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. Dont waste time on a resource that isnt making sense. Get the landscape first then the landmarks. Dont 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 Anti-staph PCNs (nafcillin, methicillin, oxacillins) Penicillin G/V Clindamycin Linezolid Fluoroquinolines Vancomyci n Rifampin Sulfonamides Aminoglycosides Tetracyclines Imipenem Meropene m Amoxicillin Ampicillin Macrolides

Gram-negatives Anti-pseudomonal PCNs (pipercillin, ticarcillin, carbenicillin)

Aztreona m

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 (PBPs) 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 PBPs
(i.e. Methicillin-Resistant S. Aureus) Once bugs have changed their PBPs, 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 PBPs

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 ts

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
Dont 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 PCNs (nafcillin, methicillin, oxacillins) Penicillin G/V 50s ribosome Vancomyci n Nucleus 30s ribosome Imipenem Meropene m Amoxicillin Ampicillin

Gram-negatives Anti-pseudomonal PCNs (pipercillin, ticarcillin, carbenicillin)

Aztreona m

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 cant take with antacids or iron.

GI distress Fanconis syndrome Photosensitivity

Boards:
Doxycycline is lipid soluble; means good STDs 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 URIs 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 Rs:
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)
TrimethoprimSulfamethoxazole, (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 PCNs (nafcillin, methicillin, oxacillins) Penicillin G/V 50s ribosome Vancomyci n Nucleus 30s ribosome

Gram-negatives Anti-pseudomonal PCNs (pipercillin, ticarcillin, carbenicillin)

Cell Wall

Aztreona m

Gram-positives Anti-staph PCNs (nafcillin, methicillin, oxacillins) Penicillin G/V 50s ribosome Vancomyci n Nucleus 30s ribosome

Gram-negatives Anti-pseudomonal PCNs (pipercillin, ticarcillin, carbenicillin)

Cell Wall

Aztreona m

1st Generation

Cephalosporin s 3rd Generation

2nd Generation

Gram-positives Anti-staph PCNs (nafcillin, methicillin, oxacillins) Penicillin G/V 50s ribosome Vancomyci n Nucleus 30s ribosome

Gram-negatives Anti-pseudomonal PCNs (pipercillin, ticarcillin, carbenicillin)

Amoxicillin Ampicillin

Aztreona m

1st Generation

Cephalosporin s 3rd Generation

2nd Generation

Gram-positives Anti-staph PCNs (nafcillin, methicillin, oxacillins) Penicillin G/V 50s ribosome Vancomyci n Nucleus 30s ribosome Imipenem Meropene m Amoxicillin Ampicillin

Gram-negatives Anti-pseudomonal PCNs (pipercillin, ticarcillin, carbenicillin)

Aztreona m

1st Generation

Cephalosporin s 3rd Generation

2nd Generation

Gram-positives Anti-staph PCNs (nafcillin, methicillin, oxacillins) Penicillin G/V Clindamycin Linezolid Vancomyci n Nucleus Aminoglycosides Tetracyclines Imipenem Meropene m Amoxicillin Ampicillin Macrolides

Gram-negatives Anti-pseudomonal PCNs (pipercillin, ticarcillin, carbenicillin)

Aztreona m

1st Generation

Cephalosporin s 3rd Generation

2nd Generation

Gram-positives Anti-staph PCNs (nafcillin, methicillin, oxacillins) Penicillin G/V Clindamycin Linezolid Fluoroquinolines Vancomyci n Rifampin Sulfonamides Aminoglycosides Tetracyclines Imipenem Meropene m Amoxicillin Ampicillin Macrolides

Gram-negatives Anti-pseudomonal PCNs (pipercillin, ticarcillin, carbenicillin)

Aztreona m

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?
Dont use tetracyclines, aminoglycosides, fluoroquinolones, sulfonamides.

Is the bug intracellular

Use a tetracycline or macrolide

Antibacterial Drugs in Pregnancy

Antibacterial Drug Aminoglycosides Chloramphenicol Fluoroquinolones Clarithromycin Ertapenem Erythromycin estolate Imipenem/cilastatin Linezolid Meropenem Metronidazole Nitrofurantoin Quinupristin/dalfop ristin Sulfonamides
Toxicity in Pregnancy Possible 8th nerve toxicity Gray syndrome in newborn Arthropathy in immature animals Teratogenicity in animals Decreased weight in animals Cholestatic hepatitis Toxicity in some pregnant animals Embryonic and fetal toxicity in rats Unknown None known, but carcinogenic in rats Hemolytic anemia in newborns Unknown Hemolysis in newborn with G6PDb deficiency; kernicterus in newborn Tooth discoloration, inhibition of bone growth in fetus; hepatotoxicity Unknown Recommendation Cautiona Caution at term Caution Contraindicated Caution Contraindicated Caution Caution Caution Caution Caution; contraindicated at term Caution Caution; contraindicated at term Contraindicated Caution

Tetracyclines Vancomycin

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