Antimicrobials part 2

CHAPTERS 40, 42, 43, 44

Camille Webb, M.D.- Infectious Diseases fellow PGY-5

 Objectives - cognitive
1. Describe the classification of drugs,
development of resistance and factors that
modify choice of antimicrobials.
2. Suggest appropriate anti-infective therapy
for common infections.
3. Describe spectrum, mechanism of action,
therapeutic uses, characteristics,
pharmacokinetics, adverse effects, drug
interactions, contraindications, dosage
administration, and patient advice for individual
agents in the following classes of anti-infectives:
Fluoroquinolones
Sulfonamides
Urinary tract antiseptics
Antiprotozoal agents
Antifungal drugs
Antihelminthics
 Objectives - affective
Recognize the basic principles of antimicrobial
therapy.
Recognize the clinical importance of antibiotic
resistance in certain conditions.
Consider how you would give patient education
regarding instructions on how to take antibiotics.
 Prequestion 1
T/F: Nitrofurantoin (Macrobid) can be used for
complicated pyelonephritis?
 Prequestion 2
Which of the following is not absorbed orally?

A. Sulfadiazine (Microsulfon)
B. Sulfasalazine (Azulfidine)
C. Sulfamethoxazole (Gantanol)
D. Sucralfate (Carafate)
 Prequestion 3
A 22 year old female presents with a 2 day history of
dysuria with increased urinary frequency and
urgency. A urine cx and U/A are done. She is
diagnosed with a UTI caused by E. coli. All of the
following would be considered appropriate therapy
for this patient except:
A. Levofloxacin (Levaquin)
B. Cotrimoxazole (TMP-SMX)
C. Moxifloxacin (Avelox)
D. Nitrofurantoin (Macrobid)
 2nd gen
1st gen Ciprofloxacin
Nalidixic acid Norfloxacin
Ofloxacin

Fluoroquinolones
Folic Acid Antagonists
Urinary Tract Antiseptics

3rd gen 4th gen

Levofloxacin Moxifloxacin
 FLUOROQUINOLONES
Mechanism of Action

Spectrum of activity

Resistance

Pharmacokinetics

Adverse reactions
Mechanism of action
Sulfa/ trimethropin:
Folate synthesis

Cell wall:
Beta lactams DNA Gyrase
Vancomycin Quinolones:

RNA polymerase
Rifampin
50s

30s

Cell membrane:
polymyxins
Ribosome (protein synthesis)
30s: Tetracyclines, AG
50s: Clindamycin, Linezolid, Macrolides, Chloramphenicol
 Mechanism of action
Inhibits replication of bacterial DNA

Interferes with bacterial cell division

Enters bacteria cell through protein channel

 FLUOROQUINOLONES
Mechanism of Action

Spectrum of activity

Resistance

Pharmacokinetics

Adverse reactions
 Spectrum of activity
Ciprofloxacin: 2nd generation
Enterobacter species, E.coli, Pseudomonas,
Bacillus anthracis
Weak against Strep pneumoniae
 Spectrum of activity
Levofloxacin: 3rd generation
Effective treatment of E.coli, S. pneumoniae,
Pseudomonas
May be used for treatment of prostatitis, UTI,
skin, sinus, chronic bronchitis, CAP,
nosocomial PNA
 Spectrum of activity
Moxifloxacin: 4th generation
Effective against S. pneumoniae and anaerobes
Used for respiratory infections but not UTIs
Not effective against Pseudomonas
Therapeutic applications
 FLUOROQUINOLONES
Mechanism of Action

Spectrum of activity

Resistance

Pharmacokinetics

Adverse reactions
Resistance
1. Altered target (mutations of DNA gyrase or topoisomerase IV)

2. Decreased concentration in cells: mutation of porin chanels or

efflux pumps DNA Gyrase
Quinolones:

50s

30s
 FLUOROQUINOLONES
Mechanism of Action

Spectrum of activity

Resistance

Pharmacokinetics

Adverse reactions
 Pharmacokinetics
Distribute well into bone, kidney, urine, prostatic
tissue, and lung

Low penetrance in CSF

Exception 1: moxifloxacin does not go in urine,

not renally excreted
Exception 2: ofloxacin does penetrate CSF
 MILK WAS
A BAD CHOICE
Figure 40.4
 FLUOROQUINOLONES
Mechanism of Action

Spectrum of activity

Resistance

Pharmacokinetics

Adverse reactions
Adverse reactions

QT
Ruptured Achilles
tendon/tendinitis prolongation

BLACK BOX
WARNING
 Fluoroquinolones
Folic Acid Antagonists
Urinary Tract Antiseptics

Folate synthesis:
Mafenide Folate reduction:
Silver Pyrimethamine
sulfadiazine Trimethropine
Sulfasalazine
Sulfisoxazole
 FOLIC ACID ANTAGONISTS
Mechanism of Action

Spectrum of activity

Resistance

Pharmacokinetics

Adverse reactions
Mechanism of action
Sulfa/ trimethropin:
Folate synthesis

Cell wall:
Beta lactams DNA Gyrase
Vancomycin Quinolones:

RNA polymerase
Rifampin
50s

30s

Cell membrane:
polymyxins
Ribosome (protein synthesis)
30s: Tetracyclines, AG
50s: Clindamycin, Linezolid, Macrolides, Chloramphenicol
Figure 40.7
Inhibition of
tetrahydrofolate
synthesis by
sulfonamides and
trimethoprim
 FOLIC ACID ANTAGONISTS
Mechanism of Action

Spectrum of activity

Resistance

Pharmacokinetics

Adverse reactions
 Spectrum of activity
Respiratory infections caused by
Haemophilis influenzae, Legionella
pneumophilia, Pneumocystis Jiroveci
pneumonia infection or prophylaxis
(CD4+ count less than 200)
Septicemia or meningitis caused by
Listeria monocytogenes
Prostatitis or UTI
GI: shigellosis, salmonella carriers
 Trimethropin/ Sulfamethoxazole
Synergistic activity
Combination has resulted in less resistance
Good distribution with oral administration
Trimethoprim concentrates well in acidic prostatic
and vaginal fluids
Crosses the blood brain barrier
Excreted in urine
 Spectrum of activity
Synergism between
trimethoprim and
sulfamethoxasole
inhibits growth of E. coli
 Spectrum of activity

Figure 40.12
 FOLIC ACID ANTAGONISTS
Mechanism of Action

Spectrum of activity

Resistance

Pharmacokinetics

Adverse reactions
 Bound to serum albumin
Distributes well in bodys water
Penetrates CNS
Crosses placenta
Eliminated by glomerular filtration >
dose adjustment for renal
dysfunction
Eliminated in breast milk
Figure 40.13
 FOLIC ACID ANTAGONISTS
Mechanism of Action

Spectrum of activity

Resistance

Pharmacokinetics

Adverse reactions
Sulfonamides: Adverse Reactions

Figure 40.9
Some adverse
reactions to
sulfonamides
Cotrimoxazole: Adverse Reactions

Fig 40.14
 Fluoroquinolones
Folic Acid Antagonists
Urinary Tract Antiseptics

Methenamine
Nitrofurantoin
 Nitrofurantoin
enzyme inhibition: DNA damage
uncomplicated lower UTI (cystitis, urethritis)
Most effective for E.coli but will cover other common
pathogens (Staph saprophyticus, Klebsiella
pneumoniae, Proteus mirabilis)
Concentrates well in the urine
SE: hemolytic anemia in G6PD deficiency, interstitial
pneumonitis (w/chronic use), neurologic probs, GI
disturbances
Dont use in pregnant women after 38 weeks
 POST question 1
T/F: Nitrofurantoin(macrobid) can be used for
complicated pyelonephritis?
 POST question 2
Which of the following is not absorbed orally?

A. Sulfadiazine (Microsulfon)
B. Sulfasalazine (Azulfidine)
C. Sulfamethoxazole (Gantanol)
D. Sucralfate (Carafate)
 POST question 3
A 22 year old female presents with a 2 day history of
dysuria with increased urinary frequency and
urgency. A urine cx and U/A are done. She is
diagnosed with a UTI caused by E. coli. All of the
following would be considered appropriate therapy
for this patient except:
A. Levofloxacin (Levaquin)
B. Cotrimoxazole (TMP-SMX)
C. Moxifloxacin (Avelox)
D. Nitrofurantoin (Macrobid)
 Take Home Points
Levofloxacin(Levaquin) & Moxifloxacin(Avelox) = Respiratory
FQ
Cant use Moxifloxacin(Avelox) for UTIs
Antacids & iron/zinc supplements reduce FQ absorption
Separate administration times
FQs can cause Cdiff & prolong QTc interval
UTI etiology: 1) E. coli 2) Staph Saprophyticus
Dont use nitrofurantoin(macrobid) in women >38 wks
pregnant
Chapter 42:

Antifungals
 Pre question 1
What is the mechanism of action of terbinafine (Lamisil)?
A. Impairs the synthesis of ergosterol, which is necessary
in fungal cell membranes
B. Inhibits squalene 2, 3-epoxidase, making it fungicidal to
sensitive organisms
C. Binds to microtubules comprising the spindles and
inhibits fungal mitosis
D. Disrupts DNA and protein synthesis in susceptible
organisms
E. A and B
 Pre question 2
About 1 hour after starting the infusion of amphotericin B ,
the patient is noticed to have fever and chills. What is
the cause, and what should be done?

A. Bacteremia/ get blood cultures immediately

B. Allergic reaction/stop the infusion and add it to the
allergy list
C. Side effect/premedicate the patient with Tylenol +/-
Meperidine (Demerol)
D. Cold room/ close the window
 Pre question 3
A 56 year old female with DM presents for routine foot
evaluation with her podiatrist. The patient complains of
thickening of the nail of the right big toe and a change in
color (yellow). The podiatrist diagnoses the pt with
onychomycosis of the toenails. Which of the following is the
most appropriate choice for treating this infection?

A. Terbinafine (Lamisil)
B. Micafungin (Mycamine)
C. Itraconazole(Sporanox)
D. Griseofulvin (Grifulvin V, Gris-Peg)
 Antifungals
Amphotericin B
Fluconazole
Itraconazole
Ketoconazole
Voriconazole
 Common organisms
Figure 42.2
Pathogenic organisms of Kingdom Fungi
 Mechanism of Action

Figure 42.3
 Amphotericin B
Life-threatening systemic mycoses
Disrupts membrane function
resulting in cell death
Effective against:
Candida albicans
Histoplasma capsulatum
Cryptococcus neoformans
Coccidioides immitis
Blastomyces dermatidis SE: Ampho-
Aspergillus Terrible
IV or intrathecal administration
Figure 42.4
Model of a pore
formed by
amphotericin B in the
lipid bilayer membrane

Fig 42.5:
Administration and
fate of amphotericin B
 Amphotericin B adverse effects
Test dose to check for anaphylaxis
Premedicate with corticosteroid or antipyretic
to prevent fever/chills
Bolus NS before and after to minimize renal
impairment
Hypokalemia may require potassium
supplementation
Use of heparin to prevent thrombophlebitis
Figure 42.6
Adverse effects of
amphotericin B
Figure 42.7
Mode of action
flucytosine.
Fig 42.8
Mode of action azole
antifungals
 Ketoconazole
Blocks step in fungal membrane synthesis

Oral administration with elimination through the liver

Second line due to limited spectrum

Histoplasma, Blastomyces, Candida, Coccioides

Topical use for tinea corporis, tinea cruris, tinea pedis,

tinea versicolor
 Ketoconazole: adverse effects
Decrease testosterone and cortisol
production may result in
gynecomastia, decreased libido,
impotence, menstrual irregularities

Increase in liver transaminases

GI effects
 Fluconazole
Inhibits synthesis of membrane ergosterol but
no endocrine effects
Excellent penetration into CSF and drug of
choice for Cryptococcus neoformans,
candidemias, and coccidiomycosis, vaginal
candidiasis
Administered PO or IV
Excreted through the kidney
 Itraconazole
Drug of choice for blastomycosis,
sporotrichosis, paracoccidiomycosis,
histoplasmosis
Not therapeutic for CSF
Metabolized in liver, no endocrine effects
No renal dose adjustment needed
Avoid in CHF patients
 Voriconazole
Newer broad spectrum antifungal
Used in place of amphotericin B for invasive
aspergillosis
Used for candidiasis and candidemia
Deep tissue, esophageal
Visual and auditory hallucinations
 Voriconazole

By inhibiting CYP450,
voriconazole can potentiate
the toxicities of other drugs

Figure 42.9
Azoles: drug interactions
 Cutaneous antifungals
Terbinafine(Lamisil)
Griseofulvin (Grifulvin V, Gris-Peg)
Nystatin(Mycostatin)
Miconazole (Fungoid, Micatin, Monistat),
clomitrazole( Lotrimin AF)
Ciclopirox (Penlac)
Tolnaftate(Tinactin)
 Terbinafine
Blocks the synthesis of ergosterol
Drug of choice for
dermatophytoses or
onychomycoses
Fungicidal and useful for topical
treatment of tinea pedis, tinea
corporis, tinea cruris
Nails: PO, 6-12 weeks,
Tinea: topically. 1 week
Baseline LFTs for onychomycosis
Figure 42.12
Mode of action of
squalene epoxidase
inhibitors.

Fig 42.13
Administration and
fate of terbinafine
 Griseofulvin
Used for ringworm and dermatophytosis
of skin and hair
Requires long treatment duration so not
used as frequently
Disrupts fungal mitosis
 Nystatin
Topical treatment of
candida infections
Useful to treat oral
candidiasis
 Other topical antifungals
Clotrimazole/ Miconazole
Wider spectrum of activity Epidermophyton, Microsporum, Trichophyton,
Candida albicans, and Malassezia furfur
Miconazole is a potent inhibitor of warfarin metabolism
Ciclopirox
Disrupts synthesis of DNA, RNA, protein
Similar coverage to terbinafine
Treat tinea pedis, tinea corporis, seborrheic dermatitis, tinea versicolor,
onychomycosis
Tolnaftate
Distorts hyphae and stunts mycelial growth
Not effective against Candida
Treat tinea pedis, tinea cruris, tinea corporis
 Post question 1
What is the mechanism of action of terbinafine?

A. Impairs the synthesis of ergosterol, which is necessary in

fungal cell membranes
B. Inhibits squalene 2, 3-epoxidase, making it fungicidal to
sensitive organisms
C. Binds to microtubules comprising the spindles and inhibits
fungal mitosis
D. Disrupts DNA and protein synthesis in susceptible organisms
E. A. and B.
 Post question 2
About 1 hour after starting the infusion of amphotericin B,
the patient is noticed to have fever and chills. What is
the cause, and what should be done?

A. Bacteremia/ get blood cultures immediately

B. Allergic reaction/stop the infusion and add it to the
allergy list
C. Side effect/premedicate the patient with Tylenol +/-
Meperidine (Demerol)
D. Cold room/ close the window
 Post question 3
A 56 year old female with DM presents for routine foot
evaluation with her podiatrist. The patient complains of
thickening of the nail of the right big toe and a change in
color (yellow). The podiatrist diagnoses the pt with
onychomycosis of the toenails. Which of the following is the
most appropriate choice for treating this infection?

A. Terbinafine (Lamisil)
B. Micafungin (Mycamine)
C. Itraconazole (Sporanox)
D. Griseofulvin (Grifulvin V, Gris-Peg)
 Quick facts
All azoles inhibit CYP450, so be mindful of interactions:
Statins, Seizure medications, Warfarin
Avoid azoles in pregnancy
Oral Terbinafine for Tinea Capitis
Topical Terbinafine for Tinea Pedis/Corporis/Cruris
Itraconazole should be avoided in CHF patients
Break
Chapter 43
Antimicrobials
Antiprotozoal Drugs
 Chapter 42:

Antiprotozoal drugs
 Pre question 1
Metronidazole (Flagyl, Protostat) should NOT be taken
with which substance?

A. Alcohol
B. Acetaminophen
C. Aspirin
D. Ampicillin
 Pre question 2
An 18-yr-old male is diagnosed with Chagas disease.
Which medication would be the best for this patient?

A. Nifurtimox
B. Suramin (Germanin)
C. Sodium stibogluconate
D. Metronidazole(Flagyl)
 Pre question 3
When giving primaquine, providers should be aware
whether patients have which of the following?

A. G6PD deficiency
B. Hypertension
C. Glaucoma
D. Diabetes mellitus
AntiProtozoals
Amebiasis
Malaria
Trypanosomiasis
Leishmaniasis
Toxoplasmosis
Giardiasis
 Protozoa???
Single cell eukaryotes

Amebiasis, malaria, trypanosoma, toxoplasma,

giardia
Amebicidal drugs
 Metronidazole
Treatment of choice for
E.histolytica,
pseudomembranous colitis,
Giardia lamblia, and
Trichomonas vaginalis

Combined with iodoquinol or

paromomycin results in 90+%
cure rates for amebiasis
 Rapidly absorbed orally
Distributes well in body
tissues & fluid:
Vaginal & seminal
fluids, saliva, breast
milk, CSF
 Metronidazole: adverse effects

Most common adverse effects relate to GI tract (nausea,

vomiting, GI pain, cramps, metallic taste, oral moniliasis).
Rare Neurotoxigenic: dizziness, vertigo, numbness,
paresthesia are reasons for discontinuation.
If taken with ETOH, Disulfuram-like reaction occurs
 Tinidazole
Same use as metronidazole but more
expensive
Shorter course of treatment
 Fig 43.4:
Some
commonly
used
therapeutic
options for
the treatment
of amebiasis
 Malaria
5 Plasmodium species:
1) P. falciparum
2) P. ovale
3) P. vivax
4) P. malariae
5) P. knowlesi
Antimalarial drugs
 Chloroquine
Used for prophylaxis and/or treatment
Drug of choice for treatment of erythrocytic P.
falciparum
Less effective versus P. vivax
Side effects significant only at higher doses
GI, pruritus, headaches, blurred vision
 Action of chloroquine on the
formation of hemozoin by
Plasmodium species (fig 43.7)
 Administration & fate
of chloroquine
Concentrates in
erythrocytes, liver,
spleen, kidney, lung,
melanin-containing
tissues & leukocytes
Penetrates CNS
Crosses placenta
 Figure 43.8
Adverse effects
associated with
chloroquine
Low dose = rare SE
High dose = GI upset,
pruritus, HA, blurred
vision
 Mefloquine
Single agent used for prophylaxis and cure
Effective against multidrug resistant P. falciparum
Long half life with continuous circulation through
the enterohepatic system
Adverse effects are similar to other agents but
with ECG changes if administered with quinine or
quinidine
 Malaria prophylaxis
Doxycycline
Atovaquone-proguanil
In Pregnancy: chloroquine or mefloquine
 Primaquine
Eradicates hypnozoites and prevents
relapses of P. vivax and P. ovale

May cause hemolytic anemia in glucose-6-

phosphate dehydrogenase (G6PD)
deficient patients
Figure 43.6
Mechanism of
primaquine-
induced
hemolytic
anemia.
Figure 43.9
Treatment
and
prevention
of malaria
 Trypanosoma

Amebiasis
Malaria
Trypanosomiasis
Leishmaniasis
Toxoplasmosis
Giardiasis
 Summary of
trypanosomiasis:
American Sleeping Sickness
T. Cruzi (South America)
African Sleeping Sickness
T. brucei gambiense
T. brucei rhodesiense

Figure 43.10
Administration & fate of
Pentamidine &
Melarsoprol
Figure 43.11
Generation of
toxic
intermediarie
s by
nifurtimax.
 Giardia
Amebiasis
Malaria
Trypanosomiasis
Leishmaniasis
Toxoplasmosis
Giardiasis
Life cycle of
Giardia
lamblia

Figure 43.12
 Post question 1
Metronidazole (Flagyl, Protostat) should NOT be taken
with which substance?

A. Alcohol
B. Acetaminophen
C. Aspirin
D. Ampicillin
 Post question 2
An 18-yr-old male is diagnosed with Chagas disease.
Which medication would be the best for this patient?

A. Nifurtimox
B. Suramin (Germanin)
C. Sodium stibogluconate
D. Metronidazole (Flagyl)
 Post question 3
When giving primaquine, providers should be aware
whether patients have which of the following?

A. G6PD deficiency
B. Hypertension
C. Glaucoma
D. Diabetes mellitus
 QUICK FACTS

Metronidazole: can cause a metallic taste; dont take with

alcohol
Primaquine is associated with drug induced hemolytic
anemia in G6PD deficiency
T. cruzi (South America)Chagas Disease
Rx: Nifurtimox
Giardia lamblia
Rx: Metronidazole or Nitazoxanide
 Chapter 44

ANTIMICROBIALS
AntiHelmintic Drugs
 Chapter 42:

Antihelminthic drugs
 Pre question 1
Pyrantel pamoate (Pin-Rid) is highly effective
against which of the following?

A. Pinworm
B. Onchocerca
C. Trichuris Trichiura
D. Strongyloides
 Pre question 2
2) Which antiparasitic drug is related to the
macrolide antibiotics?

A. Ivermectin (Eqvalan, Ivomec) (stromectol)

B. Pyrantel pamoate (Pin-Rid) (Pin-X)
C. Metronidazole (Flagyl, Protostat)
D. Primaquine (Malaride)
 Pre question 3
A 48 yr old immigrant from Mexico presents with seizures and
other neurologic symptoms. An MRI of the brain shows a
single enhancing cyst and serology points to a diagnosis of
neurocysticercosis. Which one of the following drugs would
be of benefit to this individual?

A. Ivermectin (stromectol)
B. Pyrantel pamoate (Pin-X)
C. Albendazole (Albenza)
D. Diethylcarbamazine (Banocide)
E. Niclosamide
 Helminths???

Nematodes

Trematodes

Cestodes
Helminth infections
 Albendazole, ivermectin,
mebendazole, and thiabendazole
should be avoided in pregnancy

Figure 44.3
Figure 44.4
Characteristics and therapy
for commonly encountered
nematode infections
Figure 44.4
Characteristics and
therapy for commonly
encountered nematode
infections
Figure 44.5
Characteristics and
therapy for commonly
encountered trematode
infections
Figure 44.5
Characteristics and
therapy for commonly
encountered trematode
infections
Figure 44.6
Characteristics and therapy for
commonly encountered cestode
infections
Figure 44.6
Characteristics and
therapy for
commonly
encountered cestode
infections
 Mebendazole
Effective for treatment of whipworm,
pinworm, hookworms, and roundworm

Inhibits microtubule synthesis and glucose

uptake

Causes the parasites to be expelled with

feces

Dosage varies with target organism

 Pyrantel pamoate
Effective against roundworms, pinworms, and
hookworms

Paralyzes worms in the GI tract and expelled

 Ivermectin
Used to treat
Cutaneous larva
migrans

Strongyloidiasis
(nematode round
worm)

Onchocerciasis
(River Blindness)
 Albendazole
Effective against:
1) Nematodes
2) Cestodes:
Cysticercosis
Hydatid disease (Echinococcus granulosus)

Absorption enhanced with high fat meal

Widely distributes including the CSF

Drug and metabolites excreted in bile

 Post question 1
Pyrantel pamoate (Pin-Rid) is highly effective
against which of the following?

A. Pinworm
B. Onchocerca
C. Trichuris Trichiura
D. Strongyloides
 Post question 2
2) Which antiparasitic drug is related to the
macrolide antibiotics?

A. Ivermectin (Eqvalan, Ivomec) (stromectol)

B. Pyrantel pamoate (Pin-Rid) (Pin-X)
C. Metronidazole (Flagyl, Protostat)
D. Primaquine (Malaride)
 Post question 3
A 48 yr old immigrant from Mexico presents with seizures and
other neurologic symptoms. An MRI of the brain shows a
single enhancing cyst and serology points to a diagnosis of
neurocysticercosis. Which one of the following drugs would be
of benefit to this individual?

A. Ivermectin (stromectol)
B. Pyrantel pamoate (Pin-X)
C. Albendazole (Albenza)
D. Diethylcarbamazine (Banocide)
E. Niclosamide
 Resources
Harvey RA, Clark MA, Finkel R, Rey JA, Whalen
K, Pharmacology, 6th Edition, Lippincott
Williams and Wilkins, 2015.
Thank you!