Week 14 - pharma(Ant-bacterial and anti-infective drugs)

Anti-infective drugs

— The first development during the mid-1900s, was a major milestone in medicine

— In the last 50 years, pharmacologists have worked to keep pace with microbes that rapidly develop resistance to drugs

— General term for any drug effective against pathogens(disease-causing organisms)

Pathogens

— Microbes capable of causing disease

Pathogenicity

— Ability of an organism to cause infection

— Depends on the ability to evade or overcome body defenses

— Of millions of microbes, only a few are harmful to human health

Virulence

— Degree of pathogenicity

— A highly virulent microbe can cause disease even in minute numbers

Invasiveness

— Ability to grow extremely rapidly

— Causes direct tissue damage by sheer numbers

— Immune response may take a week or more → rapid growth can overwhelm defenses

Toxin production

— Some bacteria produce toxins(poisonous substances)

— Even small amounts can disrupt normal cellular activity

— In extreme cases, toxins may cause death

Gram staining method

— Determines ability of bacterial cell all to retain a purple stain using crystal violet(or methylene blue substitute)

Bacterial toxins and resistance

— Bacteria produces toxins that cause cell lysis (cell breakdown)

Broad-spectrum antibiotics

— Used when culture/sensitivity testing is not possible (e.g, source unknown or patient too sick to wait)

— Interfere with biochemical reactions common to many organisms

— Often given at the beginning of treatment until exact organism and sensitivity are known

— Because of their wide range of effects, they are frequently associated with adverse effects

Selective toxicity and risks — Antibiotic

— Human cells share many properties with bacterial cells → antibiotics may damage human cells too.

— No antibiotic is perfectly safe

— Clinicians aim: strike foreign cells with little/no effect on human cells

Synergistic antibiotics

— Sometimes antibiotics are given in combination

— Combined effect > effect of each drug individually

— Allows lower doses of each drug → reduces adverse effect

Prophylaxis — Antibiotics

— Prevention

— Antibiotics may be used to prevent infection in high-risk situations

— Usually a large, one-time dose is given to destroy bacteria immediately and prevent serious infection

Antibacterials/antimicrobials

— Inhibit bacterial growth or kill bacteria and other microorganisms (viruses, fungi, protozoa, rickettsiae)

1928

— Alexander fleming discovered penicillin from penicillium notatum

1939

— Howard florey purified penicillin for commercial use

1945

— Penicillin marketed after use in World war II

Pharmacokinetics — Antibacterial`

— Must penetrate bacterial cell wall and bind to target sites

— Longer half-life → greater concentration at binding site → less frequent dosing

— Most are not highly protein bound

— Steady state occurs after 4-5 half lives

— Drug elimination after 7 half-lives

Pharmacodynamics — Antibacterial

— Effectiveness depends on drug concentration at site and exposure time

— Goal: achieve minimum effective concentration to halt bacterial growth

— Many antibacterials are bactericidal when concentration remains above MEC during dosing interval

Primary goal of antimicrobial therapy

— Assist the body’s defenses in eliminating a pathogen

Bactericidal drugs — Antimicrobial

— Assist the body’s defenses in eliminating a pathogen

Bacteriostatic drugs — Antimicrobial

— Slow bacterial growth, allowing natural defenses to eliminate microorganisms

Prophylactic Use (Chemoprophylaxis)

— Antibiotics sometimes given to prevent infection

Narrow-spectrum antibiotics

— Effective against smaller group or specific species

— Causes fewer side effects because they spare normal host flora

Superinfections

— Secondary infections caused when normal host flora are destroyed

—Host flora normally inhabits: skin, respiratory tract, genitourinary tract, intestines

— They protect by producing antibacterial substances and competing with pathogens

Penicillins

— First mass-produced antibiotic

— Quickly became a miracle drug, preventing thousands of death from infections

— Kill bacteria by disrupting cell walls

— Binding weakens the wall → water enters → cell burst and dies

— Most effective against gram-positive bacteria

Penicillinase-resistant penicillins

— Also called anti-staphylococcal penicillins

— Examples: oxacillin, dicloxacillin

Broad-spectrum penicillins (aminopenicillins)

— effective against wide range of microorganisms

— Commonly prescribed for sinus, upper respiratory, and genitourinary infections

— Examples: ampicillin (Principen), amoxicillin (Amoxil, Trimox)

Extended-spectrum penicillins

— Effective against more species(Enterobacter, klebsiella, bacteroides fragilis)

— Primary advantage: activity against Pseudonomas aeruginosa(Major cause of HAIs)

— Example: piperacillin

Beta-lactamase inhibitor combinations

— Protect penicillin from destruction, extend spectrum

Augmentin

— Amoxicillin + clavulanate

Timentin

— Ticarcillin + clavulanate

Unasyn

— Ampicillin + sulbactam

Zosyn

— Piperacillin + tazobactam

Cephalosporins

— Isolated shortly after penicillins → now the largest antibiotic class

— Contain a beta-lactam ring → responsible for antimicrobial activity

— Primary use: gram-negative infection and for patients ho cannot tolerate penicillins

— Bactericidal: attach to penicillin-binding proteins (PBPs) → inhibit bacterial cell-wall synthesis.

First-generation — Cephalosporins

—Most effective against gram-positive organisms (staphylococci, streptococci)

— Sometimes drugs of choice of these infections

— Resistant bacteria producing beta-lactamase usually unaffected

Second generation — Cephalosporins

— More potent, more resistant to beta lactamase

— Broader spectrum against gram-negative organisms

— Largely replaced by third-generation agents

Third generation — Cephalosporins

— Even broader spectrum against gram-negative bacteria

— Longer duration of action, resistant to beta-lactamase

Fourth generation — Cephalosporins

— Effective against organism resistant to earlier cephalosporins

— Can enter cerebrospinal fluid → treat CNS infection

Fifth generation — Cephalosporins

— Designed to be effective against MRSA infections

Tetracyclines

— Were extracted from streptomyces soil microorganisms in 1948

— Effective against many gram-negative and gram-positive organisms

— Have one of the broadest spectrums of any antibiotic class

— Inhibit bacterial protein synthesis

— Bind to bacterial ribosomes

— Slow microbial growth → bacteriostatic effect (stop growth rather than kill directly

— Rocky mountain potted fever, Typhus, cholera, lyme disease, peptic ulcers cause by H. pylori, chlamidial infections

Doxycycline and minocycline

— Longer duration of action

— More lipid soluble → can enter CSF

Tigecycline (tygacil)

— Newest agent

— Indicated for drug-resistant intra-abdominal infections and complicated skin/skin-structure infections

— Administered by IV infusion

— Adverse infection: Severe nausea and vomiting

Macrolides

— Considered safe alternatives to penicillin, though drugs of choice for relatively few infections

— Newer ones are synthetic derivatives of erythromycin with improved properties

— Effective against most gram-positive and many gram-negative species.

— Active against intracellular bacteria (Listeria, Chlamydia, Neisseria, Legionella).

Macrolides — Clarithromycin

Peptic ulcer disease (H. pylori)

Macrolides — Azithromycin

— Extended half-life, 5-day course(vs. 10 days for most antibiotics); single dose effective against N. gonorrhoeae

Macrolides — Fidaxomicin

— 2011

— Specifically for C. difficile infections; remains in GI tract, not absorbed systematically

Fidaxomicin — Macrolides

— Should be reserved for C.difficile only to prevent resistance

Aminoglycosides

— More toxic than other antibiotic classes, but important for treating Aerobic gram-negative bacteria, Mycobacteria, Some protozoa

— bactericidal → inhibit bacterial protein synthesis.

— Reserved for serious systemic infections caused by aerobic gram-negative organisms: E. coli, Serratia, Proteus, Klebsiella, Pseudomonas

— Sometimes combined with penicillin, cephalosporin, or vancomycin for enterococcal infections.

Vancomycin

— a potent glycopeptide antibiotic used primarily to treat serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus(MRSA) and Clostridioides difficile

Streptomycin — Aminoglycosides

— Now restricted mainly to tuberculosis due to resistance

Fluoroquinolones

— Usually reserved for UTIs due to toxicity

— Newer ones have a broad spectrum of activity.

— Bactericidal → inhibit DNA synthesis.

— active against gram-negative pathogens.

— Newer generations → more effective against gram-positive microbes (staphylococci, streptococci, enterococci)

Nalidixic acid

— First drug in fluoroquinolones

— Nalidixic acid (NegGram), FDAapproved in 1962 → narrow spectrum, mainly for UTIs.

Moxifloxacin

— Effective against anaerobes

Ciprofloxacin

— Drug of choice for postexposure prophylaxis of: Bacillus anthracis (anthrax), Yersinia pestis(plague), Francisella tularensis(tularemia), Brucella melitensis(brucellosis)

Gatifloxacin and besifloxacin

— Available only as eye drops for external eye infections

Sulfonamides

— Older drugs (used for over 70 years)

— Use has declined but still useful for susceptible UTIs

— Wide spectrum: gram-positive and gram-negative bacteria

— Bacteriostatic (inhibit growth, not directly kill).

— Suppress bacterial growth by inhibiting folic acid synthesis.

— Sometimes called folic acid inhibitors

— Not first choice in high-resistance communities unless confirmed by C&S testing.