Bacteriology 6: Antiboiotics Flashcards
In dentistry, prophylactic agents on used on patients who:
before the patients procedure
-amoxicillin or clindamycin
-endocarditis risk
-facial fractures, compound skull fractures, and cerebral rhinorrhea
-immunocompromised
-recently received radiotherapy to the jaws
-prosthetic hip replacements, ventriculoatrial shunts, insertion of implants or bone grafting
Which is the antimicrobial drug of choice (DOC) for prophylaxis of infectious endocarditis?
Amoxicillin
clindamycin is used when patients are allergic to amoxicillin
Why would there be failure of antimicrobial therapy?
-inadequate drainage of pus/debriddement before administering prescription
-inappropriateness of the antimicrobial agent
-impaired host response
-poor patient compliance
-poor blood supply to tissues
-possibility of an unusual infection or that the disease has no infective etiology
-presence of local factors such as foreign bodies, which may act as reservoirs of reinfection
Mechanisms of action for folic acid metabolism medications
Medications:
-trimethoprim
-sulfonamides
Mechanisms of action for cell wall synthesis medication (8)
inhibit the PG’s
-vancomycin
-bacitracin
inhibit the crosslinking of PG’s (B-lactams)
-penicillins
-monobactams
-carbapenems
-cephalosporins
-cycloserine
Mechanisms of action for cell membrane medications
Polymyxins
Mechanisms of action for protein synthesis (30s inhibitors)
Prevent the tRNA from entering the A- site of the ribosome by blocking it (tetracycline) or Some change the shape of the 30S subunit, causing misreading of the codons (streptomycin)
-tetracyclines (Doxycyline, minocycline) intracellular pathogens
-Aminoglycosides (streptomycin, gentamicin)
bactericidal
Mechanisms of action for protein synthesis (50s inhibitors)
-erythromycin
-chloramphenicol
-clindamycin
Mechanisms of action for DNA-dependent RNA polymerase
Rifampin
Mechanisms of action for DNA replication (DNA gyrase)
-nalidixic acid
-quinolones
Why is bactericidal a good selective toxicity?
B/c Eukaryotic cells lack peptidoglycan
What do cell wall agents do?
They either prevent the synthesis of wall components or the assembly of the synthesized precursors of the wall components.
-bactericidal = good selective toxicity b/c eukaryotic cells lack a cell wall (peptidoglycan)
Penicillin structure and target
structure
All have a thiazolidine ring joined to a B-lactam ring to which the side chain is attached
-the side chain dictates susceptibility to B-lactamase and spectrum of activity.
target
penicillin will inhibit the transpeptidase (referred to as penicillin-binding protein) which is the last step of the peptidoglycan synthesis (cross-linking the polymer)
Where in the carbohydrate backbone of the peptidoglycan cell wall structure does the alternating D/L amino acid peptide chain bind?
The peptide chain (D/L aa) will bind to **NAM **
D-ala being the terminal aa
Peptide Inter bridge is formed by the transpeptidase… this is what causes the cross-linking
Penicillins-resistance
Bacteria will have enzymes such as B-lactamase or penicillinase causing penicillin resistance by hydrolyzing the drug ineffective by opening the B-lactam ring in penicillin converting it to penicilloic acid (ineffective penicillin)
There are two forms of naturally occurring penicillin (Narrow spectrum)
Pen G = degraded by stomach acid thus requires injection administration (painfully b/c given intramuscular)
Pen V = taken orally = It was developed to be more stable in acidic conditions, making it suitable for oral administration.
nature INVENTED penicillin, someone DISCOVERED penicillin
Penicillin G is effective against a broad range of Gram-positive bacteria and some Gram-negative bacteria.
Penicillins - B-lactamase resistant
Synthetic penicillin generated to be Resistant to the B-lactamase of staphylococci
-oxacillin
-methicillin
-dicloxacillin
-Nafcillin
-Cloxacillin
-Flucloxacillin
Natural penicillin (like Penicillin G) mainly targets Gram-positive bacteria. Synthetic penicillins were created to extend activity to Gram-negative bacteria as well.
Synthetic penicillins like Methicillin, Oxacillin, and Nafcillin were designed to be resistant to β-lactamase, making them effective against penicillin-resistant bacteria, such as Staphylococcus aureus
Penicillins- broad spectrum/ aminopenicillins
-sensitive to B-lactamase
B-lactam antibiotics
ampicillin
amoxicillin
More effective on gram (-)
These are also synthetic penicillin
Many Gram-negative bacteria produce β-lactamase in the periplasmic space, but not all of them produce high enough levels to completely degrade amoxicillin before it can act on the bacteria.
Amoxicillin can still be effective against Gram-negative bacteria that either:
Produce low amounts of β-lactamase, or
Do not produce the specific types of β-lactamase that efficiently break down amoxicillin (some broad-spectrum or extended-spectrum β-lactamases).
Penicillins- extended spectrum/anti-pseudomonal
Sensitive to B-lactamase
-mezlocillin
-piperacillin
-ticaracillin
-carbenicillin
More effective against gram (-) RODS
-P.aeruginosa
-E.coli
-H.influenza
-K.pneumoniae
Cephalosporins
-structure
Have a B-lactam ring and a dihydrothiazine ring. It also contains 2 R groups that determine the pharmacological properties
Instead of a pentagon attached to the B-lactam ring like in penicillin is a hexagon attached to the B-lactam ring in cephalosporin antibiotics. They utilize the same mechanism of action
some bacterias produce cephalosporinases which make them resistant
-resistant to inactivation by certain B-lactamases (S.aureus)
Gram-Positive Bacteria:
Gram-positive bacteria, such as Staphylococcus aureus, can produce β-lactamase enzymes that break down β-lactam= making them resistant.
In Gram-positive bacteria, β-lactamases are secreted outside the cell, into the surrounding environment. Since Gram-positive bacteria do not have an outer membrane, their cell wall is directly exposed to the external environment.
Gram-Negative Bacteria:
In Gram-negative bacteria, β-lactamases are often found in the periplasmic space (the area between the outer membrane and the cell wall). Here, they break down β-lactam antibiotics after they pass through the outer membrane but before they can reach PBPs in the periplasmic space.
What type of antibiotics have increased generations and why?
The generations of cephalosporin antibiotics were increased to expand their spectrum of activity and to improve their effectiveness against resistant bacteria.
Cephalosporins are classified into “generations” based on their susceptibility, potency, and spectrum (activity)
First Generation:
Mostly active against Gram-positive bacteria (e.g., Staphylococcus and Streptococcus).
Examples: Cefazolin, Cephalexin.
Limited activity against Gram-negative bacteria.
Second Generation:
Expanded activity against Gram-negative bacteria HEN PEcKS (e.g., Haemophilus influenzae, Enterobacter aerogenes Neisseria, serratia).
Examples: Cefuroxime, Cefoxitin, cefprozil
Decreased against many Gram-positive bacteria
**Third Generation:
Further expanded activity against Gram-negative bacteria, including HEN PEcKS, salmonella, S.pneumoniae
Better CNS penetration, useful for treating meningitis.
Examples: Ceftriaxone, Cefotaxime, Ceftazidime, cefdinir
Less effective against Gram-positive bacteria compared to first-generation drugs.
Fourth Generation:
Broad-spectrum coverage of both Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa.
Enhanced resistance to enterobacter β-lactamases.
Example: Cefepime, cefozopran
Fifth Generation
Active against methicillin-resistant Staphylococcus aureus (MRSA) and other resistant Gram-positive organisms, in addition to Gram-negative bacteria.
Example: Ceftaroline, ceftolozane, ceftobiprole
Carbapenems
Makes them active against most bacteria
-consists of a B-lactam ring but has an semisynthetic ring attached to it (imipenem, meropenem, ertapenem, doripenem)
Poor oral bioavailability - given I.V.
Resistant to most B-LACTAMASES
Monobactams
Aztreonam
Narrow spectrum of activity
Mostly against gram (-) = aerobes
Used as a last resort when bacteria is pretty much resistant to everything, and allergic to penicillin
Resistant to most B-lactamases and cephalosporinases
Monobactams have a monocyclic β-lactam ring, which is different from the bicyclic structure of penicillins and cephalosporins. This unique structure makes them resistant to certain types of β-lactamase enzymes.
B-lactamase inhibitors
Bind more efficiently to the B-lactamase enzymes, allowing B-lactam antibiotics to be more effective
CA = Clavulanic acid
Sulbactam
Tazobactam
These have little antimicrobial activity and must be combined with a B-lactan antibiotic
Combos in a single pill
Augmentin = CA + amoxicillin
Unasyn = Sulbactam + ampicillin
Zosyn = Tazobactam + piperacillin
Zerbaxa = Tazobactam + ceftolozane
Amoxicillin is broken down by B-lactamase of bacteria,
to penicilloic acid. If Clavulanic acid is incorporated with amoxicillin, it inhibits the B-lactamase activity.
Why do we have combinations in a single pill of B-lactam antibiotics with B-lactamase inhibitors?
Combining β-lactam antibiotics with β-lactamase inhibitors in a single pill addresses the challenge of bacterial resistance to β-lactam antibiotics.
β-Lactamases are enzymes produced by many bacteria that break down the β-lactam ring in antibiotics like penicillins and cephalosporins, making them ineffective.
By combining a β-lactam antibiotic with a β-lactamase inhibitor, the inhibitor can neutralize the β-lactamase enzyme, allowing the β-lactam antibiotic to remain effective against the bacteria.
Amoxicillin is broken down by B-lactamase of bacteria,
to penicilloic acid. If Clavulanic acid (CA) is incorporated with amoxicillin, it inhibits the B-lactamase activity.
Amoxicillin + CA = augmentin
Non-B-lactam cell wall inhibitors
-medication
-mechanism
Bacitracin
Targets the lipid carrier that transports the peptidoglycan precursors across the cytoplasmic membrane where they are assembled
Toxicity limits it to topical use only = neosporin
Vancomycin
Forms hydrogen bonds with D-ala terminus. This stabilize the vancomycin, preventing the transglycosylation and transpeptidation steps of cell wall synthesis, thereby inhibiting cell wall formation.
Transglycosylation: The enzyme responsible for adding the NAG-NAM-peptide precursor to the growing peptidoglycan chain is blocked, preventing polymerization.
Transpeptidation: This step, in which transpeptidase enzymes cross-link peptidoglycan strands, is also blocked because Vancomycin prevents access to the D-Ala-D-Ala dipeptide.
Cell wall inhibitors for mycobacteria
-medication
Isoniazid
ethionamide
These medication interfere with the synthesis of mycolic acids (a unique component of mycobacterial cell walls)
Called “mycobacteria” b/c of observations of their fungal-like appearance and rod shape (bacteria)
Typically also involves a multi-drug therapy
Treating mycobacterial infections, such as those caused by Mycobacterium tuberculosis (which causes tuberculosis) and Mycobacterium leprae (which causes leprosy), requires specific antibiotics that target their unique cell wall components. Mycobacterial cell walls have distinctive features, including a high lipid content and mycolic acids, which make them different from the cell walls of other bacteria.
Cell membrane agents
Polymyxin
Disrupts the cell membrane!!!!! By inserting themselves (a fatty acid portion) into the outer bacterial membrane (onto LPS) disrupting its structure and function. Causing cell death
Polymyxin B is effective against Gram-negative bacteria, such as Escherichia coli and Pseudomonas aeruginosa.
Due to possibility of nephrotoxicity- used topically
What’s in neosporin?
This is a triple antibiotic therefore it will have 3 things
-Bacitracin (inhibiting cell wall synthesis by preventing a lipid carrier that transports peptidoglycan precursors across the cytoplasmic membrane where they are assembled)
-Polymyxin B (A polymyxin antibiotic that disrupts the bacterial cell membrane.)
- Neomycin (An aminoglycoside antibiotic that inhibits protein synthesis in bacteria.)
Capsule
Outter membrane
Perplasmic space
Cell wall
Inner membrane
Cytosol
Why add Polymyxin B into Neosporin?
Polymyxin B is effective against Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa. Including it in Neosporin helps cover a broader range of potential pathogens.
Polymyxin B disrupts the cell membrane!!!!! By inserting themselves (a fatty acid portion) into the outer bacterial membrane (onto LPS) disrupting its structure and function. Causing cell death
What do you have to consider before prescribing an antimicrobial agent?
infective etiology, specimen, when to start treatment, which agent
Why selective toxicity is important during antimicrobial therapy?
So it does not harm anything else BUT the target microorganism
So it does not harm anything else BUT the target microorganism
Bactericidal, selective toxicity, active in body/even when diluted, does not make susceptible bacteria become resistant, no side effects (ideally), not metabolize too fast, stable, soluble
Quinolones - Fluorooquinolones
-medications
-mechanism
Nucleic acid interacting agents
-Ciprofloxacin
-Levofloxacin
-Norfloxacin
-Moxifloxacin
-Sparfloxacin
good choice for intracellular pathogens b/c of their good penetration of macrophages and neutrophils
These are going to inhibit DNA replication by interfering w/ DNA gyrase (the enzyme responsible for uncoiling/relaxing DNA) these are working with topoisomerases
Metronidazole
-medication
-mechanism
-bacteria
Bactericidal
Breaking DNA braches by increasing free radicals.
Anaerobic bacteria
Protein synthesis agents
50S ribosomal subunit
-Macrolides (Azythromycin, Erythromycin)
-clindamycin
30S ribosomal subunit
-tetracyclines
-Aminoglycosides
Total = 70S subunit
Macrolides
50S ribosomal subunit
-Macrolides (Azythromycin, Erythromycin)
-clindamycin
prevents movement of the ribosome along the mRNA
Clindamycin
-mechanism
-effective against
50S ribosomal subunit
-Macrolides (Azythromycin, Erythromycin)
-clindamycin
prevents movement of the ribosome along the mRNA
- effective against gram +/- anaerobes EXCEPT for C.difficile
This medication can be the cause of C.difficile—related pseudomembranous colitis by killing off much of the intestinal flora.
Erythromycin
-mechanism
-structure
50S ribosomal subunit
-Macrolides (Azythromycin, Erythromycin)
-clindamycin
-Macrocyclic lactone ring
Azythromycin
50S ribosomal subunit
-Macrolides (Azythromycin, Erythromycin)
-clindamycin
-only requires 1dose/day
-effective against many respiratory tract and middle ear pathogens
Considered a long acting-macrolide- has prolonged levels in tissues
Shorter duration of therapy
Tetracyclines
-medication
-mechanism
-pathogens
30S ribosomal subunit
-tetracyclines
-Aminoglycosides
prevent the tRNA from emerging the A-site of the ribosome
bacteriostatic (inhibit bacterial growth)
STAIN TEETH if you take them early in life
DOXYCYCLINE
TETRACYCLINE
MINOCYCLINE
Intracellular pathogens: chlamydia, rickettsia, mycoplasma
Aminoglycosides
-medication
30S ribosomal subunit
-tetracyclines
-Aminoglycosides
STREPTOMYCIN
GENTAMYCIN
change the shape of the 30S subunit, causing misreading of the codons (mRNA)
Bactericidal (kills the bacteria rather than inhibiting their growth = bacteriostatic)
Metabolic antagonist agents (competitive inhibitors)
are compounds that interfere with a cell’s metabolic processes- specifically Folic acid synthesis by competing with natural substrates for enzyme binding.
Folic acid is necessary for synthesis of thymidine, purines and some amino acids.
These competitive inhibitors of the folic acid metabolic pathway include
SULFONAMIDES (SMX)
TRIMETHOPRIM (TMP)
Sulfonamides
(SMX)
Will inhibit the folic acid metabolic pathway
bacteriostatic
** Sulfonamides are competitive inhibitors that mimic PABA to block bacterial folic acid synthesis = structural analogs**
preventing bacteria from using PABA to synthesize folic acid, effectively stopping bacterial growth by inhibiting the enzyme that catalyzes that reaction
These competitive inhibitors of the folic acid metabolic pathway include
SULFONAMIDES (SMX)
TRIMETHOPRIM (TMP)
Sulfonamides
(SMX)
Will inhibit the folic acid metabolic pathway
bacteriostatic
** Sulfonamides are competitive inhibitors that mimic PABA to block bacterial folic acid synthesis = structural analogs**
preventing bacteria from using PABA to synthesize folic acid, effectively stopping bacterial growth by inhibiting the enzyme that catalyzes that reaction
Why are some sunscreens PABA free?
Sulfonamides are competitive inhibitors that mimic PABA to block bacterial folic acid synthesis. Sulfonamides, inhibit the enzyme that converts PABA to DHF effectively stopping bacterial growth. = bacteriostatic
Because PABA has structural similarities to sulfonamides and can cause skin sensitivity and allergic reactions (including in people with sulfonamide allergies), manufacturers have moved away from using PABA in sunscreens to make the products safer for a broader population.
Thus, while PABA and sulfonamides are not the same, their chemical relationship is a key reason why people with sensitivities to sulfa drugs are often advised to use PABA-free sunscreens.
Trimethoprim
Bacteriostatic
inhibits the enzyme that catalyzes the synthesis of THF
Which is the 2nd step in folic acid metabolic pathway.
PABA —> DHF —> THF
These competitive inhibitors of the folic acid metabolic pathway include
SULFONAMIDES (SMX)
TRIMETHOPRIM (TMP)
Bactrim
competitive inhibitors of the folic acid metabolic pathway include
SULFONAMIDES (SMX)
TRIMETHOPRIM (TMP)
These medications are usually taken together and makes Bactrim primary treatment for Pneumocystis Jiroveci pneumonia in AIDS patients
