5.1 Antibiotics
6 min read•august 20, 2024
Antibiotics are powerful drugs that fight bacterial infections. They come in various classes, each with unique mechanisms for attacking bacteria. Understanding how antibiotics work, their structure-activity relationships, and resistance mechanisms is crucial for effective treatment.
Pharmacokinetics, side effects, and drug interactions play key roles in antibiotic use. Proper clinical application, including dosage and administration, is vital. As bacteria evolve resistance, developing new antibiotics and using existing ones rationally becomes increasingly important for public health.
Classes of antibiotics
- Antibiotics are classified based on their chemical structure, mechanism of action, and spectrum of activity
- Major classes include beta-lactams (, ), , , , , and
- Each class has unique properties that determine their effectiveness against specific types of bacteria and their potential side effects
Mechanisms of action
Inhibition of cell wall synthesis
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- Antibiotics like beta-lactams (penicillins, cephalosporins) and glycopeptides (vancomycin) interfere with the synthesis of bacterial cell walls
- They inhibit enzymes involved in peptidoglycan cross-linking, leading to weakened cell walls and bacterial lysis
- Effective against gram-positive bacteria and some gram-negative bacteria
Disruption of cell membrane
- Polymyxins (colistin) and daptomycin act on the bacterial cell membrane
- They disrupt the integrity of the cell membrane, causing leakage of cellular contents and cell death
- Primarily active against gram-negative bacteria (polymyxins) or gram-positive bacteria (daptomycin)
Inhibition of protein synthesis
- Antibiotics like aminoglycosides, tetracyclines, macrolides, and chloramphenicol inhibit bacterial protein synthesis
- They bind to ribosomes (30S or 50S subunits) and interfere with various stages of translation
- Effective against a wide range of gram-positive and gram-negative bacteria
Inhibition of nucleic acid synthesis
- Quinolones () and rifamycins (rifampin) inhibit bacterial DNA replication and transcription
- Quinolones target DNA gyrase and topoisomerase IV, while rifamycins inhibit RNA polymerase
- Broad-spectrum activity against both gram-positive and gram-negative bacteria
Antimetabolite activity
- Sulfonamides and trimethoprim are antimetabolites that interfere with folic acid synthesis in bacteria
- They inhibit enzymes involved in the production of tetrahydrofolic acid, a cofactor essential for nucleic acid synthesis
- Effective against a variety of gram-positive and gram-negative bacteria
Structure-activity relationships
Structural features for activity
- Antibiotics within a class share common structural features that are essential for their activity
- Beta-lactams have a four-membered beta-lactam ring, which is crucial for binding to penicillin-binding proteins (PBPs)
- Aminoglycosides contain amino sugars linked by glycosidic bonds, enabling binding to the 30S ribosomal subunit
- Quinolones have a bicyclic aromatic core with a carboxylic acid group, allowing interaction with DNA gyrase and topoisomerase IV
Modifications for improved properties
- Structural modifications can enhance the properties of antibiotics, such as spectrum of activity, pharmacokinetics, and stability
- Addition of side chains to the beta-lactam core (ampicillin, ) improves activity against gram-negative bacteria
- Esterification of macrolides (azithromycin) improves acid stability and pharmacokinetics
- Fluorination of quinolones (ciprofloxacin) enhances potency and broadens the spectrum of activity
Resistance mechanisms
Enzymatic inactivation
- Bacteria produce enzymes that modify or degrade antibiotics, rendering them ineffective
- Beta-lactamases hydrolyze the beta-lactam ring of penicillins and cephalosporins
- Aminoglycoside-modifying enzymes (acetyltransferases, phosphotransferases) alter the structure of aminoglycosides
Efflux pumps
- are membrane proteins that actively expel antibiotics from the bacterial cell
- They reduce the intracellular concentration of antibiotics, preventing them from reaching their targets
- Efflux pumps can confer resistance to multiple classes of antibiotics (multidrug resistance)
Target modification
- Bacteria can modify the target sites of antibiotics, reducing their binding affinity
- Alterations in penicillin-binding proteins (PBPs) decrease the binding of beta-lactams
- Methylation of the 23S rRNA prevents the binding of macrolides to the 50S ribosomal subunit
- Mutations in DNA gyrase and topoisomerase IV reduce the binding of quinolones
Altered permeability
- Changes in bacterial cell envelope permeability can limit the entry of antibiotics into the cell
- Gram-negative bacteria have an outer membrane that acts as a barrier to hydrophobic antibiotics
- Mutations in porin proteins can reduce the influx of antibiotics like beta-lactams and quinolones
Pharmacokinetics of antibiotics
Absorption and bioavailability
- Antibiotics can be administered orally, parenterally (IV, IM), or topically
- Oral absorption depends on factors like solubility, stability in the GI tract, and efflux transporters
- Bioavailability varies among antibiotics (high for fluoroquinolones, variable for beta-lactams)
Distribution in body
- Antibiotics distribute differently in the body based on their physicochemical properties
- Lipophilic antibiotics (macrolides, fluoroquinolones) achieve good tissue penetration
- Hydrophilic antibiotics (beta-lactams, aminoglycosides) primarily distribute in extracellular fluids
- Some antibiotics (tetracyclines) can cross the blood-brain barrier and enter the CNS
Metabolism and elimination
- Antibiotics undergo metabolism in the liver, kidneys, or other tissues
- Beta-lactams are primarily eliminated unchanged by renal excretion
- Macrolides and quinolones undergo hepatic metabolism and biliary excretion
- Dosage adjustments may be necessary for patients with renal or hepatic impairment
Adverse effects and toxicity
Common side effects
- Gastrointestinal disturbances (nausea, vomiting, diarrhea) are common with many antibiotics
- Antibiotics can disrupt the normal gut flora, leading to Clostridium difficile infection
- Some antibiotics (tetracyclines) can cause photosensitivity reactions
Allergic reactions
- Beta-lactam antibiotics (penicillins, cephalosporins) are the most common cause of drug allergies
- Allergic reactions range from mild rashes to severe anaphylaxis
- Cross-reactivity can occur between penicillins and cephalosporins
Organ-specific toxicities
- Aminoglycosides can cause nephrotoxicity and ototoxicity (hearing loss)
- Tetracyclines can cause tooth discoloration in children and hepatotoxicity in pregnant women
- Chloramphenicol is associated with bone marrow suppression and aplastic anemia
Drug interactions
Synergistic interactions
- Combination therapy with antibiotics can result in synergistic effects, enhancing their effectiveness
- Beta-lactams and aminoglycosides exhibit synergy against gram-negative bacteria
- Trimethoprim and sulfamethoxazole (co-trimoxazole) synergistically inhibit sequential steps in folic acid synthesis
Antagonistic interactions
- Some antibiotics can antagonize the activity of others when used together
- Bacteriostatic antibiotics (tetracyclines) can antagonize the effects of bactericidal antibiotics (beta-lactams)
- Calcium supplements and antacids can reduce the absorption of tetracyclines and quinolones
Clinical applications
Spectrum of activity
- Narrow-spectrum antibiotics (penicillin G) are active against a limited range of bacteria
- Broad-spectrum antibiotics (fluoroquinolones, tetracyclines) are effective against a wide range of gram-positive and gram-negative bacteria
- The choice of antibiotic depends on the suspected or confirmed pathogen and its susceptibility profile
Indications for use
- Antibiotics are used for the treatment of bacterial infections, including respiratory tract infections, urinary tract infections, skin and soft tissue infections, and sepsis
- Prophylactic use of antibiotics is indicated in certain surgical procedures and for patients at high risk of infection (immunocompromised)
Dosage and administration
- Antibiotic dosages are based on factors like the patient's age, weight, renal function, and the severity of the infection
- Administration routes (oral, IV, IM) are chosen based on the patient's condition and the bioavailability of the antibiotic
- Duration of therapy varies depending on the type of infection and the patient's response to treatment
Development of new antibiotics
Strategies for discovery
- of natural products (soil bacteria, fungi) for antimicrobial activity
- Modification of existing antibiotics to improve their properties (semi-synthetic derivatives)
- Rational drug design based on the structure of targets (PBPs, ribosomes) and molecular modeling
Challenges in development
- Declining discovery rate of new antibiotic classes since the 1960s
- High cost and long timeline for drug development (10-15 years from discovery to approval)
- Regulatory hurdles and limited economic incentives for pharmaceutical companies
Overcoming resistance
- Developing antibiotics with novel mechanisms of action that bypass existing resistance mechanisms
- Combining antibiotics with inhibitors of resistance enzymes ( inhibitors)
- Exploring alternative therapeutic approaches (phage therapy, antimicrobial peptides, immunomodulation)
Rational use of antibiotics
Appropriate prescribing practices
- Prescribing antibiotics only when clinically indicated, based on evidence-based guidelines
- Selecting the most appropriate antibiotic, dose, and duration based on the patient's condition and local resistance patterns
- Avoiding the use of broad-spectrum antibiotics when narrow-spectrum agents are effective
Prevention of misuse
- Educating healthcare providers and the public about the judicious use of antibiotics
- Implementing programs in hospitals and healthcare facilities
- Restricting the use of antibiotics in agriculture and animal husbandry to reduce the development of resistance
Antimicrobial stewardship programs
- Multidisciplinary efforts to optimize antibiotic use and improve patient outcomes
- Key strategies include prospective audit and feedback, formulary restriction, and guidelines for empiric therapy
- Monitoring antibiotic consumption and resistance patterns to guide stewardship interventions
Key Terms to Review (26)
Aminoglycosides: Aminoglycosides are a class of antibiotics that are primarily effective against aerobic Gram-negative bacteria. They work by inhibiting protein synthesis in bacterial cells, leading to cell death, and are often used to treat severe infections caused by susceptible organisms, particularly in hospital settings. Due to their unique mechanism of action and side effects, aminoglycosides require careful monitoring during therapy.
Amoxicillin: Amoxicillin is a widely used antibiotic that belongs to the penicillin group of drugs, primarily effective against a variety of bacterial infections. It works by inhibiting bacterial cell wall synthesis, leading to cell lysis and death. Amoxicillin is commonly prescribed for infections like pneumonia, bronchitis, and infections of the ear, nose, and throat, making it a cornerstone in the treatment of bacterial infections.
Antibiotic stewardship: Antibiotic stewardship refers to a set of coordinated strategies designed to improve and measure the appropriate use of antibiotics. It aims to promote the optimal treatment of infections while minimizing the adverse effects associated with antibiotic misuse, such as resistance. This practice is crucial in preserving the effectiveness of antibiotics and ensuring patient safety.
Antimetabolite activity: Antimetabolite activity refers to the mechanism by which certain compounds interfere with metabolic processes by mimicking the structure of naturally occurring metabolites. This disruption can inhibit the synthesis of nucleic acids or other essential biomolecules, ultimately affecting cell growth and replication. Antimetabolites are commonly used in antibiotic treatments as they target the metabolism of bacteria, leading to their death or growth inhibition.
Bactericidal vs. bacteriostatic: Bactericidal and bacteriostatic refer to two different modes of action of antimicrobial agents against bacteria. Bactericidal agents kill bacteria directly, leading to a decrease in the total number of viable organisms, while bacteriostatic agents inhibit bacterial growth and reproduction without directly killing the bacteria, allowing the host's immune system to eliminate the infection. Understanding these differences is crucial for effective treatment strategies and selecting appropriate antibiotics.
Beta-lactamase: Beta-lactamase is an enzyme produced by certain bacteria that provides resistance to beta-lactam antibiotics, such as penicillin and cephalosporins. By breaking down the beta-lactam ring structure of these antibiotics, beta-lactamases render them ineffective, posing a significant challenge in treating bacterial infections.
Broth dilution method: The broth dilution method is a laboratory technique used to determine the minimum inhibitory concentration (MIC) of antimicrobial agents against specific microorganisms. This method involves diluting an antibiotic in a liquid growth medium and adding the target bacteria to each dilution to observe growth inhibition. It's a standardized way to evaluate the effectiveness of antibiotics, helping to inform treatment decisions.
Cephalosporins: Cephalosporins are a class of broad-spectrum antibiotics derived from the mold Cephalosporium acremonium, used to treat a variety of bacterial infections. They are structurally related to penicillins and work by inhibiting bacterial cell wall synthesis, making them effective against both Gram-positive and Gram-negative bacteria. Their ability to target a wide range of bacteria, along with their varying generations that enhance efficacy and resistance to beta-lactamases, makes them important in modern medicine.
Ciprofloxacin: Ciprofloxacin is a broad-spectrum antibiotic belonging to the fluoroquinolone class, primarily used to treat a variety of bacterial infections. It works by inhibiting bacterial DNA gyrase and topoisomerase IV, enzymes crucial for DNA replication and repair, effectively stopping the growth of bacteria. Its ability to target a wide range of gram-negative and some gram-positive bacteria makes it a valuable medication in treating conditions such as urinary tract infections and respiratory tract infections.
Development of cephalosporins: The development of cephalosporins refers to the evolution of a class of antibiotics derived from the fungus Acremonium, which was initially discovered in the 1940s. These antibiotics were created to combat bacterial infections and have become crucial in medical treatments due to their broad-spectrum activity and effectiveness against resistant bacteria. Over time, various generations of cephalosporins have been developed, each with improved properties and expanded antibacterial coverage.
Discovery of penicillin: The discovery of penicillin marks a pivotal moment in medical history, as it was the first true antibiotic discovered and introduced for therapeutic use. Made by Alexander Fleming in 1928, penicillin revolutionized the treatment of bacterial infections, laying the foundation for modern antibiotics and changing the landscape of medicine forever.
Disk diffusion method: The disk diffusion method is a laboratory technique used to assess the effectiveness of antibiotics against specific bacteria. In this method, paper discs impregnated with antibiotics are placed on an agar plate inoculated with bacteria. The resulting zones of inhibition around the discs indicate how well each antibiotic can inhibit bacterial growth, providing crucial information for selecting appropriate antibiotic treatments.
Disruption of cell membrane: Disruption of the cell membrane refers to the impairment or breakdown of the protective barrier that surrounds a cell, leading to changes in permeability and potential loss of cellular integrity. This process is crucial in understanding how certain antibiotics function, as they target and compromise the membranes of bacteria, ultimately resulting in cell death or inhibited growth.
Efflux pumps: Efflux pumps are protein-based transport mechanisms found in bacterial cells that actively expel various substances, including antibiotics, out of the cell. These pumps play a critical role in antibiotic resistance by lowering the intracellular concentration of drugs, making them less effective at killing or inhibiting bacterial growth. The presence and activity of efflux pumps can significantly affect the efficacy of antibiotic treatment and the overall success of antimicrobial therapy.
FDA Approval: FDA approval is the process by which the U.S. Food and Drug Administration evaluates and authorizes new drugs and medical devices for public use. This rigorous process ensures that products meet safety, efficacy, and quality standards before they can be marketed. Approval is essential for antibiotics, central nervous system drugs, and targeted drug delivery systems as it assures healthcare providers and patients of their reliability and effectiveness in treating various conditions.
Glycopeptides: Glycopeptides are a class of antibiotics that are characterized by their glycosylated peptide structures, which make them effective against Gram-positive bacteria. These compounds disrupt bacterial cell wall synthesis by binding to the D-alanyl-D-alanine terminus of peptidoglycan precursors, ultimately leading to cell lysis. Glycopeptides are essential in treating serious infections caused by resistant bacteria such as Methicillin-resistant Staphylococcus aureus (MRSA).
Inhibition of cell wall synthesis: Inhibition of cell wall synthesis refers to the mechanism by which certain antibiotics disrupt the formation of the bacterial cell wall, ultimately leading to cell lysis and death. This is crucial for fighting bacterial infections, as it targets a structural feature unique to bacteria, allowing for selective toxicity without harming human cells. By interfering with the peptidoglycan layer or other components necessary for cell wall integrity, these antibiotics effectively weaken the bacteria's defenses against osmotic pressure.
Inhibition of nucleic acid synthesis: Inhibition of nucleic acid synthesis refers to the process by which certain agents interfere with the formation of nucleic acids, such as DNA and RNA, preventing microorganisms from replicating and producing essential proteins. This mechanism is vital in the development of various antibiotics that target bacterial growth by disrupting their genetic material's synthesis, thereby stopping infection and promoting recovery in patients.
Inhibition of protein synthesis: Inhibition of protein synthesis refers to the process by which certain compounds interfere with the cellular machinery responsible for producing proteins, ultimately leading to decreased or halted protein production. This mechanism is crucial for the action of various antibiotics and other therapeutic agents, as it can selectively target bacterial cells without affecting human cells. Understanding this term is key in studying how different substances, including polyketides, can disrupt essential biological processes in microorganisms.
Macrolides: Macrolides are a class of antibiotics characterized by their macrocyclic lactone ring structure, which allows them to inhibit bacterial protein synthesis. This group of antibiotics is primarily derived from natural sources, specifically from certain species of bacteria and fungi. Macrolides are effective against a variety of gram-positive and some gram-negative bacteria, making them valuable in treating infections.
Minimum inhibitory concentration: Minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial agent that prevents the visible growth of a microorganism after a specific period of incubation. Understanding MIC is crucial in determining the effectiveness of antibiotics and plays a key role in guiding treatment decisions for infections. The measurement of MIC helps in identifying the appropriate dosage required to effectively combat bacterial infections while minimizing potential side effects.
Penicillins: Penicillins are a group of antibiotics that are derived from Penicillium fungi, primarily used to treat bacterial infections. They work by inhibiting the synthesis of bacterial cell walls, making them effective against a wide range of gram-positive and some gram-negative bacteria. Their discovery in the early 20th century marked a significant breakthrough in medicine, leading to the development of various synthetic derivatives and an important class of antibiotics.
Quinolones: Quinolones are a class of synthetic antibiotics that target bacterial DNA replication by inhibiting the enzymes DNA gyrase and topoisomerase IV. They are particularly effective against a variety of Gram-negative and some Gram-positive bacteria, making them a valuable tool in treating bacterial infections, especially those caused by pathogens resistant to other antibiotics.
Screening: Screening refers to the systematic process of testing a large number of compounds or biological samples to identify those that exhibit desired biological activities or properties. This method is crucial in drug discovery, allowing researchers to quickly evaluate the potential effectiveness of various substances in treating diseases or targeting specific biological pathways, particularly in the development of antibiotics and combinatorial chemistry.
Structure-activity relationship: A structure-activity relationship (SAR) is the relationship between the chemical structure of a compound and its biological activity. Understanding SAR helps in identifying how changes in a molecule's structure can influence its effectiveness as a drug, guiding medicinal chemists in the design of more potent and selective compounds.
Tetracyclines: Tetracyclines are a class of broad-spectrum antibiotics that are derived from the soil bacterium Streptomyces. They are characterized by their ability to inhibit bacterial protein synthesis by binding to the ribosomal 30S subunit, making them effective against a wide range of gram-positive and gram-negative bacteria. This class of antibiotics is important for treating various infections and has also played a role in agricultural applications.