Antibacterials Flashcards
Bactericidal
Kills the bacteria
Bacteriostatic
Stops active growth of the bacteria but they remain viable
Rely on use of host immune system to clear
B-lactams
Bactericidal
Effective against gram positive and negative
Activity maximal on actively growing bacteria
MOA: Inhibit transpeptidases like PBPs which catalyze cell wall cross linking; competitive and irreversible
Resistance: B-lactamase by gram positive, altered PBP, B lactate agent cannot reach PBPs (gram negative is impermeable)
Time- dependent killers (keep drug 4-fold above MIC for >50% of treatment time)
B- lactate drug classes
penicillins
B-lactamase inhibitors
Cephalosporins
Other B-lactams
Penicillin
Well distributed to most areas of body (low penetration into CSF)
Short half-lives, renal elimination (anion transport), Time dependent killer
Excretion/Metabolism: 30% hepatic metabolism/ mostly renal (20% glomerular filtration/80% tubular anionic excretion)
Some adverse reactions: allergic can be very severe (anaphylaxis, rash, fever, diarrhea, enterocolitis, elevated liver enzymes, hemolytic anemia)
Administration: some IV or IM only (penicillin G, ticarcillin), oral (ampicillin, amoxicillin, penicillin V), generally well distributed
Generally short half-lives–> procaine and benzathine penicillin are slow release IM forms that substantially increase duration over which effective drug levels are maintained
Increase CNS distribution with inflammed meninges
Penicillin Drugs
Amoxicillin Ampicillin Penicillin G Penicillin V Piperacillin Ticarcillin Oxacillin
Penicillin G and V
V is more acid-stable than G (for gram positive and negative cocci which are non B-lactamase producing)
Effective for: gram positive anaerobes (not Bacteroides fragilis), streptococcus pneumonia do, many Streptococcus, Neisseria meningitidis, Syphillus (Treponema pallidum)
Good activity against: anthrax and Listeria
Ampicillin and amoxicillin
Penicillin class of B-lactams
Uses: B-lactamase negative gram positive and some gram negatives (Haemohilus, Neisseria, Escheria, Salmonella)
Alternate choice for Lyme disease
Ticarcillin
Penicillin class of B-lactams Broad gram negative Pseudomonas with aeruginosa, some Enterobacter and Proteus Some anaerobes Used with B-lactamase inhibitor
Piperacillin
Penicillin class of B-lactam so Broad gram negative spectrum including: Pseudoonas and Klebsiella (including ticarcillin resistant) Often used with a B-lactamase inhibitor
B-lactamase inhibitors drugs
Clavulanic acid, tazobactam
B-lactamase inhibitors
Limit hydrolytic cleavage of B-lactam so by some types of B-lactamases
Given in conjunction with some B-lactams (ampicillin, amoxicillin, ticarcillin, piperacillin)
Not all B-lactam resistance is due to B-lactamase
Cephalosporins
Only some reach the CSF
Majority require injection
Short half-lives
Mechanism: similar to other B-lactams
Resistance mechanism are comparable to those of penicillins
Excretion/metabolism: renal clearance by glomerular filtration and secretion
Adverse reactions: allergic reaction, nausea, vomiting, diarrhea, enterocolitis, hepatocellular damage
Cephalosporins
1st generation: cefazolin, cephalexin
2nd generation: cefuroxime, cefoxitin
3rd generation: ceftriaxone, ceftazidime
4th generation: cefepime
First generation cephalosporins
Most effective against gram positive
Uncomplicated outpatient skin infections
Surgical prophylaxis for skin flora
Cefazolin: best gram positive activity of 1st generation cephalosporins
Cephalexin: oral
2nd generation Cephalosporins
Increased gram-negative including Haemophilus influenzae
Less active against staphylococci
Cefuroxime: only 2nd generation to penetrate CSF and best against Haemophilus
Cefoxitin: also good for some anaerobes
3rd generation cephalosporins
More active against gram negatives
Good for Klebsiella, Enterobacter, Proteus
Ceftriaxone: therapy of choice for gonorrhea and empiric therapy for menigitis
Ceftazidime: effective against many strains of Pseudomonas aeruginosa
4th generation Cephalosporin
Cefepime: IV, t1/2= 2 hour
Similar to ceftazidime, except more resistant to type 1 B-lactamases
Empirical treatment of serious inpatient infections
Imipenem
Administered IV, well distributed
Other B-lactams
Broad spectrum
Not degraded by most B-lactamases, including extended spectrum B-lactamses
Not effective against methicillin-resistant staphylococcus
Give with cilastatin (renal peptidase inhibitor)
Uses: mixed or ill defined infection, not responsive or resistant to other drugs
Adverse effects: hypersensitivity; cross-allergies with penicillins/cephalosporin , seizures, dizziness, confusion, nausea, vomiting, diarrhea, pseudomembraneous colitis, superinfection
Aztreonam
used against gram negative aerobic rods
Not useful against gram positives and anaerobes
Not degraded by several B-lactamases
Can be used in those with known hypersensitivity to penicillin
Adverse effects: seizures, cramps, nausea, vomiting, enterocolitis, anaphylaxis, transient EKG changes
Vancomycin
Glycopeptide antibiotic; not a B-lactam
Mechanism: bactericides, inhibits cell wall synthesis (binds to free carboxylase end D-Ala-D-Ala of the pentapeptide; this interferes with transpeptidation and transglycosylation
Uses: gram-positive only, MRSA, enterococcus, hemolytic streptococcus, Strep pneumonia, clostridium difficile (moderate to severe), empirical meningitis treatment: vancomycin+ceftriaxone
Administration: IV for systemic infections, oral form for enterocolitis by C. Diff, serious infections
Adverse effects: red neck syndrome, nephrotoxicity, phlebitis, ototoxicity
Fosfomycin
Mechanism: inhibits synthesis of peptidoglycan building blocks by inactivating enolpyruvyl transferase, an early stage cell wall synthesis enzyme
Uses: uncomplicated UTI caused by E.coli and Enterococcus
Toxicity: headache, diarrhea, nausea, vaginitis
Bacitracin
Polypeptide, not a B-lactam
Mechanism: interferes with cell wall synthesis by interfering with lipid carrier that exports early wall components throughout the cell membrane
Use: Topical use only with gram positive cocci and bacilli
Toxicity: allergic dermatitis
Polymyxins
Mechanism: cationic detergents that binds LPs in outer membrane of gram negatives
Polymyxin B
Polymyxins
Uses: topical use, especially for Pseudomonase and other gram negative infections
Systemic use-potential for serious nephrotoxicity and neurotoxicity
Daptomycin
Mechanism: binds to bacterial cytoplasmic membrane, causing rapid membrane depolarization
Bactericidal
Uses: complicated skin and skin structure infections (staph. Aureus, streptococcus pyogenes and agalactiae, Enterococcus), Staphylococcus bacteremia, NOT for pneumonia
Side effects: nausea, diarrhea, muscle pain, weakness, GI flora alterations
Quinolones
Mechanism: inhibits alpha subunits of DNA gyrase to interfere with control of bacterial DNA winding (replication and repair), bactericidal; killing dependent on AUC24hr/MIC
Resistance: altered DNA gyrase, combination of decreased permeability and altered DNA gyrase
Uses: nonfluorinated compounds (enterobacteriaceae in urinary tract) and fluoridated quinolone (norfloxacin, ciprofloxacin, and moxifloxacin)
Excretion: glomerular filtration and active tubular secretions for many
Adverse reactions: nausea, vomiting, abdominal pain, enterocolitis, dizziness, headache, restlessness, depression, rare seizures, contraindicated in those with seizure disorders, rashes, EKG irregularities, arrhythmias, peripheral neuropathy, precautions (with seizure disorder, pregnancy category C and children), and arthropathy and tendon rupture
Administration: IV, oral, fluoridated quinolones are well distributed
Norfloxacin/ciprofloxacin
Fluoridated Quinolones
Urinary tract infections (enterobacteriaceae–> pseudomonas aeruginoasa and staphylococcus and enterococcus)
Ciprofloxacin
Use for UTI Infectious diarrhea Skin infections Bone and joint infections Chlamydia Better quinolones for respiratory and gram positive infections
Moxifloxacin
Better gram positive activity than many quinolones
Respiratory infections but not for Strep throat, Community-acquired pneumonia, bacterial bronchitis
Nitrofurans
Nucleic Acid agents
Mechanism: nitroreductase enzyme converts them to reactive compound which can damage the DNA
Uses: nitrofurantoin for lower urinary tract infections
Adverse reactions: nausea, vomiting, diarrhea, peripheral neuropathy, hypersensitivity, fever, chills, acute and chronic pulmonary reactions, acute and chronic liver damage, granulocytopenia, leukopenia, megaloblastic anemia, acute hemolytic anemia
Rifampin
Nucleic Acid agents
Mechanism: inhibits bacterial RNA synthesis by binding RNA polymerase B, bactericidal
Uses: pulmonary tuberculosis, prophylaxis of meningococcal meningitis, prophylaxis of Haemophilus influenza type b menigitis
Adverse reactions: serious hepatotoxic its, strongly infuses hepatic enzymes that inactivate other drugs, orange color
Fidaxomicin
Nucleic Acid Agents Mechanism: Noncompetitive inhibitor of RNA polymerase thereby inhibiting RNA synthesis, bactericidal Use: C. Difficile infection Administration: oral, poorly absorbed Adverse reactions: GI upset, GI bleeding
Metronidazole
Nucleic Acid Agent
Mechanism: anaerobes reduce the nitro group and the resulting product disrupts DNA and inhibits nucleic acid synthesis, bactericidal
Uses: anaerobes, C. Difficile (mild to moderate cases), combination therapy for Helicobacter pylori, Garderella vaginalis
Adverse reactions: nausea, vomiting, anorexia, diarrhea, transient leukopenia, neutropenia, thrombophlebitis after IV infusion, bacterial and fungal super infections
Aminoglycosides
Protein Synthesis agents
Bactericidal; IV or IM or topically with poor penetration to CSF
Mechanism of action: transported into bacteria by energy requiring aerobic process; bind to several ribosomal sites to stop initiation and causes premature release of ribosomes from mRNA and mRNA misreading, post-antibiotic effect, concentration dependent killing
Resistance mechanisms: enzymatic modification of amino glycosides
Uses: more effective against gram negative aerobic bacilli, poor activity against anaerobes, gram positive activity requires combination with cell wall inhibitors
Excretion: glomerular filtration
Adverse reactions: narrow therapeutic window, nephrotoxicity (reversible), ototoxicity (delayed and irreversible), neuromuscular blockade so give for serious infections only
Gentamcin/ Tobramycin/ Amikacin
Pseudomonas aeruginosa, Klebsiella, Enterobacter
If resistant to gentamicin then use tobramycin then use amikacin (most modern)
Amikacin
For some gentamicin and Tobramycin resistant strains
Aminoglycoside drugs
Gentamicin
Tobramycin
Amikacin
Tetracycline Drugs
Tetracycline (original)
Doxycycline
Monocycline
Tetracycline
Mechanism: modern ones have longer half lives
Transported into the cells, bind to 30s ribosomal subunits; prevent attachment of amino acyl-tENA to the acceptor side
Bacteriostatic
Resistance: most common for gram positive and negative with drug efflux pump, resistance to one tetracycline is resistance to them all
Uses: resistance has increased dramatically
Preferred agents for rickettsia, chlamydia, Mycoplasma, Ureaplasma, Borrelia and alternative for syphilis and gonorrhea
Administration: Ca binds to tetracyclines inhibiting their absorption, generally rapidly absorbed after oral administration
Adverse reactions: GI disturbances (kill GI flora); pseudomembraneous enterocolitis, Candida superinfection in colon, photosensitization with rash, teeth discoloration so avoid use in children
Contraindicated in pregnancy
Tigecycline
Mechanism: binds 30s subunit and block amino acyl t-RNA entry and binds additional unique sites in the ribosome
Resistance: no cross-resistance with other antibacterial including tetracyclines
Uses: skin/skin structure infections, complicated intraabdominal infections, community acquired pneumonia (CAP
G. negatives: E.coli, Cintrobacter, Klebsiella, Enterboacter, not Pseudomonas
G. positive: Staphylococcus, Streptococcus
Anaerobes: Bacteroides, Clostridium perfringens,
Adverse: nausea, vomiting, enterocolitis (kill Gi flora), other similar to tetracyclines including calcium binding, higher death rate than with other antibacterials (last choice)
Chloramphenicol
Mechanism: interfere with binding of aminoacyl tRNA to 50s subunit and inhibits peptide bond formation
Bacteriostatic
Uses: broad spectrum activity
Serious side effects restricts use to only when other agents not suitable
Current uses: alternate agent for menigitis in B-lactam allergic patients, brain abscess
Some adverse reactions: bone marrow depression (dose related) can progress to fatal aplastic anemia (not dose related), grey baby syndrome (high levels unmetabolized drug), optic neuritis and blindness, GI effects like C. diff
Treatment of C. Diff
Metronidazole (mild to moderate)
Vancomycin (moderate to severe)
Vanco+ metronidazole (severe cases)
Fidaxomicin (less recurrence)
Aminglycoside post-antibiotic effect
sustained activity for several hours after
don’t have to give as often
concentration-dependent killers so less frequent dosing
Doxycycline
alternative for penG-senstive syphilis
uncomplicated N. gonorrhoeae
Less affinity for calcium
Minocycline
alternative for penG-senstive syphilis and uncomplicated gonorrhea
calcium binding: doxycycline
Macrolides
Erythromycin
Clarithromycin
Azithromycin
Macrolide Action
MOA: bind to 50S subunit and block translocation along ribosome
Bacteriostatic
Erythromycin
Use: primarily against gram positive
alternative for Strep. throat for penicillin allergic patient
Effective against “unusual” or “atypical” bugs (chlamydia, Mycoplasma, Legionella (azithro now preferred), Campylobacter, Bordatella)
Side Effects: nausea, vomiting (enhanced GI motility), inhibits CYP 3A metabolism/excretion of drugs, increased risk of arrhythmias and cardiac arrest (increase QTc interval in EKG)
Clarithromycin
Mechanism: similar to erythromycin Better kinetics (less frequently), less GI motility effects and wider antibacterial spectrum Extra CV risk (prolongs QT interval) Uses: same as erythromycin plus Haemophilus influenzae, Moraxella, penicillin resistant Strep. pneumonia, atypical Mycobacteria, licensed for Helicobacter pylori (3 drug combos--> clarithromycin+amoxicillin and acid blocker)
Treatment for Helicobacter Pylori
clarithromycin+amoxicillin+omeprazole
clarithromycin+metronidazole+omeprazole
metronidazole+tetracycline+bismuth subsalicylate+PPI
2 antibiotics+acid blocker are much more effective than one antibiotic+acid blocker
Azithromycin
very common for outpatient respiratory tract infection
Uses: genital infections like chlaymdia or gonorrhea (Ceftriaxone+azithromycin or doxycycline)
GI infections (campylobacter, Shigella, Salmonella)
Adverse reactions: erythromycin>clarithromycin>azithromycin
few effects on CYP3A4
Cardiac QT prolongation
Treatment for Gonorrhea
Ceftriaxone+azithromycin or doxycycline
Clindamycin
Not macrolide
Mechanism: bind to 50S ribosomal subunit, blocks translocation along ribosomes
Uses: gram positive cocci (Strep and MSSA), effective against flesh eating streptococci (suppress bacterial toxin production of Strep and Staph.)
Many anaerobes like Bacteroides fragilis (not for C. diff)
Side Effects: GI irritation, diarrhea, antibiotic associated enterocolitis, hepatotoxicity
Linezolid
Mechanism: binds to 50S ribosomal subunit but interferes with 70S initiation complex so inhibits protein synthesis
Bacteriostatic
Uses: gram-positive spectrum
skin structure infections: VRE, Staph aureus (MRSA and MSSA), Streptococcus (group A and B)
Nosocomial pneumonia (Strep pneumonia, Staph)
Side Effects: non-selective inhibitor of MAO so avoid foods with tyramine and other MAO inhibitor drugs because can give serotonin syndrome (with SSRI, tricyclics, buspirone)
diarrhea, superinfection including enterocolitis, headache, nausea/vomiting, bone marrow suppression
Anti-Folates
Inhibit folate synthesis
Sulfonamides (Sulfamethoxazole, Sulfadiazine) and Trimethoprim
Sulfonamides
Bacteriostatic
MOA: competitive analogs of p-aminobenzoic acid (precursor of folate synthesis)
Today use sulfonamides combined with other antibacterials
Side Effects: hypersensitivity (rashes, serum sickness where sunlight makes rash worse), GI disturbances, renal damage (drugs crystallize in renal tubules), Potentiated actions of other drugs (inhibit CYP 2C9–> warfarin)
Sulfamethoxazole
Used with trimethoprim as part of synergistic combination
Best pharmacokinetic match to trimethoprim
Silver Sulfadiazine
Used topically for infection prevention in burn patients
Trimethoprim
Inhibits folate synthesis by competitive inhibiting dihydrofolate reductase
Dihydrofolate analog
Used alone–> block is partial (static effect)
Uses: In combination with sulfamethoxazole(cidal effect)
TMP/SMX
First choice empiric therapy for uncomplicated UTI (enterobacteriaceae E.coli, coagulase negative Staph), Upper respiratory tract and ear infections (H. influenza, Moraxella, Strep pneumonia), Pneumocystis jivoreci (carinii) and is first choice treatment and prophylaxis
Side effects: all the sulfonamide side effects
Trimethoprim adds nausea, vomiting, diarrhea, rashes, bone marrow suppression (Trimethoprim side effects pronounced with long-term use)
Empiric Therapy
Uncomplicated cystitis in non pregnant women
1st line drugs–> TMP-SMX, nitrofurantoin, fosfomycin
2nd line drugs–> ciprofloxacin, norfloxacin
Diagnostic
Obtain culture/diagnositc test
empiric therapy
diagnostic results, sensitivity profile
Modify therapy as needed
Reasons for Antibiotic Failure
Drug Choice (susceptibility of pathogen, penetration, resistance, superinfection) Host Factors (abscess need draining, host immune response, foreign bodies)
Resistance Spread
Quinolone resistance in gram negatives has increased concurrently with quinolone use
Hospital Acquired MRSA (HA-MRSA) Treatments
Vancomycin (IV)
Linezolid (IV, oral)
daptomycin (IV)
Tigecycline (IV)
Community Acquired (CA-MRSA) Treatments
Linezolid (oral)
Doxycycline, minocycline (oral)
TMP-SMX (oral)
