Antibiotics Flashcards
Antibiotics
naturally occurring agent that inhibits growth of bacteria
Chemotherapeutics
agent that inhibits rapidly dividing cells
Antibacterials
semi- or synthetic agent that inhibits bacterial growth
Antibiotics take advantage of the difference between the host organism and the microbe
In certain instances the selectivity is relative
In order to choose the most appropriate antibiotic, the following information is vital:
The identity of the pathogenic organism
The susceptibility to various antibiotics (C&S)
Site of infection
Comorbid condition and other drugs prescribed
Safety of the antibiotic
Cost factors
CULTURE and SENSITIVITY
The fastest way to identify an organism is by Gram staining. This may not identify the organism thoroughly but it can suggest guideline on treatment
Culture of the organism and identification of sensitivity to various antibiotics is the most effective way to ensure that the choice of antibiotic is most appropriate
Starting antibiotic therapy prior to obtaining samples for culture runs the risk of delayed or inability to identify the pathogenic organism
EMPIRIC THERAPY
Often empiric therapy is started before final identification of an organism because further delay can have significant adverse consequences
Choice of antibiotic is based on Gram staining, site of infection, recent history including travel history, co-morbid conditions, immune status, whether the infection was nosocomial (hospital-acquired) or community acquired.
Once positive identification is achieved, then the choice of antibiotic can be changed if necessary
MIC
minimum inhibitory conc. is the smallest concentration necessary to inhibit growth in culture
MBC
minimum bacteriocidal conc. is the smallest concentration necessary to kill the bacteria (99.9%)
Bacteriostatic drugs
- inhibit the growth of the organism, giving the immune system time to work and eliminate the organism.
- All inhibitors of protein synthesis except aminoglycosides
- Bacteriostatic agents interfere with the efficacy of bactericidal agents (cells must be actively dividing).
Effects can be antagonistic, additive or synergistic
Bactericidal drugs
- are drugs that kill the organism in the plasma levels achieved in vivo.
- All inhibitors of cell wall synthesis
Some antibiotics can be bacteriostatic for one organism but bactericidal for another
Some antibiotics cross the blood-brain barrier easily:
chloramphenicol, metronidazole, 3rd generation cephalosporin, etc.
Some antibiotics cross the blood-brain barrier poorly:
vancomycin, penicillins (unless there is meningitis), 1st generation cephalosporin, etc.
Antibiotic must get to the site of action
If infection is in the CNS, antibiotic must cross the blood-brain barrier
Protein binding
many antibiotics are highly protein bound
Metabolism and excretion
- drugs that undergo hepatic metabolism or are concentrated in the liver can accumulate in hepatic dysfunction and cause toxicity (erythromycin, tetracycline).
- Drugs that are eliminated by the kidneys should be used with caution when renal function decreases because of accumulation and toxicity
Immune status
if the patient has a co-morbid condition that interferes with immune function, this may alter the choice of antibiotics
Very young and very old patients
have decreased ability to metabolize and excrete antibiotics, so the choice and dosage must be altered
Pregnancy and lactation can alter the choice of antibiotics. The following drugs should be avoided in pregnancy:
tetracyclines, quinolones, chloramphenicol, aminoglycosides, folic acid inhibitors, etc.
ROUTE OF ADMINISTRATION
Depending on the route of administration, the bioavailability of various antibiotics will change significantly
Some antibiotics can only be given parenterally because they are peptides or they are poorly absorbed by the GI tract
Other important routes of administration: intrathecal injections, topical application (eye & ear), intraocular
The dosage and frequency of administration will reflect the elimination of these antibiotics from their reservoirs
POST-ANTIBIOTIC EFFECT
Some antibiotics continue to work long after the MIC has been breached. The antibiotics that exhibit the PAE include aminoglycosides, fluoroquinolones, tigecycline
TIME DEPENDENT vs. CONCENTRATION DEPENDENT
Some antibiotics are found to have a direct concentration dependent efficacy. The amount of organisms killed is proportional to the plasma concentration of the anitbiotic: aminoglycosides, fluoroquinolones.
Other antibiotics have a time dependent efficacy. The major factor that affect bactericidal activity is the amount of time the drug’s plasma concentration is above a minimum level.
Increasing the concentration does not significantly increase activity: β-lactams, macrolides, glycopeptides, linezolid, clindamycin.
Narrow spectrum antibiotics
isoniazid
Extended spectrum antibiotics
ampicillin
Broad spectrum antibiotics
tetracycline, fluoroquinolones, macrolides, chloramphenicol
RESISTANCE
Most organisms have evolved a mechanism of resistance to various antibiotics.
Some specific organisms are always resistant to certain antibiotics
Other organisms acquire resistance to specific antibiotics (or classes of antibiotics that have the same mechanism of action)
Genetic alterations leading to drug resistance
Spontaneous mutations
Transfer of genes between organisms via plasmids, transduction or conjugation
Inappropriate use of antibiotics increases risk by selection process
Altered expression of proteins in resistance
Modification of target site, hence antibiotic inefficacy
Decreased accumulation of antibiotic intracellularly
Enzymatic inactivation of antibiotics
Antibiotics are given prophylactically for various situations:
surgery, MVP, traveling to endemic regions, high-risk situations
CLASSES OF ANTIBIOTICS
Cell wall inhibitors Inhibitors of protein synthesis Inhibitors of folate metabolism Inhibitors of bacterial DNA synthesis Inhibitors of cell membrane function
SIDE EFFECTS
Hypersensitivity reaction
Jarisch-Herxheimer reaction and Mazzotti Rxn
Direct toxicity - aminoglycosides
Superinfections – Broad spectrum antibiotics
Carbapenems
Doripenem
Ertapenem
Imipenem
Meropenem
Beta-Lactamase Inhibitors
Clavulanic Acid
Sulbactam
Tazobactam
Monobactams
Aztreonem
PENICILLINS
Beta lactam antibiotics including penicillins prevent the last step in peptidoglycan synthesis
Inhibition of the transpeptidase prevents the cross-linking of the D-alanine to the L-glycine
There are other PBPs aside from the transpeptidase which also contribute to the efficacy of penicillins as antibiotics
NATURAL PENICILLINS
Penicillin G is a salt that is dosed in unit.
1 unit= 0.6 μg
Penicillin G is very effective against non lactamase producing gram positive organisms: Streptococci, Neisseria, spirochetes, Listeria, Actinomyces, Clostridium, etc.
Probenecid can block tubular secretion therefore extend the half-life of penicillins
Penicillin V is an acid stable version which can be administered orally.
Gram+ coccus:
Tx: natural penicillin
Streptococcus pneumoniae
Streptococcus pyrogenes
Streptococcus viridans group
Gram+ bacilli:
Tx: natural penicillin
Bacillus anthracis
Corynebacterium diphtheriae
Gram- cocci:
Tx: natural penicillin
Neisseria Gonorrhoeae
Neisseria meningitis
Gram- rods: anaerobic organisms
Tx: natural penicillin
Clostridium perfringens
Gram- rods: spirochetes
Tx: natural penicillin
Treponema pallidum (syphillis) Treponema pertenue (yaws)
Syphillis
Tx: natural penicillin
A contagious venereal disease that progressively affects many tissues.
A single treatment with penicillin is curative for primary and secondary syphillis. No antibiotic resistance has been reported.
Gonorrhea:
Tx: natural penicillin
Silver nitrates in the eyes prevent gonoccocal ophthalmia in newborns.
Penicillinase-producing strains are treated using ceftriaxone with spectinomycin as a backup.
Pneumococcal pneumonia:
Tx: natural penicillin
Streptococcus pneumoniae is a major of bacterial pneumonia in all age groups.
Infection often occurs in an institutional setting in individuals who are ill from other causes.
Resistance to penicillin G has greatly increased worldwide due to mutations in one or more of the bacterial penicillin-binding proteins.
ANTI-STAPHYLOCOCCAL PENICILLINS:
Semisynthetic penicillins effective against penicillinase producing Staphylococcus but not MRSA
Absorption increases on an empty stomach and they are highly protein bound.
These penicillins are not as effective against non-penicillinase producing organisms
Oxacillin
Dicloxacillin
Nafcillin
Methicillin
Methicillin:
is not used clinically because of renal toxicity (interstitial nephritis)
are mostly eliminated via biliary route
Nafcillin, Oxacillin and Dicloxacillin
EXTENDED SPECTRUM PENICILLINS:
These penicillins have extended coverage to include gram negative organisms including E. Coli, H. Influenza, etc.
Often a beta lactamase inhibitor must be added for susceptibility
Amoxicillin
Ampicillin
Category A drugs:
No human fetal risk or remote possibility of harm
Category B drugs: no control studies show human risk; animal studies show potential toxicity
Beta lactams Beta lactams with inhibitors Cephalosporins Aztreolam Clindomyacin Erythromycin Azithromycin Metronidazole Nitrofurantoin Sulfanomides
Category C drugs: animal fetal toxicity demonstrated; human risk undefined.
Chloramphenicol Fluoroquinolones Clarithromycin Trimethoprim Vancomycin Gentamicin Trimethoprim-sulfa-methoxazole
Category D drugs: human fetal risk present but benefits may outweighs risks
Tetracycline Aminoglycosides (except gentomicin)
Category X drugs:
Human fetal risk present but does not outweigh benefits; contraindicated in pregnancy
ANTI-PSEUDOMONAL PENICILLINS:
These antibiotics can still be destroyed by penicillinase. They are often administered with beta lactamase inhibitors. These antibiotics are effective against Pseudomonas Aeruginosa. Usually combined with an aminoglycoside (synergy).
Mezlocillin
Carbenecillin
Ticarcillin
Piperacillin*
Mechanisms of resistance to penicillins include:
Beta lactamase activity often acquired through plasmid transfer
Efflux pumps that decrease penetration of the antibiotic and prevent accumulation at the site of action
Altered PBPs that possess a lower affinity for beta lactam antibiotics. This is the mechanism of resistance for MRSA.
SIDE EFFECTS of penicillin
Hypersensitivity Diarrhea Interstitial Nephritis Bone Marrow Suppression Neurotoxicity (intrathecal) Cation toxicity
CEPHALOSPORINS
Contains beta-lactam ring
More resistant to penicillinase than penicillin
Ineffective against MRSA, Clostridium, Enterococci, and Listeria.
1st GEN. CEPHALOSPORINS: Mostly Gram positive coverage Used as prophylaxis for surgery PEcK (Proteus, E. Coli, Klebsiella) The spectrum and efficacy is similar to natural penicillins and staphylococcal penicillins
Cefazolin Cephalexin Cefadroxil
Cefalothin
2nd GEN. CEPHALOSPORINS:
Adequate coverage for Hemophilus Influenza, Neisseria and Enterobacter species
Orally active medications
Do not cross the blood-brain barrier except Cefuroxime
HENPEcK
Cefaclor Cefoxitin Cefuroxime Cefprozil Loracarbef Cefotetan Cefamandole
3rd GEN. CEPHALOSPORIN:
These antibiotics cross the blood brain barrier so are effective against meningitis
Some are antipseudomonal: Ceftazidime and Cefoperazone
Less Gram positive coverage but extensive Gram negative coverage
Ceftibuten
Cefixime
Cefdinir
Cefotaxime
4th GEN CEPHALOSPORINS:
Broader spectrum cephalosporins with anti-pseudomonal coverage as well as Gram positive coverage
Cefipime
Cefpirome
5th Generation Cephalosporins:
Ceftaroline which is effective against MRSA as well as other Gram positive organisms and Gram negative organisms
SIDE EFFECTS of cephalosporins
There is a 5-10% cross reactivity between allergies to penicillins and allergies to cephalosporins
Patients who have had SJS or TEN with penicillins should not be placed on cephalosporins or vice versa
Other side effects: diarrhea, alcohol intolerance, thrombocytopenia and other bleeding disorders
CARBEPENEMS:
Carbepenems are synthetic beta lactam antibiotics
Broader spectrum – aerobes and anaerobes
Resistant to beta lactamase
Effective against many strains of Pseudomonas and Bacteroides
Other carbepenems are not susceptible to dipeptidase
Doripenem Ertapenem Imipenem
Meropenem
Imipenem:
is broken down by enzymes in the brush border and kidneys (dipeptidase) which can be prevented by co-administering cilastatin.
Ertapenem
is not effective against Pseudomonas and Imipenem should not be used as monotherapy against Pseudomonas Aeruginosa.
Aztreonem
is a monobactam that is resistant to beta lactamase and is effective against Gram negative organisms including Pseudomonas
has no coverage of Gram positive organisms or anaerobes
Side effects to Carbapenems:
Nausea and vomiting are the most common side effects, there can exist cross-reactivity to penicillin allergies, but this is much less common than with cephalosporins
Aztreonem has no cross reactivity with other beta lactam antibiotics
BETA LACTAMASE INHIBITORS:
These drugs have NO antimicrobial activity on their own and cannot be used to treat infections
They are effective against penicillinase producing strains of organsims in conjunction with a bet lactam antibiotic, preventing the enzyme from destroying the antibiotic
Beta lactamase inhibitors are effective against plasmid encoded beta lactamases but ineffective against chromosomal beta lactamses produced by gram negative bacilli (Enterobacter, Acenitobacter, Citrobacter)
Clavulinic Acid Sulbactam Tazobactam
VANCOMYCIN
Complex tricyclic glycopeptide that inhibits cell wall synthesis
Primarily effective against Gram positive organisms including MRSA (aerobes and anaerobes)
Ineffective against Gram negative organisms
Vanco
Relatively large molecule (MW > 1500 daltons)
Resistant strains of enterococci have emerged
Due to alteration of target D-Ala-D-Ala to
D-Ala-D-lactate or D-Ala-D-Serine
Also S. Aureus has emerged with a plasmid that confers resistance to Vancomycin
is poorly absorbed afte oral administration and has to be given parenterally for systemic effects.
Can be given orally for C. Difficile pseudo-membranous colitis
30% protein bound, large Vd and penetrates into the CNS when meningitis is present.
Eliminated 90% unchanged by the kidneys
Vancomycin
Vancomycin has to be monitored due to many adverse effects:
Red man syndrome from histamine release leading to hypersensitivity and anaphylaxis
Nephrotoxicity
Ototoxicity
Plasma Peak and Trough levels must be monitored for potential toxicity
Pre-treatment with antihistamines may be necessary
Other side effects: Fever, Chills and Phlebitis
DAPTOMYCIN
Cyclic lipopeptide antibiotic effective in treating MRSA or VRE
Induces rapid depolarization of the bacterial membrane and inhibiting DNA, RNA and protein synthesis. This effect is bactericidal and concentration dependent
Daptomycin is only effective against Gram positive organisms
Daptomycin is inactivated by pulmonary surfactants and should never be used in treating pneumonias and left-sided endocarditis
Side Effects of DAPTOMYCIN
headache, myalgia, elevated CPK, elevated LFTs, insomnia, constipation, nephrotoxicity if used with other agents that can cause this. Also, use with caution in the presence of HMG-CoA reductase inhibitors.
Pharmacokinetics: > 90% protein-bound
No significant drug-drug interactions and is excreted 80% unchanged in the urine
TELEVANCIN
Semisynthetic lipoglycopeptide derivative of Vancomycin effective against MRSA and other resistant Gram positive organisms
Inhibitor of bacterial cell wall synthesis and causes disruption of bacterial cell membrane
Effective against MRSA, Streptococcus, VSE
Side effects of TELEVANCIN
metallic taste, headache, nausea, vomiting, insomnia, foamy urine, long QT interval, contraindicated in pregnancy, can interfere with coagulation tests.
TEICOPLANIN
Glycopeptide antibiotic that inhibits cell wall synthesis. Mechanism of action is similar to Vancomycin
Binds to D-Ala-D-Ala terminus of cell wall precursor units and prevents assembly. Effective only for Gram positive organisms, including MRSA, Listeria, Corynebacterium, Clostridium and anaerobic Gram positive cocci.
Alteration of cell wall targets will create resistance to Teicoplanin
Side Effects of TEICOPLANIN
rash, hypersensitivity, fever, neutropenia and ototoxicity
Highly protein bound (90%) and a t½ = 100 hours
Elimination is renal
Dosage adjustment necessary for renal insufficiency
List of TETRACYCLINES
Tetracycline Doxycycline Minocycline Demeclocycline Tigecycline (Glycylcycline)
List of AMINOGLYCOSIDE
Netilmicin Kanamycin Tobramycin Gentamycin Streptomycin Amikacin Neomycin Paromomycin
List of MACROLIDES
Erythromycin
Clarithromycin
Azithromycin
Telithromycin
OTHER protein synthesis inhibitors
Clindamycin Chloramphenicol Linezolid Quinupristin/Dalfopristin Spectinomycin
TETRACYCLINES
Bacteriostatic antibiotics
Inhibit protein synthesis by binding to 30S subunit
Broad spectrum aerobes, anaerobes, Gram positive, Gram negative
Effective against Rickettsia, Mycoplasma, Chlamydia, Legionella, etc.Ureaplasma, Borrelia, Treponema, etc.
Resistance is widespread
Many side effects
Absorption of tetracycline
Variable absorption via oral administration:
Doxycycline > Minocycline > Tetracycline
Absorption is decreased with dairy products or antacids
Large volume of distribution
Metabolized by the liver and excreted by kidneys and entero-hepatic circulation
Indication for tetracycline
Rickettsial Infections Mycoplasma Pneumoniae Chlamydial infections Often used in STD treatment to ensure eradication of Chlamydia Anthrax Brucellosis Tularemia Cholera Borrelia Gram Positive Cocci including MRSA and Strep
SIDE EFFECTS of tetracyclines
GI Irritation which can improve with foods Pseudomembranous Colitis Photosensitivity Hepatic Toxicity Renal Toxicity (except Doxycycline) Vestibular problems such as vertigo, dizziness Effects on Teeth and Bone Hypersensitivity Reactions Pseudotumor Cerebri Contraindicated in Pregnancy
Resistance to Tetracyclines
Resistance to Tetracyclines is emerging. Several mechanism of resistance:
Active efflux of the drug from the cytoplasm via a Mg++ dependent pathway
Enzymatic inactivation of the drug
Alterations in ribosome binding sites – production of proteins that displace drug from ribosomal binding sites
Cross resistance is very common among the tertracyclines
Tigecycline has activity against MRSA and other resistant strains of microorganisms but no effect against Pseudomonas or Proteus strains
AMINOGLYCOSIDES
Most effective against aerobic Gram negative bacilli. They are bactericidal.
Synergistic effects with beta lactams
Very toxic which limits usefulness
Mechanism of Action – diffuse through porins and bind to 30S subunit causing misreading of codon. Also premature termination of translation and impaired assembly of polysomes.
Some aminoglycosides also bind to the 50S subunit
Indications for aminoglycosides
Aminoglycosides are rarely if ever used as single agents
They are most effective against aerobic gram negative bacilli: Pseudomonas, Proteus
Enterococcus are highly resistant to all aminoglycosides
Streptomycin is used primarily for Mycobacterium species and many enteric organisms are resistant to Streptomycin
Endocarditis, pneumonia, tularemia, UTIs
Resistance to Aminoglycosides
Bacteria may acquire resistance to aminoglycosides by failure to allow penetration of the drug intracellularly
Also low affinity of the drug for bacterial ribosomes
Drug inactivation by modification: acetylation, phosphorylation or adenylation
Amikacin is least modified of the aminoglycosides therefore little resistance develops in comparison to other aminoglycosides
SIDE EFFECTS of Aminoglycosides
Aminoglycosides are particularly toxic and require monitoring of drug levels via peaks and troughs.
Ototoxicity – vestibular and cochlear. Aminoglycoside administration in pregnancy will cause the newborn deafness. Neomycin, Kanamycin, Amikacin are more apt to cause hearing loss. Gentamycin and Streptomycin are more apt to cause vestibular problems. These are effects are dose dependent.
These effects may be permanent.
Co-administration of loop diuretics can worsen the damage
Nephrotoxicity – Effects of aminoglycosides on proximal tubular cells can interfere with calcium-mediate transport and damage the kidney. Some of these effects may be irreversible.
Nephrotoxicity
The most nephrotoxic agents are Gentamycin, Tobramycin and Neomycin.
Nephrotoxicity is always preceded by a rise in plasma creatinine
Vancomycin, ACEI, Amphotericin, Cisplatin and cyclosporine can worsen the nephrotoxicity
Other side effects of Aminoglycosides
Neuromuscular blockade – Aminoglycosides can potentiate neuromuscular blockers and other anesthetic agents. This will also be seen in patient who have Myasthenia Gravis.
Neuromuscular blockade can be reversed by the administration of calcium gluconate or neostigmine.
This effect is most likely to be seen with intrapleural or intraperitoneal administration of aminoglycosides
Mechanism of action is decreased release of Acetylcholine and decreased sensitivity of muscarinic receptors
Streptomycin can cause optic neuritis and scotomas.
Aminoglycosides do not cause pseudomembranous colitis or allergic reactions
MACROLIDES
Bacteriostatic antibiotic that is concentration dependent
Drug of choice for patients allergic to Penicillins
Indications:
Mycoplasma Infections
Legionnaire’s Disease
Chlamydial Infections
Hemophilus Influenza
Heliobacter Pylori
Diphtheria
Pertussis
Effective against Gram positive bacilli such as Clostridium
Erythromycin and Clarithromycin inhibit CYP3A4 and can cause drug-drug interactions with substrates such as
carbamazepine, theophylline, antihistamines, coumadin, valproic acid, benzodiazepines, etc.
Food inhibits absorption of Erythromycin and Azithromycin but increases absorption of
Clarithromycin
Side effects of Macrolides
GI upset and hypermotility – binds motilin in GI tract
Cholestatic Jaundice
Ototoxicity
Hepatotoxicity
Long QT Syndrome
Drug-drug interactions
Allergic Reactions: fever, eosinophilia, rash, etc.
CLINDAMYCIN
Bacteriostatic inhibitor of protein synthesis that binds to the 50S subunit
Shows greater efficacy against anaerobic organisms
Streptococci and MSSA are sensitive but aerobic Gram negative bacilli are resistant
