Antibacterial drugs - Part 1 (Intro - Inhibitors of Cell Wall Synthesis) Flashcards
Antibiotics definition
Substances produced by micro-organisms to kill other micro-organisms or to protect them from toxins produced by other microorganisms
“Antibiosis”
Life destroys life amongst lower species
What are desirable pharmacologic properties of ideal Antibacterial Drugs
Stability Solubility Diffusability Slow Excretion Large Theraputic index - Selective
In response to a pathogen, a host may respond with what?
Active Immunity
Passive Immunity
Overt Disease
In response to a drug, a host may respond with what?
Allergy
Toxicity
What effects may drugs have on a host?
Selective toxicity
Effects on non-pathogenic flora
Microbes may respond to drugs with what?
Resistance
Secondary products of bacterial destruction
Prophylaxis
Temporarily decreases most likely pathogens below critical level required to cause infection
One-quarter to one-half of antibacterial drug use is for prophylaxis
What might prophylaxis drugs be useful for?
Prevent epidemic meningitis, bacterial endocarditis
Prosthetics - artificial valves, arteries
Transplants
Surgery
Empiric Therapy
Initiation of treatment before etiology of infection is known with agents known to be effective against the most likely pathogen acquired (suspected from source of infection)
Pathogen-directed Therapy
Identify bacterial species, and then treat
Identify via staining with crystal violet (gram stain)
Drug resistance is a determinant of what?
Choice of drug
How much drug
Drug combinations
Gram+ bacteria will stain what color?
Purple
Gram- bacteria will stain what color
Pink
How does the cell wall of a gram+ bacteria compare to gram-
Gram+ = Thick Peptidoglycan layer (50-100 cells thick) outside the plasma membrane
Gram- = Thin Peptidoglycan layer (1-2 cells thick), then wide Periplasmic space, then the plasma membrane
What can be used to determine Antibiotic sensitivity
Minimum inhibitory concentration (MIC)
Minimum bactericidal concentration (MBC)
Disk diffusion Assays and E-test
Minimum inhibitory concentration
Lowest concentration of drug which completely inhibits growth at 24 hrs
What are we able to do once we know the antibiotic sensitivity profile?
Select effective drugs with the narrowest spectrum of activity in order to avoid emergence of resistant micro-organisms
Why is it important to know the location of an infection?
Many agents don’t cross the blood brain barrier
Pharmacokinetics
Route and time course of…
- Absorption
- Metabolism
- Excretion
- Toxicity
Emergence of different resistant strains in different locales is depndent on what?
Clinical use and/or natural selection
What are some host factors to keep in mind when selecting a drug?
Age Allergy history Food/hydration effects on pharmacokinetics, absorption, solubility, and renal function Hepatic funciton Pharmacogenetics Pregnancy status Immune status
Antibiotic combinations are helpful for what?
Empiric Therapy
Mixed Infections
Synergism
Antagonism
What are the different mechanisms of action of antibacterial drugs?
Inhibition of Nucleic Acid Synthesis DNA Damaging Agents Inhibition of Cell wall synthesis Damage of Cell Membranes Inhibitors of Protein Synthesis
What drugs Inhibit Nucleic Acid Synthesis
Sulfonamides, Trimethoprim (Antifolates)
Rifampin
What drugs are DNA damaging agents?
Quinolones
Nitrofurantoin
Metronidazole
Methenamine
What drugs inhibit cell wall synthesis?
Beta-lactams
Vancomycin
Bacitracin
What drugs damage cell membranes?
Polymyxins
Daptomycin
What drugs inhibit protein synthesis?
Aminoglycosides Tetracyclines Tigecycline Macrolides (Erythromycin, Clarithromycis, Azithromycin) Clindamycin Linezolid Quinupristin/Dalfopristin
Sulfonamides mechanism
Competitive inhibitor of Dihydropteroate synthase - which is required for synthesis of folic acid
Bacteriostatic
Sulfonamides selectivity
Selective because bacteria must synthesize their own folate, while humans utilize dietary folate
Sulfonamides Antibacterial spectrum
Inhibits growth of gram positive and gram negative organisms
Resistant strains are numerous
Sulfonamides clinical uses
Uncomplicated UTIs
Toxoplasmosis - a parasite infection
Malaria
Prophylactic - topical for burn patients, and in AIDS patients to prevent P. jirovecii
Sulfonamide Absorption
Good oral absorption
Poorly absorbed forms are used to decrease colonization density before surgery
Sulfonamide Distribution
Widely distributed including penetration into the CSF
Sulfonamide Excretion
Renal
Sulfonamide Toxicity
Dose related
- Crystalluria (that’s why you should take it with lots of water)
- Hemolytic anemia
- GI upset
- Kernicterus (sulfa drug displaces albumin bound bilirubin - which can then pass BBB in newborns. CNS deposition leads to encephalopathy)
Dose unrelated
- Hypersensitvity (mild rash to Stevens-Johnson syndrome)
- Photosensitivity
Trimethoprim Mechanism
Inhibitor of Dihydrofolate reductase (DHDR) - required for folic acid synthesis
Structural analog of pteridine
Bacteriostatic
Trimethoprim Selectivity
Need much higher concentration to inhibit human DHFR compared to bacterial DHFR
Trimethoprim Antibacterial Spectrum
Broader spectrum of activity against both gram+ and gram- compared to sulfonamides
Resistance is associated with alterations in DHFR
Trimethoprim Clinical Uses
Usually used in combination with Sulfamethoxazole (5:1 ratio of Sulfa to Trimeth) -becomes bacteriocidal
UTI treatment
Intestinal infections
Community acquired MRSA treatment
P. jarovecii treatment and prevention in AIDS pts
Trimethoprim Absorption
Oral
GI absorption is also good
Trimethoprim Distribution
Wide
penetrates into CNS
Trimethoprim Excretion
Renal
Trimethoprim Toxicity
Slight blood dyscrasias - Usuually associated with sulfa combination
Anemias in patients that are already folate deficient
Rifampin Mechanism
Binds to an inhibits RNA polymerase
Bactericidal
Rifampin Resistance
Induction of resistance is rapid
Not usually used as monotherapy because of this
Rifampin Selectivity
Doesn’t bind to human RNA polymerase - bacteria only
Rifampin Antibacterial Spectrum
Potent against M. tuberculosis at both intracellular and extracellular sites
Some activity against staphylococci
Rifampin Clinical uses
First-line antituberculosis drug
Used in combination with other first-line anti-tubercular drugs
Some use in combination with other agents for treatment of prosthetic valve endocarditis, resistant staph infections
Prophylaxis against meningococcal disease and meningitis
Rifampin Absorption
Oral - peak levels within 2-4 hours
Rifampin Distribution
Widely distributed to organs, tissues, and body fluids (including CSF)
Can impart red-orange color to urine, feces, saliva, tears - so just inform patient so they don’t go ape-shit
Rifampin Metabolism
In the liver via P450 enzyme-mediated deacetylation
Metabolite remains full antibacterial activity, but intestinal reabsorption is diminshed
Why is a Rifampin-substitute given to HIV+ patients with tuberculosis?
It is a potent inducer of hepatic microsomal enzymes, and can therefore increase metabolism and decrese the half-lifke of HIV proteases and nonnucleoside reverse transcriptase inhibitors
Rifampin Excretion
Rapid elimination in bile as parent and as deacetylated metabolite - so daily dosing is encouraged
Rifampin Toxicity
Liver damage - jaundice
Quinolones Mechanism
Inhibit DNA replication through “poisoning” of DNA Gyrase A
Specifically, they inhibit the uncoiling funciton of DNA gyrase ahead of the replication fork
Alo inhibit the separation of newly replicated sstrands of DNA (decatenation) through the inhibition of DNA topoisomerase IV
Bacteriocidal
Quinolones Selectivity
Mammalian DNA topoisomerase II is not inhibited to the same extent as DNA gyrase and DNA topoisomerase IV in bacteria
Quinolones Antibacterial Spectrum
A variety of analogs are effective against either gram- or gram+ bacteria
Quinolones Clinical Uses
UTI
RTI
Anti-tubercular (when there’s resistant to other anti-tubercular drugs)
Ciprofloxacin & Levofloxacin are effective against P. aeruginosa
Quinolone Drug resistance mechanisms
1) Mutations in Gyrase or Topoisomerase target
2) Increased Efflux pumps
3) Altered porins (gram-)
1st Generation Quinolones
Nalidixic acid (Historical)
2nd Generation Quinolones
Ciprofloxacin
Ofloxacin
Norfloxacin
3rd Generation Quinolones
Levofloxacin - for gram+ bacteria
4th Generation Quinolones
Moxifloxacin - for gram- abcteria
Quinolone Absorption
Rapid absorption after oral administration
Cations can chelate Quinolones and limit absorption
Quinolone Excretion
Rapid renal elimination
Quinolone Distribution
High concentrations in kidney and urine
Except Moxifloxacin, which is not cleared by the kidney
Ciprofloxacin penetrates into prostatic fluid - good for prostatitis
Quinolone Toxicity
Generally well tolerated
Ciprofloxacin can rupture tendons in children
Can lead to GI intolerance/nausea
Nitrofurans Mechanism
DNA damage caused by the formation of O2 free radicals subsequent to reduction of nitro group
Nitrofurans Selectivity
High concentrations in urine and renal interstitial fluid
Bacteria cause reductive activation more extensively than mammalian cells
Low serum concentrations prohibits use for systemic infections
Nitrofurans Antibacterial Spectrum
Broad spectrum against gram+ and gran- strains
Not effective against P. aerudinosa
Nitrofurans Clinical uses
Only for treatment of UTIs
Nitrofurans Pharmacokinetics
Well absorbed orally
Rapidly metabolized
Renal excretion
High concentrations in urine achieved - good for treatment of UTIs
Nitrofurans Contraindications
Low creatinine clearance (Poor renal function)
Nitrofurans Toxicity
Toxicity includes acute fever, rashes, urticaria
Possible pleural effusions
Chronic toxicity is associated with pulmonary fibrosis (often reversible)
Methenamine Mechanism
Hydrolyzed at acid pH to form formaldehyde
Acidify urine to increase selectivity
Denature proteins
In addition, formaldehyde has been shown to damage DNA
Bacteriocidal
Methenamine Clinical Uses
Only for prophylaxis for lower UTIs
Methenamine Antibacterial Spectrum
Gram-
Methenamine Pharmacokinetics
Oral administration
Well distributed into total body water
Stomach hydrolysis is 10-30% unless tablets enterically coated
Methenamine Toxicity
Include gastric distress, bladder irritation, crystalluria due to precipitation of acidifying agents if there’s inadequate urine flow
Metronidazole Mechanism
Reductive activation of nitro group specifically in anaerobic bacteria leads to free radical species and reactive intermediates that bind to and affect DNA function
Also activation and DNA damage activity in some protozoa
Therefore, it is a pro-drug that requires metabolic activation
Metronidazole Antibacterial Spectrum
Bactericidal against most obligate anaerobic gram+ and gram- bacteria
Not active against aerobes or facultative anaerobes
Active against some protozoa
Metronidazole Clinical Uses
Anaerobic and some protozoal infections
Metronidazole Resistance
Due to reduced activation
Metronidazole Absorption
Well absorbed orally
Metronidazole Distribution
Widely distributed into fluid compartments
Penetrates into the CNS
Metronidazole Excretion
Renal –> metabolites
Metronidazole Toxicity
Mild nausea and vomitting
Metallic taste
Can have disulfiram-like effect where complete metabolism of alcohol is prevented, leading to nausea, vomiting, GI distress if alcohol is consumed
Bactericidal Effects of Inhibition of Cell Wall Synthesis
High internal osmotic pressure of bacteria requires a rigid cell wall to maintain integrity and shape.
During growth and division, bacteria require new cell wall synthesis, and therefore, inhibitors render growing bacteria susceptible to osmotic rupture, with no effect on mammalian cells which do not contain cell walls
T/F - Bactericidal effects of Cell wall synthesis inhibitors only occur when cells are growing
True
What bacteria are resistant to drugs that Inhibit Cell wall synthesis? Why?
Mycoplasma - lack cell walls, so intrinsically resistant
L-forms of bacteria - lack cell walls
The kidney is also a sanctuary for bacteria against these drugs, because osmotic pressure is high
Cell wall synthesis
1) Linkage of L-ala to D-ala OR Linkage of two D-ala peptides
2) Linkage of D-ala dipeptide to three other amino acids and N-acetylmuramic acid to form a pentapeptide with a UDP-carrier + isoprene
3) Coupling to N-acetylglucosamine
4) Sugar-peptide structure linked to isoprenyl-phosphate lipid carrier is transported to exterior of cell membrane
5) Sugar-peptide added to polymer via Peptidoglycan synthase
6) Transpeptidation reaction cross-linking peptidoglycan strands by connecting penultimate D-ala from one strand to a diaminopimelic acid unit in a sugar-peptide of an adjacent strand
What are the different types of Beta-Lactams?
Penicillins Cephalosporins Monobactams Carbapenems B-Lactamase Inhibitors
Penicillin Mechanism
Miminx D-ala-D-ala structure of pentapeptide on peptidoglycan and ties up transpeptidase
Bacteriocidal
Penicillin Selectivity
Penicillins and all B-lactams work to inhibit cell wall synthesis
Since eukaryotic cells do not contain cell walls, there are no direct cytotoxic effects in the host
What are the different types of Penicillin Classifications?
Natrually Occuring Penicillins
Anti-staphlococcal (B-lactamase resistant) Penicillins
Amino-penicillins
Anti-Pseudomonal Penicillins
What is the spectrum of Naturally Occurring Penicillins?
Narrow spectrum -
effective against streptococci, many anaerobes, enterococcus, and a few gram- organisms
What is the spectrum of Anti-staphylococcal Penicillins?
Narrow spectrum -
effective against infections caused by staphylococci and streptococci
What is the spectrum of Amino-penicillins
Broader spectrum
- effective against streptococci, entrococci, and some gram- organisms
- not effective against P. aeruginosa
What is the spectrum of Anti-pseudomonal penicillins?
Extended spectrum
-effective against streptococci and many gram- bacteria including various Enterobacteriae and Pseudomonas
What are clinical uses of Penicillins?
Streptococcus pneumoniae (pneumonia, meningitis, ottis media, bacteremia)
Haemophilus influenza (Meningitis, epiglotitis)
STDs (syphilis)
UTIs
What are the mechanisms of Drug resistance to Penicillins and B-Lactams?
1) B-lactamases
2) Altered Penicillin Binding Proteins
3) Altered porins (doesn’t allow B-lactams in)
4) Increased efflux (enhanced efflux pump mechanisms)
Penicillin Absorption
Poor oral absorption (only ~50%) - food intake will decrease absorption (so take before eating)
Acid destruction is a factor and therefor give an acid stable drug such as Pen-V
Short blood or plasma half life after reaching max level within 2 hours
Penicillin Distribution
Varies
Lipid insoluble and therefore no good penetration of the BBB
CSF entry is increased with inflammation of meninges
Protein binding varies
Distribution can be affected by pathology of infection
Penicillin Excretion
Renal - by glomerular and tubular secretion
Penicillin Toxicity
Relatively nontoxic but direct toxic effects in the kidney are noted as well as hypersensitivity reactions
Why are Penicillins “time-dependent” drugs?
Since concentrations in the blood must be maintained for a sufficient period to inhibit cell wall synthesis and kill all bacteria
Cephalosporins Mechanism
Same as for Penicillins - Mimics D-ala-D-ala structure of pentapeptide on peptidoglycan and ties up transpeptidase
Bacteriocidal
First Generation Cephalosporins Selectivity
Penicillin alternative
Effective against gram positive organisms
Added activity against E. coli
Second Generation Cephalosporins Selectivity
Increased activity against gram- bacteria compared to first generation
3rd Generation Cephalosporin Selectivity
Even grater activity against gram- bacteria
4th Generation Cephalosporin Selectivity
Effective against Pseudomonas
More resistant to B-lactamase breakdown
Only administered via IV
Cephalosporins Absorption
Oral and Parenteral
Cephalosporins Distribution
Wide
3rd and 4th can cross BBB and penetrate CSF
Cephalosporins Metabolism
Not extensively metabolized
Cephalosporins Excretion
Similar to penicillins
Renal elimination via filtration and tubular excretion
Cephalosporins Toxicity
Relatively non-toxic and better tolerated than penicillins
Hypersensitivity and cross-sensiticiy (1-10%) in patients who have allergic reactions to penicillin
Carbapenems Spectrum
Broad/Extended spectrum against gram- and gram+ bacteria
Resistant to B-lactamases
Carbapenems Absorption
IV only
Carbapenems Excretion/Metabolism
Undergoes hydrolysis in renal system
Carbapenems Clinical Uses
Use reserves for serious noscomial infections
Carbapenems Toxicity
Can be limiting (Seizures)
Monobactams Spectrum and Use
Effective against aerobic gram- organisms (including P. aeruginosa)
Essentially no activity against gram+ organisms because of poor binding to PBPs in gram+ organisms
Monobactams Pharmacokinetics
Given only IV or IM injection
Elimination same as penicillins
Hypersensitivity reactions are rare
B-lactamase Inhibitors Mechanism
Inhibits B-lactamase
Binds irreversibly to serine at active site of lactamase
Suicide inactivator
B-lactamase Inhibitor Clinical uses
Used in combination with beta-lactam antibiotics to extend the spectrum
Vancomyocin Mechanism
Binds to carboxyl terminus of D-ala-D-ala and therby…
1) Inhibits Peptidoglycan synthase
2) Inhibits transpeptidation reaction
Bactericidal
What is a major problem with Vancomyocin?
Resistance - due to altered D-ala-D-ala peptide structures so Vancomyocin doesn’t bind as readily
Strains of Enterococcus faecium and Staphylococcus aureus are becoming vancomyocin resistant (VRE-type resistance)
Vancomyocin Spectrum
Active against gram+ staphylococci and streptococci
Large size means it can’t penetrate the outer membrane of gram- bacteria
Vancomyocin Absorption
Given IV
Not absorbed form GI
Can be used orally to trat C. difficle, but results in rapid emergence of resistant enterococci
Vancomyocin Metabolism/Excretion
Not metabolized
Renal excretion
Half-life = 6-9 hours
Vancomyocin Toxicity
Hearing loss is dose-related and often related to an underlying renal imapirment which leads to slower excretion
Rash can occur if Vancomyocin is infused too quickly
Bacitracin Mechanism
Binds to isoprenyl-phosphate lipid carrrier, inhibiting dephosphorylaiton and utlization
Bacitracin Spectrum
Inhibits gram+ cocci
Some activity against gram-
Bacitracin Clinical Uses
Superficial skin infections, opthalmic infections
Used in creams and ointments
Bacitracin Pharmacokinetics
Poorly absorbed - only administered topically
If given IV, then can cause renal damage
