that the antibiotic concentrations achieved at the infection site mirror those measured in plasma. This assumption can vary depending on the antibiotic and the nature of the infection or patient. For some pathogens, the breakpoint can vary based on the infection's localization, such as pneumococcal meningitis versus non-meningeal infections. These breakpoints are internationally agreed upon and form the basis for therapeutic guidelines. Conversely, the measured MIC or zone of inhibition diameter can change between isolates from the same patient, for instance, if a bacterium is sensitive (S) before therapy but develops a higher MIC or smaller inhibition zone during treatment [19](#page=19). #### 4.1.3 Pharmacokinetic/Pharmacodynamic (PK/PD) characteristics of the antibiotic Given that antibiotic pharmacokinetics are dynamic, predicting in vivo activity from static MIC tests is challenging. PK/PD characteristics, derived from animal and human studies, help predict the elimination of infection through antibiotic therapy. Key parameters correlating with effectiveness are [20](#page=20): 1. **Time above MIC (T > MIC):** The duration for which the antibiotic concentration remains above the MIC [20](#page=20). 2. **AUC/MIC ratio:** The ratio of the area under the concentration-time curve to the MIC [20](#page=20). 3. **Cmax/MIC ratio:** The ratio of the maximum peak concentration to the MIC [20](#page=20). Animal studies help determine which of these PK/PD parameters best predicts activity, informing the establishment of standard dosages and breakpoints. Understanding these parameters is vital for deviating from standard dosages [20](#page=20). **Best effect based on "time above the MIC" (T > MIC)** [22](#page=22). * **Mechanism:** Time-dependent action [22](#page=22). * **Effectiveness:** Approximately 50% of the time with concentrations above the MIC is considered sensitive. For β-lactams, a T > MIC of at least 40-60% is generally required. Specifically, 40% for carbapenems, 50% for penicillins, and 60% for cephalosporins [21](#page=21) [22](#page=22). * **Key group:** β-lactams [22](#page=22). * **Dosing considerations:** Many β-lactams have short half-lives, necessitating frequent administration. Dosing adjustments involve spreading the administration throughout the day or using continuous infusion [22](#page=22). **Example:** For ceftazidime, a target of 60% T > MIC is aimed for cephalosporins. If the MIC is 4 mg/L or less, this target is typically met with a standard dosing regimen of 500 mg IV three times daily. With an updated guideline of 1 gram IV three times daily, the target is met for bacteria with an MIC of 8 mg/L or less. This demonstrates how breakpoints can evolve with changes in dosing strategies [23](#page=23) [24](#page=24). **Intermediate (I) vs. Sensitive (S) and Resistant (R)** [25](#page=25). * An intermediate result signifies a "grey zone" where clinical success is difficult to predict due to variability in patient response and testing methods. For instance, a bacterium with an MIC of 8 mg/L might be considered intermediate if the standard dose targets an MIC of 4 mg/L, but could be sensitive if a higher dose can be safely administered [25](#page=25). **Best effect based on Cmax/MIC ratio** [26](#page=26). * **Mechanism:** Concentration-dependent action; higher peak concentrations lead to better efficacy [26](#page=26). * **Effectiveness:** Sensitive if the peak/MIC ratio is sufficiently high (minimum 3, sometimes 10). The PK/PD target is Pk/MIC > 3 or 10 [26](#page=26). * **Key group:** Aminoglycosides [26](#page=26). * **Dosing considerations:** Ensure high peak concentrations are achieved [26](#page=26). **Best effect based on AUC/MIC ratio** [26](#page=26). * **Mechanism:** Mixed PK/PD behavior; AUC/MIC provides the best prediction [26](#page=26). * **Effectiveness:** The AUC/MIC ratio should be greater than 30 or 100, depending on the bacterial group. The PK/PD target is AUC/MIC > 30 or 100 [26](#page=26). * **Key groups:** Glycopeptides, macrolides, tetracyclines, quinolones [26](#page=26). * **Dosing considerations:** Ensure a sufficiently large daily dose, while the peak concentration is less critical [26](#page=26). **Tip:** For β-lactams (e.g., ceftazidime), T > MIC is the best parameter of activity, while for quinolones (e.g., levofloxacin), AUC/MIC is more predictive [27](#page=27). #### 4.1.4 Influence of local conditions, specific bacterial properties, or the patient The predictive power of an antibiogram is based on normal pharmacokinetics (serum concentrations in an average patient) with systemic administration. However, situations with altered pharmacokinetics require careful consideration. This can occur when antibiotic concentrations are lower in specific tissues like the prostate, abscesses, or brain, or in the sputum and throat mucus. Critically ill patients, such as those in intensive care or with burns, can also experience altered distribution and elimination, leading to less effective bacterial elimination and easier selection of resistant mutants [30](#page=30). **Tip:** The antibiogram provides a guide but must be interpreted within the context of the individual patient: the pathogen, the antibiotic, and the infection site. Patients with significantly different characteristics than those in PK/PD studies may require dose adjustments. Consultation with infectious disease specialists or microbiologists is recommended when in doubt [30](#page=30). ### 4.2 Moving towards a concrete antibiotic therapy Prescribing antibiotic therapy involves a structured approach, considering multiple factors to ensure optimal patient outcomes [64](#page=64). #### 4.2.1 Initial decision-making process **a. Choice of antibiotic** [64](#page=64). * **Is it necessary?** First, confirm if antibiotic therapy is indicated [64](#page=64). * **Which antibiotic?** Consider the spectrum of likely pathogens and the drug's concentration at the site of infection (which can vary between urine, lungs, and brain) [64](#page=64). * **Is a culture and antibiogram needed?** Cultures are not always necessary, especially for less severe or more predictable infections. However, for severe infections with unpredictable pathogens, testing is crucial [64](#page=64). **Tip:** Antibiotics are often initiated empirically, meaning treatment starts based on expected pathogens and their susceptibility before laboratory results are available, as there is no time to lose in serious infections [64](#page=64). **Starting Antibiotics:** * **Empirical therapy:** Initiated based on suspected pathogens and their likely sensitivities [64](#page=64). * **Culture and Antibiogram:** If performed, results are usually available within 2-3 days [64](#page=64). * If the patient improves, the result may no longer be relevant [64](#page=64). * If the patient does not improve due to bacterial resistance, the treatment is adjusted based on the antibiogram [64](#page=64). * If a broad-spectrum antibiotic was initially used (which can be expensive, toxic, promote resistance, and are often reserve products), it may be switched to a narrower-spectrum antibiotic, a process known as de-escalation [64](#page=64). #### 4.2.2 Details of antibiotic use **b. Route of administration** [65](#page=65). * **Oral:** Convenient and patient-friendly, but compliance can be harder to monitor [65](#page=65). * **Parenteral (IM, IV):** Used when oral administration is not possible, for more certain pharmacokinetics, or if the patient cannot swallow. This can be via bolus or continuous infusion [65](#page=65). **c. Dosage** [65](#page=65). * Dosage selection depends on the type of infection, e.g., a wound infection versus osteomyelitis [65](#page=65). **d. Duration of treatment** [65](#page=65). * Duration varies; some infections require short courses (e.g., 3 days for cystitis in women), while others require longer courses (e.g., 6 months for tuberculosis). Research is ongoing for optimal durations [65](#page=65). **e. Combination therapy** [65](#page=65). * True benefits of combination therapy are few (e.g., tuberculosis); often used at the start of severe infections to broaden the spectrum. Potential for reduced efficacy due to interactions exists [65](#page=65). **f. Other aspects** [65](#page=65). * **Drainage of abscesses, removal of foreign bodies, and surgical repair** are crucial to prevent re-infection and resistance [65](#page=65). * **Clinical and biochemical monitoring** for complications [65](#page=65). * **Therapeutic drug monitoring** (measuring drug levels) may be necessary in some cases to ensure adequate concentration or prevent toxicity [65](#page=65). ### 4.3 Tools for antibiotic selection Selecting an appropriate antibiotic involves utilizing various resources and knowledge bases [66](#page=66). #### 4.3.1 Information sources * **Literature:** Books, journals, hospital newsletters, and local guidelines provide information on infectiology and resistance patterns [66](#page=66). * **Practical resources:** * **Formularies:** These are guidelines specific to a country, region, hospital, or general practice. Examples include the "Formularium for the Belgian ambulant practice" (BAPCOC) and local hospital formularies [66](#page=66). #### 4.3.2 Antibiotic "cheat sheets" and cross-tables These tools, often tailored to different levels of medical training, help in selecting antibiotics. A "cheat sheet" for an antibiotic would typically include [67](#page=67) [68](#page=68): * Mechanism of action [67](#page=67) [69](#page=69). * Spectrum of activity [67](#page=67) [69](#page=69). * Effect on flora [67](#page=67) [69](#page=69). * PK/PD properties [67](#page=67) [69](#page=69). * Laboratory resistance determination and interpretation [67](#page=67) [69](#page=69). * Resistance rates [67](#page=67) [69](#page=69). * Clinical syndromes where it is used [67](#page=67). * Side effects and toxicity [67](#page=67). * Interactions [67](#page=67). * Standard dosage for key representatives [67](#page=67). * Influence of patient characteristics and comorbidities [67](#page=67). * Societal considerations (cost, ease of use, toxicity profile) [67](#page=67). * IV administration policies [67](#page=67). * Possibility of level determination [67](#page=67). **Cross-tables** provide a quick overview of antibiotic coverage against different bacterial groups. For example, a cross-table might list various antibiotics and indicate their effectiveness (e.g., using + signs) against specific bacteria like *Streptococcus* (and *pneumococcus*), *Staphylococcus*, *E. coli*, *Pseudomonas aeruginosa*, and anaerobes [68](#page=68). **Example Case Study - Acute Otitis Media** [69](#page=69) [70](#page=70) [71](#page=71). * **Case:** A 6-year-old child presents with ear pain for 5 days, reduced activity, and a sick appearance [69](#page=69). * **Considerations:** Acute otitis media is often viral, and most children improve without antibiotics within 3 days. Antibiotics are generally not indicated (GRADE 1A) [70](#page=70). * **Indications for antibiotics:** Oral antibiotics may shorten pain and fever duration in specific situations, such as bilateral acute otitis media in children under 2 years, or with a perforated eardrum with discharge. They are also indicated in those at higher risk for complications, with severe general illness, or if there's no improvement after 3 days of paracetamol [70](#page=70). * **First-line antibiotic:** Amoxicillin is the first choice for acute otitis media [71](#page=71). * **Pediatric dose:** 75-100 mg/kg per day in 3 divided doses for 5 days [71](#page=71). * **Adult dose:** 3 times 1 gram per day for 5 days [71](#page=71). * **Cheat Sheet content for Amoxicillin:** Would detail its mechanism, spectrum, PK/PD, etc. [71](#page=71). **Example Case Study - COPD Exacerbation** [72](#page=72). * **Case:** A 65-year-old patient with COPD experiences increasing symptoms for one week, with fever up to 39°C, necessitating antibiotic initiation during a home visit. The same question arises for a patient with an IgE-mediated penicillin allergy [72](#page=72). **Example Case Study - Erysipelas** [73](#page=73). * **Case:** A 40-year-old woman sustained a minor leg wound while gardening. Two days later, she presents with fever and erysipelas. The question of antibiotic choice also arises if *Methicillin-resistant Staphylococcus aureus* (MRSA) is cultured from the wound [73](#page=73). **Example Case Study - Gonococcal Urethritis** [74](#page=74). * **Case:** A 23-year-old student presents with purulent urethral discharge one week after unprotected anal sex, clinically diagnosed as gonococcal urethritis [74](#page=74). **Example Case Study - Chlamydia Trachomatis Vaginitis** [75](#page=75). * **Case:** A 22-year-old student presents with unusual vaginal discharge and pelvic pain one week after unprotected vaginal sex. PCR confirms *Chlamydia trachomatis*. The same question applies if *Trichomonas vaginalis* is found [75](#page=75). --- ## Common mistakes to avoid - Review all topics thoroughly before exams - Pay attention to formulas and key definitions - Practice with examples provided in each section - Don't memorize without understanding the underlying concepts

| Term | Definition | |---|---| | Antibiotics | Medications that specifically inhibit the multiplication of microorganisms, primarily used for the treatment of bacterial infections. They possess selective toxicity, meaning they are toxic to bacteria but not to human cells. | | Virostatica | Medications used to treat viral infections by inhibiting viral replication. | | Selective Toxicity | The principle that a drug should be toxic to the targeted pathogen (e.g., bacteria) but have minimal toxicity to the host (human cells). | | Antimicrobial Therapy | The use of antimicrobial agents to treat infections caused by microorganisms. | | Pharmacokinetics (PK) | The study of how the body absorbs, distributes, metabolizes, and excretes a drug. This influences the concentration of the drug at the site of infection over time. | | Pharmacodynamics (PD) | The study of the biochemical and physiological effects of drugs and their mechanisms of action. This relates the drug concentration to its biological effect on the microorganism. | | Minimum Inhibitory Concentration (MIC) | The lowest concentration of an antibiotic that inhibits the visible growth of a microorganism after overnight incubation in broth or agar. | | Dilution Antibiogram | A laboratory test that determines the MIC of an antibiotic against a specific bacterium by serial dilution of the antibiotic in a growth medium. | | Diffusion Antibiogram | A laboratory test where antibiotic-impregnated discs are placed on an agar plate inoculated with bacteria. The diameter of the zone of inhibition around the disc indicates the susceptibility of the bacteria to the antibiotic. | | Clinical Breakpoint | The in vitro susceptibility level of a microorganism to an antibiotic that separates susceptible (clinically useful) isolates from resistant (clinically not useful) isolates. It is determined based on animal and human studies and is linked to standard dosing regimens. | | Time above MIC (T > MIC) | A pharmacokinetic/pharmacodynamic (PK/PD) parameter representing the duration for which the antibiotic concentration remains above the MIC. This is a key predictor of efficacy for time-dependent antibiotics like beta-lactams. | | Cmax/MIC Ratio | A PK/PD parameter that relates the peak serum concentration (Cmax) of an antibiotic to its MIC. This is an important predictor of efficacy for concentration-dependent antibiotics like aminoglycosides. | | AUC/MIC Ratio | A PK/PD parameter representing the ratio of the area under the concentration-time curve (AUC) to the MIC. This is a valuable predictor of efficacy for antibiotics exhibiting mixed PK/PD characteristics, such as fluoroquinolones and macrolides. | | Peptidoglycan | A major component of the bacterial cell wall, essential for maintaining cell integrity. Many antibiotics target its synthesis. | | Beta-lactam Antibiotics | A broad class of antibiotics characterized by a beta-lactam ring structure, which inhibit bacterial cell wall synthesis by targeting penicillin-binding proteins (PBPs). Examples include penicillins, cephalosporins, and carbapenems. | | Beta-lactamase | An enzyme produced by some bacteria that inactivates beta-lactam antibiotics by breaking the beta-lactam ring. | | Beta-lactamase Inhibitors | Compounds (e.g., clavulanic acid) that inhibit the activity of beta-lactamase enzymes, thereby protecting beta-lactam antibiotics from degradation and extending their spectrum of activity. | | Glycopeptides | A class of antibiotics, such as vancomycin, that inhibit bacterial cell wall synthesis by binding to the peptide side chains of peptidoglycan precursors. They are primarily active against Gram-positive bacteria. | | Aminoglycosides | A class of antibiotics (e.g., gentamicin, amikacin) that inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit. They are typically bactericidal and often used for serious Gram-negative infections. | | Macrolides | A class of antibiotics (e.g., erythromycin, azithromycin, clarithromycin) that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit. They have a broad spectrum and are effective against many Gram-positive bacteria, atypical pathogens, and some Gram-negative bacteria. | | Tetracyclines | A class of antibiotics (e.g., doxycycline) that inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit and preventing the binding of tRNA. They have a broad spectrum of activity. | | Quinolones (Fluoroquinolones) | A class of synthetic antibiotics (e.g., ciprofloxacin, levofloxacin) that inhibit bacterial DNA replication by targeting DNA gyrase and topoisomerase IV. They have broad-spectrum activity. | | Metronidazole | An antibiotic effective against anaerobic bacteria and certain protozoa. It is activated in anaerobic conditions to form toxic metabolites that damage bacterial DNA. | | Sulfonamides | A class of synthetic antimicrobial drugs that inhibit bacterial folic acid synthesis by acting as competitive inhibitors of dihydropteroate synthase. | | Trimethoprim | An antimicrobial drug that inhibits bacterial folic acid synthesis by targeting dihydrofolate reductase. Often used in combination with sulfonamides (cotrimoxazole). | | Cotrimoxazole | A combination drug containing trimethoprim and sulfamethoxazole, which work synergistically to inhibit bacterial folic acid synthesis. | | Antibiotic Resistance | The ability of bacteria to withstand the effects of an antibiotic. This can be due to genetic mutations or acquisition of resistance genes from other bacteria. | | Horizontal Gene Transfer | The transfer of genetic material between organisms other than by vertical transmission (from parent to offspring). In bacteria, this can occur via conjugation, transformation, or transduction, leading to the spread of antibiotic resistance genes. | | Plasmid | A small, circular DNA molecule that replicates independently of the bacterial chromosome. Plasmids often carry genes for antibiotic resistance. | | Conjugation | A mechanism of horizontal gene transfer where genetic material is transferred from one bacterium to another through direct cell-to-cell contact, often mediated by plasmids. | | Transduction | A mechanism of horizontal gene transfer where bacterial DNA is transferred from one bacterium to another by a bacteriophage (a virus that infects bacteria). | | Transformation | A mechanism of horizontal gene transfer where a bacterium takes up naked DNA from its environment. | | Persisters | A subpopulation of bacteria within a larger population that are phenotypically tolerant to antibiotics. They are not resistant mutants but survive antibiotic exposure due to altered physiological states and can regrow when the antibiotic is removed. | | Prophylactic Use | The administration of antimicrobial agents to prevent infection before exposure or before the development of symptoms. | | Empiric Therapy | Antibiotic treatment initiated based on the most likely causative organism and its presumed susceptibility, without waiting for laboratory culture and sensitivity results. | | De-escalation | The process of switching from a broad-spectrum antibiotic to a narrower-spectrum antibiotic once the causative pathogen and its sensitivities are identified, aiming to reduce collateral damage to the microbiome and lower resistance pressure. | | Resistance Mutants | Bacteria that have undergone genetic mutations leading to heritable resistance to an antibiotic. These mutations are typically irreversible and detected by laboratory tests. | | Biofilm | A community of microorganisms encased in a self-produced matrix of extracellular polymeric substances, adhering to a surface. Biofilms can confer increased tolerance and resistance to antibiotics. | | Quorum Sensing | A cell-to-cell communication system in bacteria that regulates gene expression, including the formation of biofilms and the production of virulence factors. | | MRSA (Methicillin-Resistant Staphylococcus aureus) | A strain of Staphylococcus aureus that has developed resistance to methicillin and other beta-lactam antibiotics. | | ESBL (Extended-Spectrum Beta-Lactamase) | Beta-lactamase enzymes with a broader spectrum of activity, capable of hydrolyzing a wider range of beta-lactam antibiotics, including third-generation cephalosporins. | | Carbapenemase | A type of beta-lactamase enzyme that can hydrolyze carbapenem antibiotics, which are often used as a last resort for multidrug-resistant bacterial infections. | | Antiretroviral Therapy (ART) | A combination of medications used to treat HIV infection. It aims to suppress viral replication, prevent disease progression, and reduce transmission. | | cART (Combination Antiretroviral Therapy) | A specific type of ART that uses a cocktail of drugs from different classes to effectively manage HIV infection. | | Drug Resistance in Viruses | The ability of viruses to withstand the effects of antiviral medications, often due to mutations in viral genes that alter the target of the drug. | | Acyclovir | An antiviral medication used to treat herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. It works by inhibiting viral DNA synthesis. | | Valacyclovir | A prodrug of acyclovir that is converted to acyclovir in the body, offering improved bioavailability. | | Neuraminidase (NA) Inhibitors | Antiviral drugs (e.g., oseltamivir, zanamivir) that inhibit the activity of neuraminidase, an enzyme on the surface of influenza viruses essential for their release from infected cells. | | Reverse Transcriptase Inhibitors | A class of antiretroviral drugs used in HIV treatment that block the action of reverse transcriptase, an enzyme essential for HIV replication. | | Protease Inhibitors | A class of antiretroviral drugs used in HIV treatment that block the action of protease, an enzyme essential for the maturation of new virus particles. |