Antibiotics

Question 0

Antibiotics

Answer 0

naturally occurring agent that inhibits growth of bacteria

Question 1

Chemotherapeutics

Answer 1

agent that inhibits rapidly dividing cells

Question 2

Antibacterials

Answer 2

semi- or synthetic agent that inhibits bacterial growth

Question 3

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:

Answer 3

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

Question 4

CULTURE and SENSITIVITY

Answer 4

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

Question 5

EMPIRIC THERAPY

Answer 5

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

Question 6

MIC

Answer 6

minimum inhibitory conc. is the smallest concentration necessary to inhibit growth in culture

Question 7

MBC

Answer 7

minimum bacteriocidal conc. is the smallest concentration necessary to kill the bacteria (99.9%)

Question 8

Bacteriostatic drugs

Answer 8

• 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

Question 9

Bactericidal drugs

Answer 9

• 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

Question 10

Some antibiotics cross the blood-brain barrier easily:

Answer 10

chloramphenicol, metronidazole, 3rd generation cephalosporin, etc.

Question 11

Some antibiotics cross the blood-brain barrier poorly:

Answer 11

vancomycin, penicillins (unless there is meningitis), 1st generation cephalosporin, etc.

Question 12

Antibiotic must get to the site of action

Answer 12

If infection is in the CNS, antibiotic must cross the blood-brain barrier

Question 13

Protein binding

Answer 13

many antibiotics are highly protein bound

Question 14

Metabolism and excretion

Answer 14

• 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

Question 15

Immune status

Answer 15

if the patient has a co-morbid condition that interferes with immune function, this may alter the choice of antibiotics

Question 16

Very young and very old patients

Answer 16

have decreased ability to metabolize and excrete antibiotics, so the choice and dosage must be altered

Question 17

Pregnancy and lactation can alter the choice of antibiotics. The following drugs should be avoided in pregnancy:

Answer 17

tetracyclines, quinolones, chloramphenicol, aminoglycosides, folic acid inhibitors, etc.

Question 18

ROUTE OF ADMINISTRATION

Answer 18

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

Question 19

POST-ANTIBIOTIC EFFECT

Answer 19

Some antibiotics continue to work long after the MIC has been breached. The antibiotics that exhibit the PAE include aminoglycosides, fluoroquinolones, tigecycline

Question 20

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.

Answer 20

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.

Question 21

Narrow spectrum antibiotics

Answer 21

isoniazid

Question 22

Extended spectrum antibiotics

Answer 22

ampicillin

Question 23

Broad spectrum antibiotics

Answer 23

tetracycline, fluoroquinolones, macrolides, chloramphenicol

Question 24

RESISTANCE

Answer 24

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)

Question 25

Genetic alterations leading to drug resistance

Answer 25

Spontaneous mutations Transfer of genes between organisms via plasmids, transduction or conjugation Inappropriate use of antibiotics increases risk by selection process

Question 26

Altered expression of proteins in resistance

Answer 26

Modification of target site, hence antibiotic inefficacy Decreased accumulation of antibiotic intracellularly Enzymatic inactivation of antibiotics

Question 27

Antibiotics are given prophylactically for various situations:

Answer 27

surgery, MVP, traveling to endemic regions, high-risk situations

Question 28

CLASSES OF ANTIBIOTICS

Answer 28

``` Cell wall inhibitors Inhibitors of protein synthesis Inhibitors of folate metabolism Inhibitors of bacterial DNA synthesis Inhibitors of cell membrane function ```

Question 29

SIDE EFFECTS

Answer 29

Hypersensitivity reaction Jarisch-Herxheimer reaction and Mazzotti Rxn Direct toxicity - aminoglycosides Superinfections – Broad spectrum antibiotics

Question 30

Carbapenems

Answer 30

Doripenem Ertapenem Imipenem Meropenem

Question 31

Beta-Lactamase Inhibitors

Answer 31

Clavulanic Acid Sulbactam Tazobactam

Question 32

Monobactams

Answer 32

Aztreonem

Question 33

PENICILLINS

Answer 33

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

Question 34

NATURAL PENICILLINS

Answer 34

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.

Question 35

Gram+ coccus: | Tx: natural penicillin

Answer 35

Streptococcus pneumoniae Streptococcus pyrogenes Streptococcus viridans group

Question 36

Gram+ bacilli: | Tx: natural penicillin

Answer 36

Bacillus anthracis | Corynebacterium diphtheriae

Question 37

Gram- cocci: | Tx: natural penicillin

Answer 37

Neisseria Gonorrhoeae | Neisseria meningitis

Question 38

Gram- rods: anaerobic organisms | Tx: natural penicillin

Answer 38

Clostridium perfringens

Question 39

Gram- rods: spirochetes | Tx: natural penicillin

Answer 39

``` Treponema pallidum (syphillis) Treponema pertenue (yaws) ```

Question 40

Syphillis | Tx: natural penicillin

Answer 40

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.

Question 41

Gonorrhea: Tx: natural penicillin

Answer 41

Silver nitrates in the eyes prevent gonoccocal ophthalmia in newborns. Penicillinase-producing strains are treated using ceftriaxone with spectinomycin as a backup.

Question 42

Pneumococcal pneumonia: | Tx: natural penicillin

Answer 42

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.

Question 43

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

Answer 43

Oxacillin Dicloxacillin Nafcillin Methicillin

Question 44

Methicillin:

Answer 44

is not used clinically because of renal toxicity (interstitial nephritis)

Question 45

are mostly eliminated via biliary route

Answer 45

Nafcillin, Oxacillin and Dicloxacillin

Question 46

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

Answer 46

Amoxicillin | Ampicillin

Question 47

Category A drugs:

Answer 47

No human fetal risk or remote possibility of harm

Question 48

Category B drugs: no control studies show human risk; animal studies show potential toxicity

Answer 48

``` Beta lactams Beta lactams with inhibitors Cephalosporins Aztreolam Clindomyacin Erythromycin Azithromycin Metronidazole Nitrofurantoin Sulfanomides ```

Question 49

Category C drugs: animal fetal toxicity demonstrated; human risk undefined.

Answer 49

``` Chloramphenicol Fluoroquinolones Clarithromycin Trimethoprim Vancomycin Gentamicin Trimethoprim-sulfa-methoxazole ```

Question 50

Category D drugs: human fetal risk present but benefits may outweighs risks

Answer 50

``` Tetracycline Aminoglycosides (except gentomicin) ```

Question 51

Category X drugs:

Answer 51

Human fetal risk present but does not outweigh benefits; contraindicated in pregnancy

Question 52

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).

Answer 52

Mezlocillin Carbenecillin Ticarcillin Piperacillin*

Question 53

Mechanisms of resistance to penicillins include:

Answer 53

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.

Question 54

SIDE EFFECTS of penicillin

Answer 54

``` Hypersensitivity Diarrhea Interstitial Nephritis Bone Marrow Suppression Neurotoxicity (intrathecal) Cation toxicity ```

Question 55

CEPHALOSPORINS

Answer 55

Contains beta-lactam ring More resistant to penicillinase than penicillin Ineffective against MRSA, Clostridium, Enterococci, and Listeria.

Question 56

``` 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 ```

Answer 56

Cefazolin Cephalexin Cefadroxil Cefalothin

Question 57

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

Answer 57

``` Cefaclor Cefoxitin Cefuroxime Cefprozil Loracarbef Cefotetan Cefamandole ```

Question 58

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

Answer 58

Ceftibuten Cefixime Cefdinir Cefotaxime

Question 59

4th GEN CEPHALOSPORINS: | Broader spectrum cephalosporins with anti-pseudomonal coverage as well as Gram positive coverage

Answer 59

Cefipime | Cefpirome

Question 60

5th Generation Cephalosporins:

Answer 60

Ceftaroline which is effective against MRSA as well as other Gram positive organisms and Gram negative organisms

Question 61

SIDE EFFECTS of cephalosporins

Answer 61

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

Question 62

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

Answer 62

Doripenem Ertapenem Imipenem | Meropenem

Question 63

Imipenem:

Answer 63

is broken down by enzymes in the brush border and kidneys (dipeptidase) which can be prevented by co-administering cilastatin.

Question 64

Ertapenem

Answer 64

is not effective against Pseudomonas and Imipenem should not be used as monotherapy against Pseudomonas Aeruginosa.

Question 65

Aztreonem

Answer 65

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

Question 66

Side effects to Carbapenems:

Answer 66

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

Question 67

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)

Answer 67

Clavulinic Acid Sulbactam Tazobactam

Question 68

VANCOMYCIN

Answer 68

Complex tricyclic glycopeptide that inhibits cell wall synthesis Primarily effective against Gram positive organisms including MRSA (aerobes and anaerobes) Ineffective against Gram negative organisms

Question 69

Vanco

Answer 69

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

Question 70

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

Answer 70

Vancomycin

Question 71

Vancomycin has to be monitored due to many adverse effects:

Answer 71

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

Question 72

DAPTOMYCIN

Answer 72

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

Question 73

Side Effects of DAPTOMYCIN

Answer 73

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

Question 74

TELEVANCIN

Answer 74

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

Question 75

Side effects of TELEVANCIN

Answer 75

metallic taste, headache, nausea, vomiting, insomnia, foamy urine, long QT interval, contraindicated in pregnancy, can interfere with coagulation tests.

Question 76

TEICOPLANIN

Answer 76

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

Question 77

Side Effects of TEICOPLANIN

Answer 77

rash, hypersensitivity, fever, neutropenia and ototoxicity Highly protein bound (90%) and a t½ = 100 hours Elimination is renal Dosage adjustment necessary for renal insufficiency

Question 78

List of TETRACYCLINES

Answer 78

``` Tetracycline Doxycycline Minocycline Demeclocycline Tigecycline (Glycylcycline) ```

Question 79

List of AMINOGLYCOSIDE

Answer 79

``` Netilmicin Kanamycin Tobramycin Gentamycin Streptomycin Amikacin Neomycin Paromomycin ```

Question 80

List of MACROLIDES

Answer 80

Erythromycin Clarithromycin Azithromycin Telithromycin

Question 81

OTHER protein synthesis inhibitors

Answer 81

``` Clindamycin Chloramphenicol Linezolid Quinupristin/Dalfopristin Spectinomycin ```

Question 82

TETRACYCLINES

Answer 82

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

Question 83

Absorption of tetracycline

Answer 83

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

Question 84

Indication for tetracycline

Answer 84

``` 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 ```

Question 85

SIDE EFFECTS of tetracyclines

Answer 85

``` 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 ```

Question 86

Resistance to Tetracyclines

Answer 86

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

Question 87

AMINOGLYCOSIDES

Answer 87

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

Question 88

Indications for aminoglycosides

Answer 88

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

Question 89

Resistance to Aminoglycosides

Answer 89

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

Question 90

SIDE EFFECTS of Aminoglycosides

Answer 90

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.

Question 91

Nephrotoxicity

Answer 91

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

Question 92

Other side effects of Aminoglycosides

Answer 92

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

Question 93

MACROLIDES

Answer 93

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

Question 94

Erythromycin and Clarithromycin inhibit CYP3A4 and can cause drug-drug interactions with substrates such as

Answer 94

carbamazepine, theophylline, antihistamines, coumadin, valproic acid, benzodiazepines, etc.

Question 95

Food inhibits absorption of Erythromycin and Azithromycin but increases absorption of

Answer 95

Clarithromycin

Question 96

Side effects of Macrolides

Answer 96

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.

Question 97

CLINDAMYCIN

Answer 97

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