Antibiotic Resistance & Development

• Antimicrobial drugs are also known as antibiotics for NURS1059 in 2024-2025
• Understand the organism's structure by looking at Bacteria and Viruses to learn about antimicrobials
• The general MOA should give a guide to understand the basic way to kill the organism
• Understand how the medications work by linking drug names to MOA, purpose and adverse effects

Bacteria Structure Review

• Cell walls and capsules, with an emphasis on how MOA is key to bacterial structure

Cell Walls and Capsules

• Nearly all prokaryotes (bacteria) have a cell wall
• Cell walls provide physical protection and they prevent the cell from bursting in a hypotonic environment

Gram Staining

• Gram stain is used to identify bacteria cell walls
• Gram-positive bacteria have simpler cell walls containing peptidoglycan
• Gram-negative bacteria have less peptidoglycan and are more complex, more likely to cause disease
• Gram-negative contain outer membrane, peptidoglycan, and cytoplasmic membrane

Bacterial Capsules

• The cell wall of many bacteria is covered by a sticky capsule made of polysaccharides or protein
• Capsules help the bacteria adhere to their substrate or to other colony individuals
• They shield pathogenic bacteria from attacks by a host's immune system

ANTI-BACTERIAL AGENTS: Bactericidal vs Bacteriostatic

• Anti-microbial agents produce a "cidal" (killed; bactericidal, germicides) or "stasis" effect
• "Stasis" effect inhibits growth; bacteriostatic effect means growth limits or stops
• Sepsis = bacterial contamination
• Asepsis = the absence of significant contamination: necessary for surgery to minimize contamination

SOURCES OF ANTIBIOTICS: Natural, Semi-Synthetic and Synthetic

• Natural antibiotics are derived from fungal sources, and more toxic than synthetic antibiotics
• Organisms develop resistance faster to natural antimicrobials as they have been pre-exposed to these compounds in nature
• Semi-synthetic drugs were developed to decrease toxicity and increase effectiveness; they are partly natural, partly synthetic
• Synthetic drugs have an advantage in that the bacteria are not exposed to these compounds in their natural environment
• They are also designed to have greater effectiveness and less toxicity

STRUCTURE & FUNCTION (MOA)

• Antibiotics are classified based on their structure and/or function
• Structure refers to molecular structure
• β-Lactams contain a Beta-lactam ring
• Aminoglycosides vary only by side chains attached to basic structure
• Function is how the drug works, its mode of action
• There are 5 functional groups, all components or functions necessary for bacterial growth
• These indicate the "Target” of action for antibiotics in a bacteria

Classification by Chemical "Structure”

• Antibiotics are categorized into broad groups based on their chemical structures and MOA, including
• Penicillins, Sulphonamides, Cephalosporins, Carbapenems, Macrolides, Quinolones, Aminoglycosides, Tetracyclines

FUNCTION CLASSIFICATION: MOA

• The five functional groups that cover most antibiotics classify bacteria by how to kill the organism
• These groups classify by MOA
• Inhibitors of cell wall synthesis
• Inhibitors of protein synthesis
• Inhibitors of membrane function
• Anti-metabolites
• Inhibitors of nucleic acid synthesis

FUNCTION CLASSIFICATION: Inside vs Outside

• Outside functions in antimicrobial agents relate to alteration of membranes and cell wall
• Membranes control passage of nutrients and wastes
• Damage from antimicrobial agents cause leakage which interferes with growth or causes death of the cell
• Inside functions relate to damage to proteins or nucleic acids
• Denaturation of proteins causes them to change shape and lose function
• DNA and RNA control the production of proteins, so this would be incompatible with life if disrupted

Inhibitors of Cell Wall Synthesis

• Classes include Beta-lactams, Glycopeptides, and Fosfomycins

Beta-lactams

• Beta-lactam ring is in its molecular structure
• Mode of action is it inhibits cell wall synthesis by the bacteria
• It is the most widely used group of antibiotics, with about 50 currently on the market
• Humans have no cell wall (no peptidoglycan), making this medication selective
• Most Beta-lactams are bactericidal, non-toxic, relatively inexpensive and are all organic acids, most are soluble in water
• Beta-lactam subclasses include Penicillins, Cephalosporins, Monobactams (Aztreonam) and Carbapenems (Penems)

Beta Lactams subgroups and names:

• Penicillin (Narrow Spectrum) Names: Pen G, Pen V, Cloxacillin, Oxacillin
• Penicillin (Extended Spectrum) Names: Amoxicillin, Ampicillin, Carboxypenicillins, Ureidopenicillins
• Carbapenems Names: Imipenem, Ertapenem
• Cephalosporins Names: Cefazolin, Cefaclor, Cefixime, Cefuroxime, Ceftriaxone
• Monobactams Name: Aztreonam
• B-lactamase Inhibitors Name: Tazobactam, Clavulanic acid
• Combinations Names: Amoxicillin/clavulanic acid, Imipenem/cilastatin, Piperacillin/tazobactam

Penicillin Sublcass

• The MOA of Penicillin is Bactericidal
• Penicillin interferes with the synthesis of bacterial cell walls in bacteria, but doesn't hinder growth of human cells
• The effect is that it weakens bacteria cell walls and destroys bacteria by osmotic lysis
• Most effective against bacteria that rapidly multiply
• Used to for treats otitis media, pneumonia, meningitis, UTI's, syphilis, gonorrhoea, prophylaxis for surgical or dental procedures
• Contraindications include Drug allergy
• Adverse effects such Diarrhea, Gl upset, Thrombophlebitis (IV penicillin), electrolyte imbalance, hyperkalemia & hypernatremia
• Contraindications and Cautions; NSAIDS, Methotrexate, Warfarin, Oral contraceptive

Cephalosporin Sublcass

• The MOA of Cephalosporin is Bactericidal
• Broad- spectrum, interferes with bacterial cell wall synthesis and bind to penicillin-binding proteins (PBP) in bacteria cell wall
• They have Four generations producing various actions
• The medication is semi-synthetic, produced by a fungus but synthetically altered to produce an antibiotic
• They are structurally and pharmacologically related to penicillin
• Can be used on Penicillin allergies (with caution), and can treat Urinary and Respiratory Tract Infections (UTI, RTI), abdominal infections, septicemia, meningitis, ear infections
• Adverse effects include diarrhea, secondary infection (oral thrush, yeast infections)
• Adverse events include thrombophlebitis, electrolyte imbalances (hyperkalemia, hypernatremia), renal (potentially nephrotoxic), liver
• Contraindications (Drug Interactions) include Absorption may be inhibited by Antacids, H2 antagonist, FE supplements, Alcohol

Carbapenum Subclass

• The MOA of is bactericidal
• It binds to penicillin-binding proteins that inhibits bacterial cell wall synthesis
• They act against gram-positive and gram-negative aerobic and anaerobic organisms
• It provides the broadest antibacterial spectra of any antibiotic to date; used for body cavity, connective tissue infections
• Examples: Meropenem, Ertapenem and imipenem
• The adverse events is, it may cause drug-induced seizure activity in a small percentage of clients

Glycopeptides Subclass

• The MOA is bactericidal
• They inhibit cell wall synthesis at a site different from the beta-lactams
• Resistance is largely restricted to nosocomial enterococcus faecium
• Glycopeptides are used for MRSA, endocarditis (gram + infections)

Vancomycin

• Inhibits bacterial cell wall by binding to a cell wall precursor and causing cell lysis, or it may also inhibit RNA synthesis
• Used primarily to treat serious infections that cannot be treated with less toxic agents such as penicillin or cephalosporins
• It can be useful in treating clostridium difficile, MRSA and only comes in IV formulations

Adverse effects of Vancomycin

• Adverse effects includes, Diarrhea (bloody), nausea, tinnitus, irritation at IV site, hearing loss, kidney damage, hypokalemia
• Red man syndrome is an infusion-related reaction which typically consists of pruritus, an erythematous rash that involves the face, neck, and upper torso.
• It can lead to shock, so the infusion is stopped while Benadryl is given and then restarted slowly

B-Lactam RESISTANT BACTERIA

• Bacteria may adapt to beta-lactams by reducing the access or binding affinity of the protein receptors or production of beta lactamase
• Natural and acquired resistance
• There has been a Problem in medicine since penicillin was discovered and immediately overprescribed
• Staphylococcus Aureus (MRSA) is a type

Anti-Metabolites

• Used primarily as a Bacteriostatic
• These are called folate pathway inhibitors or anti-metabolites
• Folic acid is essential for the synthesis of DNA and chromosomes in bacteria
• These drugs compete for folate binding sites and block DNA metabolism
• Humans do not synthesize folic acid

Sulfonamides

• Sulfonamides are bacteriostatic in low doses, and bactericidal in higher doses
• Introduced in the 1930's, sulfanilamide was the first effective systemic antimicrobial agent
• Sulfasalazine is another sulfonamide used for RA and ulcerative colitis
• Synthetic derivatives of sulfanilamide are commonly prescribed agents
• Achieve high levels of concentration in the kidneys that produce bactericidal effects
• Adverse Effects include Nausea, vomiting, anorexia, diarrhea, Rash, photosensitivity, Tinnitus, headache, dizziness, drowsiness, confusion
• Drug Interactions (Cautions): Oral hypoglycaemic , Enhances warfarin effect, Enhances Methotrexate toxicity
• Contraindications: Known cases of sulphonamides allergy, Pregnancy

Inhibitors of Protein Synthesis:

• Include the subclasses
• Aminoglycosides
• MLSK (Macrolides, lincosamides, streptogramins, ketolides)
• Tetracyclines
• Focus on the three most common medications.

AMINOGLYCOSIDES: Inhibit Protein Synthesis

• Bactericidal effects when binding to ribosomes and preventing protein synthesis in bacterial cells
• Usually used alongside other antibiotics
• Primarily effective in treating Gram (-) bacteria that cause UTI
• Or treating wound infections or septicaemia
• Also used as a Mainstay treatment of nosocomial infections
• They are reserved mainly for use in life-threatening infections, monitoring of drug levels required

Aminoglycosides subclasses

• Natural antibiotics include, Gentamicin, Kanamycin, Neomycin, Streptomycin, Tobramycin
• Semi-synthetic antibiotics includes, Amikacin, Netilmicin, Poorly absorbed when administered orally
• Adverse Effects involves Dizziness, headache, skin rash, fever, ototoxic, vertigo, reduced amount of Vit K
• Not favorable for long-term use due to possible renal failure
• Nephrotoxicity is reversable in some instances
• Contraindicated in pregnancy

MLSK

• Includes Macrolides, lincosamides, streptogramins, ketolides) antibiotics
• Bacteriostatic with possible bactericidal characteristics in high enough doses
• Four different classes of antibiotics which are unrelated in terms of structure, but which have a similar mode of action and spectrum of activity.

MACROLIDES

• MOA is Bacteriostatic, but may be bactericidal at in high doses
• They can Inhibit protein synthesis in susceptible bacteria that are RNA based
• They can fight bacteria that get into host cells as opposed to bloodstream
• Erythromycin, Azithromycin, and Clarithromycin are macrolides
• Used to treat GIT infections, and respiratory infections
• Can be used when beta lactams are contraindicated or cannot be used in STDs or soft tissue infections
• Adverse effects include, GI upset, Vertigo, rash, headache, QT prolongation, Hepatoxicity, hearing loss and tinnitus
• Avoid macrolides with pimozide, as death has resulted from combination drug therapy
• May interact with Drugs that compete with liver metabolism

LINCOSAMIDES

• Bacteriostatic MOA inhibits protein synthesis by binding to bacterial ribosomes and preventing peptide bond formation
• Lincosamides do not interfere with human cells
• Example drugs include Lincomycin and Clindamycin
• Clindamycin is a semi-synthetic derivative lincomycin

TETRACYCLINES: Inhibit Protein Synthesis

• The MOA is Bacteriostatic
• Inhibits protein synthesis in susceptible bacteria by binding to portion of ribosome to inhibit bacterial growth
• Natural tetracyclines; Demeclocycline, Oxytetracycline, and Tetracycline
• Semisynthetic tetracyclines; Doxycycline, and Minocycline
• Tetracyclines are effective againist a wide range of gram -ve and gram +ve bacteria
• Effective against acne in adolescents, Lyme Disease, Syphilis, Chlamydia, Mycoplasma, and some protozoa
• Adverse effects include superinfection, Gl upset, photosensitivity
• Cautions when interacting with Warfarin and Methoxyflurane
• Contraindicated with Children under 8 years (inhibits skeletal growth) and Pregnancy

Inhibitors of Nucleic Acid Synthesis and Quinolones

• Quinolones are Bactericidal antibiotics that interfere with DNA synthesis
• This is a shared process that may disrupt human cells
• There are 2 generations of this category of drugs
• First Generation Quinolones had a narrow spectrum and are not used very much and are more susceptible to bacterial resistance
• Gen 2 drugs are widely used, including Fluorquinolones

FLUROQUINOLONES

• FLUROQUINOLONES are Bactericidal
• MOA Inhibits and impair the replication of bacterial DNA
• Metabolized by liver and excreted by urine (except for Moxifloxacin)
• Used to treat, Fluoroquinolones (taken by mouth or by injection), for many types of bacterial infections
• Used to UTI's, soft tissue infections, and resp tract infections
• Adverse Effects may include, Gl upset, Headaches, dizziness, fever, and Tinnitus
• Adverse events includes, Tendonitis/Tendinopathy, Peripheral Neuropathy, CNS disorders, and Cardiac arrythmias
• Decreases (Interactions) absorption when used with antacids, calcium and/or magnesium
• Contraindications: Previous allergic reaction to the medications, certain cardiac disorders that predispose to arrhythmias or bradycardia
• QT-interval prolongation, uncorrected hypokalemia and hypomagnesemia
• Avoid when possible due to adverse events in pregnancy and children under 8 yrs

Fluroquinolones drugs of use

• Starred, Red font and bolded on previous slide
• Nalidixic and Cinoxacin are first generation
• Norfloxacin, Ciprofloxacin*, Ofloxacin*, Enoxacin are 2nd generation
• Levofloxacin, Sparfloxacin, Gatifloxacin, Gemifloxacin are 3rd generation
• Trovafloxacin, Moxifloxacin, Clinafloxacin, Sitafloxacin are 4th generation
• Only Ciprofloxacin, Norfloxacin, Ofloxacin (Gen 2), Levofloxacin (Gen 3) and Moxifloxacin are approved for uses in Canada

General Nursing Considerations for Antibiotics

• Take microbiology specimens before antibiotics are started
• Blood, Urine C/S (culture and sensitivity), or tissue swabs C/S (throat, wounds)
• Alert MD or NP to new C&S results
• Check allergies and be aware of cross-allergies and contribute to resistance- pt teaching?
• Ensure pre-op antibiotics are given as per protocol
• Screen for history of resistant infections
• Follow IV drug instructions, monitor IV site with Food and drug interactions

Explore the factors influencing antibiotic resistance development and the design of synthetic antimicrobials. Discusses evolutionary pressures on microbial populations. Analyzes the relationship between toxicity, effectiveness, and origin of antibiotics.