Antibiotics

Antibiotics
Things to keep in your lab coat.
● The Sanford Guide to Antimicrobial
Therapy
● Johns Hopkins Abx Guide (not free any
more)
● Palm
○ iSilo program
○ Epocrates
Tips for the boards
● Study hard and efficiently. Don’t waste time on a
resource that isn’t making sense.
● Get the landscape first then the landmarks.
● Don’t be afraid to study outside of the review
books.
● Think like a question writer. Anticipate questions
for each topic.
● Forget about learning everything because the
gaps in your knowledge will be random.
Gram-positives
Gram-negatives
Imipenem
Meropene
m
Amoxicillin
Anti-staph PCN’s
(nafcillin, methicillin,
oxacillins)
Ampicillin
Anti-pseudomonal PCN’s
(pipercillin, ticarcillin,
carbenicillin)
Macrolides
Penicillin G/V
Clindamycin
Linezolid
Fluoroquinolines
Vancomyci
n
Rifampin
Sulfonamides
Aztreona
m
Aminoglycosides
Tetracyclines
1st Generation
Cephalosporin
s
3rd
Generation
2nd
Generation
How to approach the daunting task
of learning antibiotics
Create a general rule and know the
exception to the rule.
Rule: All cell-wall inhibitors are beta-lactams,
except vancomycin.
● Beta-lactam ABX
○ Penicillins
○ Cephalosporins
○ Aztreonam
○ Carbapenems
● Exception
○ Vancomycin
Beta-lactam structure
Gram-positive vs. Gram-negative
Mechanism of Action
1. All beta-lactams bind penicillin-binding
proteins (PBP’s)
2. All beta-lactams block transpeptidase
cross-linking of cell wall
3. Activate autolytic enzymes, causing
osmotic damage (bactericidal)
Beta-lactams:
1st mechanism of resistance
Beta-lactamase production (i.e. S. aureus)
We can get around this mode of resistance by
making beta-lactamase resistant penicillins (i.e.
nafcillin)
Beta-lactams:
2nd mechanism of resistance
Change the structure of PBP’s
(i.e. Methicillin-Resistant S. Aureus)
Once bugs have changed their PBP’s, we only
have one drug that will work, vancomycin.
Beta-lactams:
3rd mechanism of resistance
Efflux pump or change in porin structure:
Relevant for gram-negative bacteria
Summary of resistances to betalactamases
1st beta-lactamase production (S. aureus)
2nd change in PBP (MRSA)
3rd efflux pump or change in porin structure
(gram-negatives i.e. pseudomonas)
1st Generation
● Drugs
○ Penicillin G and V
● Clinical use
○ Narrow spectrum (mainly gram-positives)
● Sensitive to beta-lactamases
○ Means: on an exam, penicillin G or V is never the
answer for treating Staph
● Exam questions:
○ DOC for syphillis (benzathine penicillin),
○ DOC in strep infections, especially to prevent
rheumatic fever
○ DOC for susceptible pneumococci
2nd Generation
● Drugs
○ Nafcillin, Methicillin, Oxacillin, Cloxacillin,
Diclaxicillin
● To overcome the beta-lactamase resistance,
these drugs were developed but they became so
narrow spectrum that they only clinically are
used for Staph.
● These drugs created the superbug MRSA
○ Beta-lactamase
○ Altered PBP’s
3rd Generation
● Drugs
○ Aminopenicillins
■ Ampicillin
■ Amoxicillin
● Clinical use
○ Broad spectrum (gram positive and gram negatives, but NOT
beta-lactamase resistant)
■ Famous for treating:
■ H. flu and Listeria (ampicillin)
■ Lyme Disease (amox) DOC in peds and pregnancy
■ Enterococci
○ Drug companies made body guards, clavulanic acid and
sulbactam, to protect the aminopenicillins from beta-lactamases.
4th Generation
● Drugs
○ Anti-pseudomonal penicillins
■ Ticarcillin
■ Piperacillin
■ Carbenicillin
● Clinical use
■ Pseudomonas
■ Synergistic effect when combined with aminoglycosides.
■ Parenteral penicillins usually combined with beta-lactamase
inhibitors
Pharmacokinetics of Penicillins
● Rule: All penicillins are water soluble, except nafcillin.
● Water soluble substances:
○ Are excreted by the kidneys.
■ Means adjustments in renal failure and are potentially renal toxic
○ Do not cross the blood brain barrier
■ Means no good for meningitis
● Lipid soluble substances:
○ Are metabolized in the liver
■ Means many p450 interactions
○ Cross the blood brain barrier
■ Means could potentially be used for meningitis
Toxicity
● Rule: Penicillins cause allergies
○ Come from fungal organisms
■ Means already immunogenic
○ Contain sulfur to enhance solubility
■ Means bad for allergies
○ Can cause ANY hypersensitivity reaction (Type I-IV)
■ Methicillin famous for interstitial nephritis (type III)
■ Hapten mediated hemolysis
■ About 5-10% cross-allergenicity with cephalosporins
Toxicity
● Jarisch-Herxheimer reaction in Rx of syphilis
○ Fever, chills, headache, myalgias, and
exacerbation of syphilitic cutaneous lesions
● Ampicillin causes a famous maculopapular rash
when given to patients with infectious mono
(EBV).
Cephalosporins
● Mechanism of action and resistance:
○ same as penicillins
1st Generation Cephalosporins
● Drugs
○ Any drug with “ph” in name b/c from Europe
■ Cephalexin, cephradine
■ Except cefazolin (famous for surgical prophylaxis b/c of long
half-life)
● Clinical use
○ Gram positives
■ And a few gram negatives PEcK (Proteus, E. coli, Klebsiella)
● Pharmacokinetics
○ Do not enter CNS
2nd Generation Cephalosporins
● Drugs
○ Cefoxitin, cefaclor, cefuroxime
● Clinical use
○ Gram negatives: HEN PEcKS (H. flu,
Enterobacter, Neisseria, Proteus, E. coli,
Klebsiella, Serratia)
● Pharmacokinetics
○ Do not enter CNS, except cefuroxime
3rd Generation Cephalosporins
● Drugs
○ Ceftriaxone, cefotaxime, ceftazidime
○ notice the “t’s”
● Clinical use
○ 1st generation + 2nd generation = 3rd generation (gram positive
and negative) +anaerobes
● Pharmacokinetics
○ Ceftriaxone is lipid soluble
■ Means good entry into CNS
■ Means metabolized and excreted into bowel
■ Can cause sludge in gallbladder
● Boards:
○ Ceftazidime for pseudomonaz
○ Ceftriaxone for gonorrhea and meningitis
4th Generation Cephalosporins
● Drugs
○ Cefepime
○ Cefpirome
● Clinical use
○ 3rd Generation + more beta-lactamase
resistance
Toxicity
● Same as penicillins
● Disuliram-like reaction w/ ethanol
○ In cephalosporins with a methylthiotetrazole
group, i.e. cefamandole, cefoperazone,
cefotetan
■ “azole” portion gives us the disulfiram-like reaction
■ Metronidazole
Aztreonam
● Mechanism:
○ Monobactam resistant to beta-lactamases
○ Inhibits cell wall synthesis (same as
penicillins)
○ Synergistic with aminoglycosides
● Clinical use
○ Gram negative rods only (pseudomonas)
● Toxicity
○ No cross-allergenicity w/ penicillins
Imipenem/cilastatin, Meropenem
● Mechanism
○ Carbapenems resistant to beta-lactamases
○ Inhibits cell wall synthesis (same as penicillins)
○ Cilastatin inhibits renal dihydropeptidase I which
decreased inactivation of imipenem in kidney.
● Clinical use
○ “Decerebrate Antibiotics”
■ Don’t need to think about coverage, can work on almost
anything
● Toxicity
○ Imipenem famous for CNS toxicity (seizures)
○ Meropenem has reduced risk of seizures
Vancomycin
● Mechanism
○ Inhibits cell wall mucopeptide formation by binding
○ D-ala D-ala portion of cell wall precursors (USMLE TQ)
■ Resistance occurs when changed to D-ala D-lac
● Clinical use
○ Gram positive multidrug-resistant organisms
■ MRSA (IV)
■ C. difficile (PO)
● Toxicity
○ Nephro and ototoxic
○ “Red man syndrome” with rapid infusion
■ Can prevent w/ antihistamine pretreatment
Gram-positives
Anti-staph PCN’s
(nafcillin, methicillin,
oxacillins)
Gram-negatives
Imipenem
Meropene
m
Amoxicillin
Ampicillin
Anti-pseudomonal PCN’s
(pipercillin, ticarcillin,
carbenicillin)
Penicillin G/V
50s ribosome
Vancomyci
n
Nucleus
Aztreona
m
30s ribosome
1st Generation
Cephalosporin
s
3rd
Generation
2nd
Generation
Protein Synthesis Inhibitors
Rule: All protein synthesis inhibitors are
bacteriostatic, except for the
aminoglycosides.
Tetracyclines
● Drugs
○ Doxycycline
○ Minocycline
○ Demeclocycline
○ Tetracycline
● Mechanism
○ Reversibly bind to the
30S ribosome and
inhibit binding of
aminoacyl-t-RNA to the
acceptor site.
Tetracyclines
● Clinical use
○ Very broad spectrum
○ Important use for spirochetes and intracellular bugs
■ Rickettsial Infections
■ Chlamydia
● Toxicity
○ Chelators of divalent ions
■ Means they deposit in bones and teeth
■ Means contraindicated in pregnancy and in kids who are still growing
■ Means can’t take with antacids or iron.
○ GI distress
○ Fanconi’s syndrome
○ Photosensitivity
● Boards:
○ Doxycycline is lipid soluble; means good STD’s and prostatitis
○ Minocycline is very water soluble and enters all secretions, especially saliva;
means useful for meningococcus prophylaxis
○ Demeclocycline inhibits the release of ADH; means can be used for SIADH
Aminoglycosides
● Drugs
○ Gentamycin, neomycin, amikacin, tobramycin, streptomycin
● Mechanism
○ Taken up by an oxygen dependent pump and bind to the 30S ribosomal unit
and Induce the binding of the “wrong” t-RNA-AA complex, resulting in the
synthesis of false proteins. (Bactericidal)
Aminoglycosides
● Clinical use
○ Gram negative aerobes only!
(pseudomonas)
○ Synergistic w/ beta-lactams
○ Neomycin for bowel surgery
○ Tobramycin for Pseudomonas
● Toxicity
○ Amino (NH3) + glycoside (OH) makes
extremely polar
■ Means membrane penetration in a
bacteria is dependent on a special
oxygen pump and only covers gram
negative aerobes
■ Means renally excreted and renal toxic
■ Means can be trapped in inner ear and
is ototoxic
○ Neuromuscular blockade
Macrolides
● Drugs:
○ Erythromycin
○ Azithromycin
○ Clarithromycin
● Mechanism
○ Inhibit protein synthesis
by blocking
translocation, bind to
50S ribosomal subunit
(resistance is through
methylation at binding
site)
Macrolides
● Clinical use
○ Same broad coverage as tetracyclines
○ URI’s and atypical pneumonias (Mycoplasma,
Legionella, Chlamydia)
○ Neisseria
○ Alternative for penicillin allergic patients
● Toxicities
○ Stimulate motilin receptor (erythromycin) causing GI
upset
○ Lipid soluble, except azithromycin
■ Means P450 interactions (erythromycin is a famous inhibitor)
and liver problems (acute cholestatic hepatitis)
Clindamycin
● Mechanism
○ Blocks peptide bond formation at 50S
ribosomal subunit (bacteriostatic)
● Clinical use
○ Gram-positives and anaerobes
■ Means can easily cause C. diff colitis
○ Good penetration into bones
■ Means can be used for S. aureus osteomyelitis
Linezolid
● Mechanism
○ Linezolid binds on the 23S portion of the 50S subunit close to the
peptidyl transferase and chloramphenicol binding sites.
● Clinical
○ Famous for treating gram-positive drug resistant bugs (MRSA,
and multidrug resistant pneumococcus)
● Toxicity
○ Usually well tolerated
○ Thrombocytopenia
○ MAOI (avoid tyramine containing food)
Quinupristin/Dalfopristin
● Mechanism
○ Protein synthesis inhibitors that bind the 50S
ribosomal subunit
● Clinical use
○ VRE
● Toxicity
○ P-450 inhibitor
Inhibitors of DNA synthesis
Fluoroquinolones
Rifampin
Sulfonamides
Fluoroquinolones
● Drugs
○ Ciprofloxacin
○ Gatifloxacin
○ Levofloxacin
○ Moxifloxacin
○ Ofloxacin
● Mechanism
○ Inhibits DNA gyrase (topoisomerase II) (Bactericidal)
Fluoroquinolones
● Clinical use
○ Gram-negative rods of UTI and diarrhea
○ Were 1st oral treatment of gram-negative sepsis
■ Means were overused, leading to resistance
○ Distributes into all tissues and fluids (including bones)
■ Means can inhibit cartilage and tendon damage leading to tendonitis
and tendon rupture in adults
■ Means can be used for Salmonella osteomyelitis
■ Means contraindicated in pregnancy and in children
○ Respiratory fluoroquinolones (levofloxacin) for drug resistant
pneumococcus
○ Anthrax (ciprofloxacin)
● Toxicity
○ QT prolongation and arrhythmias
○ Hypo/hyperglycemia
○ Achilles tendon rupture or tendinitis has occurred rarely
Rifampin
● Mechanism
○ Inhibits DNA-dependent RNA polymerase
● Clinical use
○ TB (in combo and in prophylaxis)
○ Famous for prophylaxis of meningococcus and H. flu
● Toxicity
○ Hepatotoxic
○ Revs up P-450
○ R’s:
■ RNA polymerase inhibitor
■ Revs up P-450
■ Red/orange body fluids
Sulfonamides and Trimethoprim
Sulfonamides
● Mechanism
○ Inhibits bacterial dihydropteroate synthase
by competing for binding sites with paminobenzoic acid (PABA), a precursor
required for bacterial synthesis of folic acid.
○ Trimethoprim binds tightly to bacterial
dihydrofolate reductase. Synergistic with
sulfonamides.
Sulfonamides
● Clinical use
○ Resistance to sulfonamides is common
○ PCP prophylaxis (PO) and treatment (IV)
■ Trimethoprim–Sulfamethoxazole, (TMP-SMX)
■ If sulfa allergy use pentamidine (antiprotozoal agent)
○ Toxoplasmosis (Pyrimethamine + Sulfadiazine)
● Toxicity
○ Allergies (sulfa allergies, hemolytic anemia, SJS)
○ Carried by albumin
■ Means can cause kernicterus
○ Crystalluria
○ Folic acid can be given to avoid some toxicities
Metronidazole
● Mechanism
○ Toxic metabolites
■ Means causes GI disturbance, glossitis (metallic taste in
mouth), urethritis
● Clinical use
○ Anaerobes
○ “G.E.T. on the Metro” (Giardia, Entamoeba,
Trichomonas)
○ C. diff colitis (PO)
● Toxicity
○ Metronidazole
■ Disulfiram-like reaction w/ ethanol
Mechanisms of Resistance
How to approach antibiotic
coverage
Rule: Every bacteria is gram negative,
except for the gram-positives and oddballs.
Exceptions to everything is gramnegative
● Gram-positives
○ Staph/Strep
○ Listeria
○ Bacillus
○ Clostridium
○ Corynebacterium
● Oddballs
○ Mycoplasma (no cell wall)
○ Ureaplasma (no cell wall)
○ Legionella (silver stain)
○ Chlamydia (obligate
intracellular)
○ Rickettsia (obligate
intracellular)
○ Mycobacterium (acid-fast)
○ Treponema (spirochete)
○ Borrelia (spirochete)
Gram-positives
Gram-negatives
Cell Wall
50s ribosome
Nucleus
30s ribosome
Gram-positives
Gram-negatives
Cell Wall
50s ribosome
Vancomyci
n
Nucleus
30s ribosome
Aztreona
m
Gram-positives
Anti-staph PCN’s
(nafcillin, methicillin,
oxacillins)
Gram-negatives
Cell Wall
Anti-pseudomonal PCN’s
(pipercillin, ticarcillin,
carbenicillin)
Penicillin G/V
50s ribosome
Vancomyci
n
Nucleus
30s ribosome
Aztreona
m
Gram-positives
Anti-staph PCN’s
(nafcillin, methicillin,
oxacillins)
Gram-negatives
Cell Wall
Anti-pseudomonal PCN’s
(pipercillin, ticarcillin,
carbenicillin)
Penicillin G/V
50s ribosome
Vancomyci
n
Nucleus
Aztreona
m
30s ribosome
1st Generation
Cephalosporin
s
3rd
Generation
2nd
Generation
Gram-positives
Anti-staph PCN’s
(nafcillin, methicillin,
oxacillins)
Gram-negatives
Amoxicillin
Ampicillin
Anti-pseudomonal PCN’s
(pipercillin, ticarcillin,
carbenicillin)
Penicillin G/V
50s ribosome
Vancomyci
n
Nucleus
Aztreona
m
30s ribosome
1st Generation
Cephalosporin
s
3rd
Generation
2nd
Generation
Gram-positives
Anti-staph PCN’s
(nafcillin, methicillin,
oxacillins)
Gram-negatives
Imipenem
Meropene
m
Amoxicillin
Ampicillin
Anti-pseudomonal PCN’s
(pipercillin, ticarcillin,
carbenicillin)
Penicillin G/V
50s ribosome
Vancomyci
n
Nucleus
Aztreona
m
30s ribosome
1st Generation
Cephalosporin
s
3rd
Generation
2nd
Generation
Gram-positives
Gram-negatives
Imipenem
Meropene
m
Amoxicillin
Anti-staph PCN’s
(nafcillin, methicillin,
oxacillins)
Ampicillin
Anti-pseudomonal PCN’s
(pipercillin, ticarcillin,
carbenicillin)
Macrolides
Penicillin G/V
Clindamycin
Linezolid
Vancomyci
n
Nucleus
Aztreona
m
Aminoglycosides
Tetracyclines
1st Generation
Cephalosporin
s
3rd
Generation
2nd
Generation
Gram-positives
Gram-negatives
Imipenem
Meropene
m
Amoxicillin
Anti-staph PCN’s
(nafcillin, methicillin,
oxacillins)
Ampicillin
Anti-pseudomonal PCN’s
(pipercillin, ticarcillin,
carbenicillin)
Macrolides
Penicillin G/V
Clindamycin
Linezolid
Fluoroquinolines
Vancomyci
n
Rifampin
Sulfonamides
Aztreona
m
Aminoglycosides
Tetracyclines
1st Generation
Cephalosporin
s
3rd
Generation
2nd
Generation
My rules for antibiotics questions.
● Is the bug gram-positive or gram-negative?
○ Use the chart we just made for what antibiotic to use
● Look for contraindications to using your
antibiotic. Is the patient too young or too
pregnant?
○ Don’t use tetracyclines, aminoglycosides,
fluoroquinolones, sulfonamides.
● Is the bug intracellular
○ Use a tetracycline or macrolide
Antibacterial Drugs in Pregnancy
Antibacterial
Drug
Toxicity in Pregnancy
Recommendation
Aminoglycosides
Possible 8th nerve toxicity
Cautiona
Chloramphenicol
Gray syndrome in newborn
Caution at term
Fluoroquinolones
Arthropathy in immature animals
Caution
Clarithromycin
Teratogenicity in animals
Contraindicated
Ertapenem
Decreased weight in animals
Caution
Erythromycin
estolate
Cholestatic hepatitis
Contraindicated
Imipenem/cilastatin
Toxicity in some pregnant animals
Caution
Linezolid
Embryonic and fetal toxicity in rats
Caution
Meropenem
Unknown
Caution
Metronidazole
None known, but carcinogenic in rats
Caution
Nitrofurantoin
Hemolytic anemia in newborns
Caution; contraindicated at
term
Quinupristin/dalfop
ristin
Unknown
Caution
Sulfonamides
Hemolysis in newborn with G6PDb deficiency; kernicterus in
newborn
Caution; contraindicated at
term
Tetracyclines
Tooth discoloration, inhibition of bone growth in fetus; hepatotoxicity
Contraindicated
Vancomycin
Unknown
Caution
GBS, E. coli, H. flu, Listeria, Meningococcus, Pneumococcus
Newbor
n
Adul
t
Practice Question
A 16-year-old high school cheerleader presents
with low grade fever, pleuritic pain and a nonproductive cough. A sample tube of her blood was
placed in ice, and "grains of sand" appeared in the
glass portion of the tube. Therapy should include
which of the following?
A. Ampicillin
B. Erythromycin
C. Oxygen and external cooling
D. Penicillin G
E. Ribavirin
Practice Question
A 58-year-old alcoholic man with multiple dental caries
develops a pulmonary abscess and is treated with
antibiotics. Several days later, he develops nausea,
vomiting, abdominal pain, and voluminous green diarrhea.
Which of the following antibiotics is most likely responsible
for this patient's symptoms?
A. Chloramphenicol
B. Clindamycin
C. Gentamicin
D. Metronidazole
E. Vancomycin
Practice Question
Which of the following organisms is most
likely to be implicated as a cause of
urethritis that persists after antibiotic therapy
for gonorrhea?
A. Actinomyces
B. Chlamydia
C. Mycobacteria
D. Nocardia
E. Rickettsia
Practice Question
A 33-year-old woman presents with fever, vomiting, severe
irritative voiding symptoms, and pronounced costovertebral
angle tenderness. Laboratory evaluation reveals
leukocytosis with a left shift; blood cultures indicate
bacteremia. Urinalysis shows pyuria, mild hematuria, and
gram-negative bacteria. Which of the following drugs would
best treat this patient's infection?
A. Ampicillin and gentamicin
B. Erythromycin
C. Gentamicin and vancomycin
D. Tetracycline
Practice Question
A 35-year-old male undergoes an appendectomy. Several days later,
an abscess has formed at the surgical site. It does not improve with
administration of a cephalosporin, but does respond to nafcillin. The
infecting organism most likely produced an enzyme that would
hydrolyze which bond in the above molecule?
A. A
B. B
C. C
D. D
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