Antimicrobial Therapies 2 (Protein Synthesis Inhibitors Quinolones / Folic Acid Antagonists / Urinary Tract Antiseptics)

Question 1

Protein Synthesis Inhibitors

Answer 1

▪ Many antibiotic families work by targeting bacterial ribosomes and inhibiting
bacterial protein synthesis—these drugs are bacteriostatic
▪ Bacterial ribosomes are composed of 30S and 50S subunits [mammals have 40S and 60S subunits]
▪ Being selective for bacterial ribosomes decreases potential AEs from disrupting
protein synthesis in the host
▪ However high doses of some of these agents can be toxic effects—as a result of an
interaction with the mitochondria ribosomes in the human—because the
mitochondrial ribosomes closely resemble those of the bacteria

Tetracyclines
Glycylcyclines
Aminoglycosides
Macrolide/Ketolides
Macrocyclics
Lincosamides
Oxazolidinones
Others

Question 2

Tetracyclines

Answer 2

▪ Tetracycline—prototype drug
▪Doxycycline
▪ Minocycline

MOA

• Enter susceptible bugs via passive diffusion & energy-dependent transport protein mechanism unique to bacterial inner cytoplasmic membrane
• Concentrate intracellularly in susceptible pathogens
• Binds reversibly to 30S subunit—this prevents binding of tRNA to the
mRNA-ribosome complex & inhibiting protein synthesis

Antibacterial Spectrum

• Bacteriostatic
• Cover:
• Gram +
• Gram –
• Protozoa
• Spirochetes
• Mycobacteria
• Atypical species
• Commonly used to treat
Chlamydia

Resistance

• Most common naturally occurring
resistance is from an efflux pump that
expels the drug out of the cell—preventing
intracellular accumulation
• Other mechanisms:
• Enzyme inactivation of the drug
• Production of bacterial proteins that
prevent tetracyclines from binding to the ribosome
• Resistance to one tetracycline does not
mean resistance to all in the class

Question 3

Tetracyclines–Pharmacokinetics

Answer 3

Absorption

• Adequately absorbed when taken orally
• Giving with dairy, Magnesium, Calcium,
aluminum antacids or iron decreases
absorption—as a nonabsorbable chelate is
formed [worse with tetracycline]
• Doxycycline and Minocycline available in
PO and IV forms

Distribution

• Concentrate well in bile, liver, kidney, gingival fluid and skin
• Bind to tissues undergoing calcification
[teeth/bones] and tumors high in Ca++
content
• Penetration into most body fluids is
acceptable
• Only Minocycline and Doxycycline get to
therapeutic levels in the CSF
• Minocycline obtains high levels in saliva and
tears—can be used to treat meningococcal
carrier states
• ALL tetracyclines cross placental barrier and concentrate in fetal bones and teeth

Elimination

• Tetracycline mainly in the urine
• Minocycline is metabolized in the mainly in the liver, to a lesser degree in the kidney
• Doxycycline is preferred in the patient with renal disease—as it is eliminated via the bile
into the feces

Question 4

Tetracyclines–ADEs

Answer 4

GI Discomfort

• Epigastric distress from irritation of gastric mucosa
• Esophagitis—can be decreased by giving with food [except dairy] or fluids and by prescribing tablets
• Tetracycline should always be given on empty stomach

Effects on Calcified Tissues

• In children, deposition in bones and teeth occurs during calcification process—leading to discoloration, hypoplasia of teeth and a temporary stunning of growth
• Do not use tetracyclines in pediatric care

Liver Toxicity

• Rarely, liver toxicity can occur with high doses, especially in pregnant women, those with preexisting liver or kidney disease

Sun Sensitivity

• Severe sunburn can occur with all
tetracyclines—most frequently seen with
Tetracycline and Demeclocycline

Vestibular Dysfunction

• Dizziness, vertigo and tinnitus can be
seen with Minocycline—which concentrates in endolymph of the ear and affects the
function of the 8th CN

Pseudotumor Cerebri

• Benign intracranial hypertension [HA,
blurred vision] can occur rarely in adults
• Stopping the drug reverses this condition,
but permanent sequelae may occur—worse with Tetracycline

Contraindications

• Should not be used in pregnancy, breast
feeding or in children younger than age 8

Question 5

Newest Tetracycline—Sarecycline [Saysera]

Answer 5

▪ Approved for limited course [12 weeks] of therapy for acne vulgaris
▪ Weight based dosing
▪ Drug with very long ½ life—21 – 22 hours
▪ Bacteriostatic, exact MOA unknown
▪ Need baseline ophthalmologic exam—can cause blurred vision, and a change in green/blue color perception
▪ Main SE with this tetracycline is Pseudotumor Cerebri

Question 6

Glycylcyclines

Answer 6

▪ Tigecycline [Tygacil]—prototype drug
▪Derivative of Minocycline—1st member of this new antibiotic class
▪Indicated for treatment of complicated soft tissue infections, complicated intra-abdominal infections and CAP

MOA

Bacteriostatic by reversibly binding to the 30S ribosome subunit and inhibiting
bacterial protein synthesis

Antibacterial Spectrum

Broad Spectrum
Covers:
• MRSA
• Multi-drug resistant streptococci
• VRE
• Extended spectrum ß-lactamase-producing Gram – pathogens
• Acinetobacter baumanni
• Many anaerobes
Does NOT cover:
• Morganella
• Proteus
• Providencia
• Pseudomonas species

Resistance

• Drug developed to overcome emergence of tetracycline-resistant bugs that utilize efflux pumps and ribosomal protection to cause
resistance
• Resistance has been seen to this
agent—mainly due to overexpression of efflux pumps

Pharmacokinetics

• Given IV, large volume of distribution
• Penetrates tissues well but gets low plasma levels
• Poor option for bloodstream infections
• Eliminated via bile and feces
• No dose reduction for renal disease, but dose reduction is needed in those with liver disease

ADEs

• Nausea and vomiting
• Acute pancreatitis [including death]
• Increased LFTs and creatinine can occur
• All cause mortality in those getting this agent is higher than with other agents
• BB warning—this agent should be used for situations where other treatments are not an option
• Other ADEs—similar to tetracyclines—photosensitivity, pseudotumor cerebri, discolored teeth [if used during tooth
development], fetal harm if given during pregnancy
• Tigecycline decreases the clearance of Warfarin

Question 7

Aminoglycosides

Answer 7

▪ Amikacin
▪ Gentamicin—prototype drug
▪ Neomycin
▪ Streptomycin
▪ Tobramycin

▪ Used for the treatment of serious infections from aerobic Gram – bacilli, but utility is limited by serious toxicities

Question 8

Aminoglycosides

Answer 8

MOA

• Diffuse through porin channels in outer membrane of susceptible pathogens
• Also have an O2-dependent system that transports the drug across the cytoplasmic
membrane
• In the cell, they bind the 30S ribosomal subunit where they interfere with assembly
of the functioning ribosome and/or cause the 30S subunit of the complete ribosome
to misread genetic code
• They are concentration-dependent bactericidal agents—their efficacy is dependent on
the Maximum Concentration [Cmax] of the drug above the MIC of the pathogen
• For this family, the target Cmax is 8 to 10 times the MIC
• They have a postantibiotic effect [PAE]—continued bacterial suppression after the
drug concentrations fall below the MIC [the larger the dose, the longer the PAE]
• Because of this PAE, high-dose extended interval dosing is often used—and this
prescribing strategy reduces renal damage

Antibacterial Spectrum

▪ Majority of aerobic gram negative bugs, including [many drug-resistance species]:
▪ Pseudomonas aeruginosa
▪ Klebsiella pneumonia
▪ Enterobacter species
▪ Often given with a ß-lactam antibiotic to get a synergistic effect, when treating:
▪ Enterococcus faecalis
▪ Enterococcus faecium infective endocarditis

Resistance

Occurs from:
▪ Efflux pumps
▪ Decreased uptake
▪ Modification and inactivation by plasmid-associated synthesis of enzymes [each of these enzymes is specific to one aminoglycoside]—so cross-resistance is NOT the rule

Question 9

Aminoglycosides—Pharmacokinetics

Answer 9

Absorption

• Polar, polycation structure prevents adequate oral absorption
• All [except Neomycin] must be given IM or IV [neomycin causes renal damage if given
parenterally—it is given topically for skin infections** or orally as a prep to
decontaminate the bowel before GI surgery]

Distribution

• Tissue concentration may be subtherapeutic and penetration is variable due to hydrophilicity
• Levels in CSF no adequate, even when meninges are inflamed
• To treat CNS infections, intrathecal or intraventricular routes needed
• All of these agents cross the placental barrier and can accumulate in fetal plasma and in amniotic fluid

Elimination

• Neomycin excreted unchanged in feces
• Other drugs in the family—90% of the agent is excreted unchanged in the urine after parenteral dosing—accumulation
occurs in those with kidney disease—so these drugs must be renal dosed

** at least 1/3 of people are sensitive to the neomycin topically and will develop a dermatitis, that takes the appearance of cellulitis, so not suggested 1st line as topical therapy

Question 10

Aminoglycosides—ADEs

Answer 10

Drug monitoring of Gentamicin, Tobramycin and Amikacin is a MUST to get
appropriate dose and to avoid toxicity
▪ Older adults most susceptible to nephrotoxicity and ototoxicity

Ototoxicity—vestibular and auditory—related to high peak levels and duration
of therapy
▪ The drugs accumulate in the endolymph and perilymph of inner ear
▪ Deafness is usually irreversible and can affect a fetus
▪ Those getting other ototoxic drugs, such as Cisplatin or loop diuretics are especially

Nephrotoxicity

• Retention of the agent by the proximal renal tubular cells disrupts Ca++ mediated
transport processes
• This retention causes kidney damage ranging from mild, reversible renal impairment to severe, potentially irreversible
ATN at risk

Vertigo may occur also occur in those receiving Streptomycin

Neuromuscular Paralysis

• Associated with a rapid increase in concentration OR concurrent administration with neuromuscular blockers
• Those with MG are especially at risk
• Prompt administration of Ca++ gluconate or Neostigmine can reverse the block that causes neuromuscular paralysis

Allergic Reactions

• Contact dermatitis is a common reaction to
topically applied Neomycin—so avoid triple
antibiotic ointments [TAO]

Question 11

Macrolides and Ketolides

Answer 11

Erythromycin—prototype drug
Clarithromycin
Azithromycin
Telithromycin

▪ Antimicrobials with a macrocyclic lactone structure to which one or more deoxy sugars are attached
▪ Erythromycin—1st drug in the class
▪ Alternative to PCN in those with allergies to ß-lactam antibiotics
▪ Clarithromycin—methylated form of Erythromycin
▪ Azithromycin—has a larger lactone ring, has some features with other macrolides, while improving upon Erythromycin
▪ Telithromycin—semisynthetic derivative of Erythromycin is a “ketolide” agent [not currently used in US]—because of liver issues

MOA

▪ Bind irreversibly to a site on the 50S ribosome subunit of the bacterial ribosome and inhibiting translocation steps of protein synthesis
▪ These agents are bacteriostatic, and may be bacteriocidal at higher doses
▪ Their binding site is either identical to or near to that for Clindamycin and Chloramphenicol

Antibacterial Spectrum

Erythromycin
• Same coverage as PCN G
• Considered alternative for those with PCN
allergy

Clarithromycin
• Coverage is similar to Erythromycin, and also covers:
• H. influenzae
Has greater activity
against intracellular
pathogens, such as:
• Chlamydia
• Legionella
• Moraxella
• Ureaplasma species
• H. pylori

Azithromycin
Less active than Erythromycin against
Streptococci and Staphylococci, YET
Much more active against
respiratory bugs:
• H. influenzae
• Moraxella catarrhalis
Excess use of this agent has caused growing Streptococcus pneumoniae resistance

Telithromycin
• Spectrum is much like that of Azithromycin
• Structural change with ketolides neutralizes
the most common resistance mechanisms
that cause macrolide resistance
• Ketolides are suspected to become important antimicrobials in the future, as new drugs are in development

Resistance

▪ Inability of the organism to take up the antibiotic
▪ Presence of efflux pumps
▪ Decreased affinity of the 50S ribosomal subunit for the due to methylation
of an adenine in the 23S bacterial ribosomal RNA in Gram + pathogens
▪ Presence of plasmid-associated Erythromycin esterases in Gram –pathogens
▪ Ketolides thought to be effective against macrolide-resistant organisms

Question 12

Macrolides and Ketolides—Pharmacokinetics

Answer 12

Absorption

• Erythromycin base is destroyed by HCl- acid, so EC or esterified pills are given
• All forms are stable in stomach acid and are
easily absorbed PO
• Food interferes with absorption of Erythromycin and Azithromycin, but
increases absorption of Clarithromycin
• Erythromycin/Azithromycin are available IV

Distribution

• Erythromycin well distributed in all tissues except CSF—one of few antimicrobials that gets into prostate and it accumulates in
macrophages
• All drugs concentrate in the liver
• Clarithromycin, Azithromycin and Telithromycin widely distributed in tissues
• Azithromycin concentrates in neutrophils, macrophages and fibroblasts, but serum levels are LOW—it has the highest volume
of distribution of all macrolides

Elimination

• Erythromycin and Telithromycin are
metabolized in liver—they inhibit oxidation of many drugs through their interaction with CYP 450
• Clarithromycin interferes with metabolism of theophylline, statins and many AEDs

Excretion

• Azithromycin concentrated and excreted in bile as active drug
• Erythromycin and metabolites are excreted in bile
• Clarithromycin metabolized in liver
as an active drug and metabolites excreted
in urine—dose adjust this drug in renal
disease

Question 13

Macrolides and Ketolides—ADEs

Answer 13

GI

• GI upset is most common SE [especially Erythromycin]
• High doses of Erythromycin can cause smooth muscle contractions that cause
gastric contents to move into the duodenum—and the ADE used to treat gastroparesis and post-operative ileus

Cholestatic Jaundice

• Occurs most commonly with estolate form of Erythromycin [no longer available in the US]
• Has been reported with other formulations in this family

Ototoxicity

• Transient deafness has been seen with
high dose Erythromycin
• Azithromycin has been associated with
irreversible sensorineural hearing loss

QTc Prolongation

• May prolong QTc interval and should
be used with caution in patients with
proarrhythmic conditions or taking
proarrhythmic drugs

Contraindications

• Patients with liver disease should be treated cautiously if prescribing Erythromycin, Telithromycin and Azithromycin as these agents accumulate in
the liver
• Severe liver toxicity has occurred with Telithromycin and is the reason it is not currently used in the US

Drug Interactions

• Erythromycin, Telithromycin and
Clarithromycin can interfere with liver metabolism of many drugs which can result in toxic levels of these agents—Alfuzosin [Uroxatrol], Atorvastatin [Lipitor];
Carbamazepine [Tegretol], PIs, Sildenafil [Viagra], Simvastatin [Zocor], Valproate [Depakote], Warfarin
• Change in gut flora from these antibiotics can lead to digoxin toxicity

Question 14

Fidaxomicin [Dificid]

Answer 14

▪ Macrocyclic drug similar to a macrolide, with a unique MOA
▪ Acts on sigma subunit of the RNA polymerase, disrupting bacterial
transcription, terminating protein synthesis and causing cell death
▪ Very narrow spectrum of coverage—Gram + aerobes and anaerobes
▪ Is covers Staphylococcus and Streptococcus, mainly used for bactericidal
activity against Clostridium difficile
▪ Because of unique target site, cross-resistance has NOT been seen
▪ Given orally—minimal systemic absorption and remains in GI tract
▪ Making it ideal to treat Clostridium difficile
▪ ADEs—nausea, vomiting and abdominal pain
▪ Anemia and neutropenia have been seen, but not common
▪ Hypersensitivity, angioedema, SOB and itching have occurred
▪ Use with caution in those allergy to a macrolide
▪ Seems ideal—BUT… AWP for 10 day course is $3100 [cost to patient or
insurance is 100 to 200% of AWP—so $6200-9300 for a course of therapy], in
spite of this, in 2019, this is the first line agent in severe C. diff infections

Question 15

Chloramphenicol [Chloromycetin]

Answer 15

▪ Broad spectrum antibiotic restricted to life-threatening infections for which no
alternatives exist
▪ Considered salvage therapy here in the US
▪ Used more often in other parts of the world, than it is used here

MOA

• Binds reversibly to the bacterial 50S
ribosomal subunit and inhibits protein
synthesis at the peptidyl transferase reaction
• Some of the host mitochondrial ribosomes
closely resemble those of the pathogen,
protein and ATP production in the host’s
organelles may be impaired at high
circulating Chloramphenicol levels—causing
bone marrow toxicity
• The oral form of Chloramphenicol was
removed from the market in the US [1992]
because of this toxicity

Antibacterial Spectrum

Active against many many pathogens, including:
• Chlamydia
• Rickettsia
• Spirochetes
• Anaerobes
Bacteriostatic, but can be
bactericidal—depending on dose
and organism

Resistance

• Takes place by the presence of enzymes
that inactivate Chloramphenicol

Question 16

Chloramphenicol
Pharmacokinetics/ADEs/Drug Interactions

Answer 16

• After IV dose, it is widely distributed
throughout the body and in the CSF
• Primarily undergoes hepatic
metabolism to an inactive glucuronide, which is then secreted via renal tubules and excreted in the urine
• Reduce dose in liver disease and cirrhosis
• Secreted in breast milk, so avoid in
breastfeeding mums

ADEs

Anemias

• Dose related anemia
• Hemolytic anemia in those with G6PD deficiency
• Aplastic anemia [not related to dose and can occur after drug is stopped]

Gray Baby Syndrome

• Infants have decreased ability to
glucuronidate this drug and their renal
system is not fully developed—so they have decreased ability to excrete the drug—this results in drug build up and this then interferes with function of mitochondrial ribosomes—causing poor feeding, respiratory depression, CV collapse, cyanosis and death
• Adults who have received high doses
of this drug have experienced this
syndrome

Drug Interactions

• This drug interferes with the
metabolism of Warfarin and Phenytoin—which potentiates their effects

Question 17

Clindamycin

Answer 17

▪ MOA is similar to macrolides
▪ Mainly used to treat Gram + bugs, including MRSA, Streptococcus and
anaerobes
▪ Resistance mechanisms are the same as they are for Erythromycin and cross-
resistance has been described
▪ C. difficile is resistant to Clindamycin, and using it for Gram – anaerobes
[Bacteroides species] is decreasing due to resistance
▪ Available orally and IV—oral use is limited by GI side effects
▪ Distributes well into all body fluids, but has poor entry into the CSF
▪ This agent undergoes extensive oxidative metabolism to active and inactive forms—and is excreted into the bile and urine
▪ Low urinary excretion of the active drug limits its use for UTIs
▪ Accumulation has been seen in those with severe renal and/or liver disease
▪ ADEs—rash; diarrhea [which may be an overgrowth of C. difficile]
▪ Oral Vancomycin or Metronidazole is usually effective to treat C. difficile from
Clindamycin

Question 18

Quinupristin/Dalfopristin

Synercid

Answer 18

▪ Mixture of [2] streptogramins in a ratio of 30:70, respectively
▪ Because there are many ADEs—this agent is reserved for the treatment of severe infections caused by Vancomycin-resistant Enterococcus faecium [VRE], where there are not other options [salvage therapy]

MOA

• Each part of this drug binds to a separate
sit on the 50S bacterial ribosome
• Dalfopristin disrupts elongation by
interfering with the addition of new amino
acids
• Quinupristin prevents elongation similar to
the macrolides and causes release of
incomplete peptide chains
• Synergistically interrupt protein synthesis
• Bactericidal against most susceptible
organisms and this drug has a long PAE

Antibacterial Spectrum

• Gram + cocci—including those resistant to other antibiotics
• Primary use is for E. faecium, including VRE strains [it is bacteriostatic against this strain]
• NOT effective against E. faecalis

Resistance
• Enzymatic processes cause resistance
• In some cases, enzyme changes can
change the drug from bactericidal to
bacteriostatic
• Plasmid-associated acetyltransferase
inactivates Daslfopristin

Pharmacokinetics

• Given IV
• Does not achieve therapeutic levels in CSF
• Both drugs are metabolized in the liver
and excreted in the feces

ADEs

• Venous irritation if given through a peripheral IV
• Hyperbilirubinemia in 25%–from competition with antibiotic for excretion
• Arthralgias and myalgias with high doses
• Inhibits CYP 450 3A4 isoenzyme; concomitant use of drugs that are metabolized by this route may cause toxicity

Question 19

Oxazolidinones

Linezolid [Zyvox]—
prototype drug
Tedizolid [Sivextro]

Answer 19

▪Synthetic oxazolidinones developed to treat Gram + organisms, including resistant pathogens:
▪ MRSA
▪ VRE
▪Penicillin-resistant
Streptococci

MOA

• Binds to bacterial 23S ribosomal RNA
of the 50S subunit—inhibits the
forming of 70S initiation complex and
translation of bacterial proteins

Antibacterial Spectrum

Main action is against Gram + pathogens
• Streptococci
• Staphylococci
• Enterococci
• Corynebacterium species
• Listeria monocytogenes
-Moderately active against Mycobacterium TB
• Main use is for drug resistant Gram + infections
• Bacteriostatic, yet Linezolid is bactericidal against Streptococcus
• Linezolid is an alternative to Daptomycin for infections from VRE
• Because these agents are bacteriostatic—not recommended as 1st line for MRSA bacteremia

Resistance

• Occurs from reduced binding at target sites
• Reduced susceptibility and resistance has been seen to S. aureus and Enterococci
species
• Cross-sensitivity to other protein synthesis inhibitors does not occur

Pharmacokinetics

• Well absorbed orally and IV
• Distribute widely throughout the body
• Metabolic pathway of Linezolid not fully
known, is metabolized to 2 inactive
metabolites, excreted by renal and
nonrenal routes
• Tedizolid is metabolized by sulfidation
and majority of elimination is via the liver
and excreted in the feces
• No dose reduction is needed for either
drug in the presence of renal compromise

ADEs

• GI [nausea/diarrhea]*
• Headache*
• Rash*
• Thrombocytopenia has been seen when drugs used >10 days
• These agents possess nonselective MAO activity and may cause a Serotonin syndrome with large quantities of tyramine-containing foods, SSRIs or MAOIs [reversible when the antimicrobial is stopped]
• Irreversible peripheral neuropathy [seen when used >28 days]
• Optic neuritis [seen when used >28 days]

Question 20

Fluoroquinolones

Answer 20

▪ Ciprofloxacin—prototype drug
▪ Delafloxacin [Baxdela]
▪ Gemifloxacin [Factive]
▪ Levofloxacin [Levaquin]
▪ Moxifloxacin [Avelox]
▪ Ofloxacin

▪ 1st quinolone was Nalidixic acid—early 1960s
▪ The nucleus of this drug was modified and it expanded its spectrum of coverage,
improved its pharmacokinetics and stabilized
compounds from many types of resistance
▪ Overuse has caused resistance in Gram +
and Gram – pathogens, and it has increased
the amount of C. difficile infections, and
unmasked many of the untoward ADEs
▪ Currently, these drugs are now considered 2nd line agents for many infections

MOA

▪ Following cell wall entry through porin channels, the quinolones bind to DNA gyrase and topoisomerase IV, and then interfere with DNA ligation
▪ This interference increases chromosomal breaks—causing cell lysis
▪ Quinolones have different targets;
▪ Gram – pathogens—DNA gyrase
▪ Gram + pathogens—topoisomerase IV
▪ These agents are bactericidal and exhibit AUC/MIC dependent killing
▪ Modifying the quinolone nucleus has enhanced its coverage with each new
generation of drugs in this family

Antibacterial Spectrum

1st Generation
• Naladixic acid
• Narrow spectrum
• Covers Gram – bacilli, mainly Enterobacteriaceae

2nd Generation
• Ciprofloxacin
Improved intracellular penetration and
broader coverage, including:
• Enterobacteriaceae
• Pseudomonas aeruginosa
• Haemophilus influenzae
• Neisseria species
• Chlamydia species
• Legionella species

3rd Generation
• Levofloxacin
Cover the same pathogens as the
2nd generation drugs, but with
expand coverage of Streptococcus subspecies:
• Streptococcus pneumoniae
• MSSA
• Strenotrophomonas maltophilia
• Mycobacterium species

4th Generation

• Moxifloxacin
• Gemifloxacin
• Delafloxacin
• Enhanced Gram + and more Staphylococcus and Streptococcus coverage
• Delafloxacin active against MRSA and Enterococcus faecalis
• Delafloxacin and Moxifloxacin cover Bacteroides fragilis and Prevotella species, while still covering Enterobacteriaceae
and Haemophilus influenzae
• In the 4th generation drugs—only Delafloxacin covers
Pseudomonas aeruginosa
• These drugs cover atypical bacteria—Moxifloxacin and Delafloxacin cover Mycobacteria species well

Question 21

Fluoroquinolones

Answer 21

Resistance

Altered Target Binding

• Mutations in bacterial
genes reduce binding of
the quinolone

Decreased Accumulation

Reduced intracellular levels is from:
• Decrease in membrane
permeability OR
• Efflux pumps
Alterations in membrane permeability are mediated through a reduction in outer
membrane porin proteins, so drug cannot access topoisomerases
Efflux pumps remove the quinolone from the cell

Fluoroquinolone Degradation
• Aminoglycoside acetyltransferase variant
acetylates the quinolone

Pharmacokinetics

Absorption

• Well absorbed after oral dosing
• Levofloxacin and Moxifloxacin have
bioavailability of >90%
• Sucralfate, Aluminum or Magnesium
containing antacids, dietary supplements with Zinc or Iron reduce absorption
• Ca++ and dairy products interfere with
absorption

Distribution

• Plasma binding is variable 20 – 80%
• These agents distribute well into all tissues and body fluids
• Concentration are high in bone, urine
[except Moxifloxacin], kidney, prostate
tissue and lungs [as compared to serum]
• Penetration into the CNS is good
• Accumulation in macrophages and
PMN leukocytes allows good coverage
against intracellular pathogens—
Listeria, Chlamydia, Mycobacterium

▪ Elimination—excreted renally
▪ Dosage adjustment needed in renal disease
▪ Moxifloxacin is metabolized primarily by the liver—so no dose adjustment is needed for renal disease

ADEs

▪ Nausea
▪ Vomiting
▪ Headache
▪ Dizziness
▪ Photosensitivity—patients need to use sunscreen and avoid excess UV light exposure
▪ Arthropathy is uncommon—but
arthralgia and arthritis is often reported in the pediatric patient
▪ All of these agents carry a BB warning for tendinitis, tendon rupture, peripheral neuropathy and CNS effects—hallucinations,
anxiety, insomnia, confusion, seizures
▪ Use in pediatrics should be limited to specific scenarios—CF exacerbations
▪ Hepatotoxicity or BS disturbances [usually low BS] has been seen in diabetics
▪ Severe ADEs require immediate cessation of these agents
▪ Fluoroquinolones may prolong the QTc interval—and should be avoided in those predisposed to arrythmias or those already on drug associated with QT prolongation
▪ Cipro inhibits CYP 450 1A2 and 3A4 metabolism—so drug levels of Theophylline, Tizanidine, Warfarin, Ropinirole, Duloxetine,
Caffeine, Sildenafil and Zolpidem levels can be increased

Question 22

Clinically Usefulness of Fluoroquinolones

Answer 22

These drugs should be used with caution because of increasing resistance and BB warnings—consider in those who do not tolerate other agents—or as definitive therapy after susceptibility is available

Ciprofloxacin
▪ Coverage against Gram – bacilli, including Pseudomonas aeruginosa
▪ Used in traveler’s diarrhea, typhoid fever, anthrax
▪ 2nd line for intra-abdominal, lung, skin or urine sourced infection
▪ High dose therapy should be used to treat Pseudomonas

Levofloxacin
▪ Similar activity to Ciprofloxacin
▪ Enhanced coverage for Streptococcus pneumoniae, and can be used 1st line for CAP
▪ 2nd line therapy for Stenotrophomonas maltophilia

Moxifloxacin
• Enhanced activity against Gram +
organisms—Streptococcus pneumoniae,
Gram – anaerobes, Mycobacterium
subspecies
• Can be used for CAP, but not for hospital-
acquired pneumoniae [poor coverage of
Pseudomonas]
• Can be used for mild to moderate intra-
abdominal infections—but avoid in patient’s
have had a fluoroquinolone in previous 90
days, due to emerging B fragilis resistance
• 2nd line for drug susceptible TB

Gemifloxacin
• Indicated for community acquired
respiratory infections
• Only available orally

Delafloxacin
• Improved activity against Gram + cocci, including MRSA and Enterococcus
• An option for acute bacterial skin and skin
structure infections
• Available IV and PO

Question 23

Folate Antagonists

Answer 23

▪ Folic acid is a coenzyme essential in synthesis of RNA, DNA and certain amino acids
▪ In the absence of folate, cells cannot grow and divide
▪ Humans use dietary folate to synthesize tetrahydrofolic acid
▪ Many bacteria are impermeable to folate derivatives, and rely on
their ability to synthesize folate de novo
▪ Sulfonamides inhibit de novo synthesis of folate; Trimethoprim prevents pathogens from converting dihydrofolic acid to
tetrahydrofolic acid
▪ Sulfonamides and Trimethoprim interfere with the ability of the pathogen to perform DNA creation and allow essential cellular functions
▪ Combining Sulfamethoxazole with Trimethoprim
[Cotrimoxazole/Bactrim/Septra] provides a
synergistic effect

Question 24

Sulfonamides

Answer 24

▪ Some of the first antibiotics used clinically
▪ Today, they are seldom prescribed alone—except in developing countries—where
they are inexpensive and effective

MOA
• Bacteria use dihydropteroate synthetase to create dihydrofolic acid from its precursor p-
aminobenzoic acid [PABA]
• Sulfonamides are synthetic analogs of PABA
• They compete with PABA to inhibit
dihydropteroate synthetase and creation of bacterial dihydrofolic acid
• Cotrimoxazole is the prototype drug
and is bacteriostatic

Antibacterial Spectrum

In vitro action against Gram – and
Gram + pathogens:
• Enterobacteriaceae
• Haemophilus influenzae
• Streptococcus spp.
• Nocardia
Sulfadiazine [combined with
Pyrimethamine] is DOC for Toxoplasmosis

Resistance
• Pathogens that get folate from the
environment are naturally resistant to Sulfa drugs
Acquired resistance can arise from:
• Plasmid transfers
• Random mutations
• Resistance can be from:
• Altered dihydropteroate synthetase
• Decreased cellular permeability to Sulfa drugs
• Enhance production of natural substrate, PABA
• Resistance to one member of the drug family means resistance to ALL

Question 25

Sulfonamides–Pharmacokinetics

Answer 25

Absorption
• Well absorbed after oral dose
• Exception is Sulfasalazine—not absorbed when given PO or per rectum, reserved for treatment of chronic inflammatory diseases [especially those affecting the bowel]
• IV use is reserved for those who cannot take oral dosages or who have severe
infection
• Because of risk of sensitization, Sulfa drugs are usually not given topically
• Exception is Silver Sulfadiazine or Mafenide acetate—creams have been used in reducing burn-associated sepsis because they prevent colonization of bacteria
• Silver Sulfadiazine is preferred because Mafenide produces pain with application and can contribute to acid-base disturbances

Distribution
• Bound to serum albumin in circulation
and widely distributed throughout body tissues
• Penetrate well into CSF [even without
inflammation] and cross placental barrier to
enter fetal tissues

Metabolism
• Acetylated and conjugated in the liver
• Acetylated product does not have any
antimicrobial activity, but retains toxic
potential to precipitate at neutral or acidic pH—this can cause crystal lurid [“stone
formation”] and potential damage to the
kidney

Excretion
• Unchanged Sulfa drug and metabolites
eliminated via glomerular filtration and
secretion
• Dose adjustments are needed in renal disease
• Are eliminated in breast milk

Question 26

Sulfonamides–ADEs

Answer 26

Crystalluria

• Adequate hydration and alkalization of
the urine prevent this by reducing
concentration of drug and promoting
ionization

Hypersensitivity

• Rash
• Angioedema
• Stevens-Johnson syndrome

Hematological Effects

• Hemolysis can occur in those with G6PD deficiency
• Granulocytopenia and thrombocytopenia can also occur
• Fatal reactions from agranulocytosis, aplastic anemia and other blood dyscrasias have been seen

Kernicterus

• Bilirubin associated brain damage can
occur in newborns, because Sulfa drugs
displace bilirubin from binding sites on
serum albumin; bilirubin is then free to pass into the CNS—because the blood-brain barrier is not fully developed

Drug Potentiation

• Sulfamethoxazole potentiates the anticoagulant effect of Warfarin by inhibiting CYP 450 2C9—causing reduced clearance of Warfarin
• Sulfonamides also displace Warfarin from binding sites on serum albumin
• DO NOT PRESCRIBE SULFONAMIDES to patients on Warfarin—unless there are NO OTHER ALTERNATIVES, and in that case, the Warfarin dose must be reduced by 50 PERCENT
• Methotrexate levels can rise through protein binding displacement
• Phenytoin levels can increase when sulfonamides are given

Contraindications

• Do not give to newborns and infants less than 2 months of age
• Do not give to pregnant women at term
• Do not give to patients taking Methenamine, since they can crystallize in the presence of formaldehyde produced by Methenamine

Question 27

Trimethoprim

Answer 27

▪ Potent inhibitor of bacterial dihydrofolate reductase—initially available in combination with Sulfamethoxazole, and later approved for use as a single antimicrobial
▪ Most commonly used in combination with Sulfamethoxazole
• Inhibits bacterial dihydrofolate reductase
• Inhibiting this enzyme prevents formation of the metabolically active form of folic acid, tetrahydrofolic acid an interferes with normal functioning of the bacteria

Antibacterial Spectrum

• Coverage similar to that of Sulfamethoxazole
• Trimethoprim is 20 – 50 fold more potent than the Sulfonamides
• May be used alone to treat UTI, bacterial prostatitis [although quinolones and Cotrimoxazole are preferred]

Resistance

• Resistance in Gram – bacteria is from the presence of an altered dihydrofolate reductase that has a lower affinity for
Trimethoprim
• Efflux pumps and decreased permeability to the drug may be part of resistance

Pharmacokinetics

• Rapidly absorbed after an oral dose
• Weak base—high levels are achieved in acidic prostate and vaginal fluids
• Widely distributed in the body
tissues and fluids—including CSF
• Undergoes some O-demethylation, but 60-80% is renally excreted

ADEs

• Can produce folic acid deficiency
• Megaloblastic anemia
• Leukopenia
• Granulocytopenia
• Pregnant and those with poor diets are
especially at risk
• These effects can be reversed by giving
Folinic acid [Leucovorin] which does not
enter bacteria
• Has a K+ sparing effect and may cause
elevated K+, especially in high doses and
when given with other drugs that can elevate
K+ [ACE inhibitors]

Question 28

Cotrimoxazole

Answer 28

▪ Trimethoprim + Sulfamethoxazole
▪ Shows greater coverage than either drug used alone
▪ Synergistic activity and similar ½ lives to each of its components

MOA
• Synergistic activity of Cotrimoxazole is
from the inhibition of 2 steps in the
synthesis of tetrahydrofolic acid

Antibacterial Spectrum
• Broader coverage than the sulfa drugs
• Used to treat UTIs, respiratory infections, as well as:
• Pneumocystis jirovecii
• Toxoplasmosis
• Listeria monocytogenes
• Salmonella
• Active against MRSA—and can be used in skin and soft tissue infections
• DOC for Nocardia and Stenotrophomonas maltophilia

Resistance
• Encountered less often than resistance
to either of the components—because the bug would have to have simultaneous
resistance to both drugs
• Resistance has been seen to E.coli

Pharmacokinetics
• Usually given orally
• Can be given IV for severe pneumonia
from Pneumocystis
• Both components distribute throughout the body
• Trimethoprim concentrates in acidic
fluids—prostate; and explains the
effectiveness in prostatitis
• The combined agent crosses the
blood-brain barrier
• Both drugs and their metabolites are
excreted in the urine

ADEs
• Similar to those seen with the individual
components
• Nausea
• Vomiting
• Skin rash
• Hematological toxicity
• Elevated K+

Question 29

Urinary Tract
Antiseptics/Antimicrobials

Answer 29

▪ Methenamine—Hiprex, Urex
▪ Nitrofurantoin—Macrodantin, MacroBid—prototype drug
▪ In the past, quinolones and Trimethoprim
Sulfa have been 1st line for UTIs
▪ Resistance has increased among these
pathogens [E. coli and others] in the last
decade—and as a result, these older
antimicrobials must be considered in our
therapies and suppression of UTIs

Question 30

Methenamine Salts

Answer 30

MOA
• Hydrolyzed to ammonia and formaldehyde in acidic urine [pH </= 5.5]
• Formaldehyde deactivates proteins and nucleic acids and cells the bacteria
• Methenamine is combined with a weak acid [Methenamine Hippurate] to keep the urine acidic and promote formation of formaldehyde

Antibacterial Spectrum
• Covers E. coli, Enterococcus spp.,
Staphylococcus spp.
• Some activity against Proteus spp. and Pseudomonas aeruginosa but urine must be kept acidic
• Main benefit is lack of selection for
resistant organisms
• Mainly used for chronic suppression

Pharmacokinetics
• Absorbed orally
• 30% is broken down by gastric juices,
unless protected by enteric coating
• Reaches the urine through tubular
secretion and glomerular filtration
• Concentrations are sufficient to treat
susceptible organisms
• Because of ammonia formation, avoid
in liver disease

ADEs
• GI distress
• At high doses—albuminuria, hematuria
and rash
• Methenamine mandelate contraindicated in those with renal disease as the mandelate can precipitate—use Methenamine
Hippurate
• Sulfa drugs react with formaldehyde
and cannot be used concomitantly
with Methenamine—they can crystalize
and mutually antagonize each other

Question 31

Nitrofurantoin

Answer 31

▪ Been around since 1950s for cystitis—re-emerged with all of the resistance to Enterobacteriaceae
▪ Now considered 1st line for uncomplicated cystitis
▪ This drug works by inhibiting DNA and RNA synthesis
▪ Covers E. coli, Klebsiella spp., Enterococcus spp., and Staphylococcus spp.
▪ Following oral dose, it is absorbed; near 40% is excreted unchanged in the urine

▪ ADEs—nausea, vomiting, diarrhea
▪ Use of microcrystalline formula reduces the GI toxicity
▪ Rare complications—pulmonary fibrosis [do not use in patients
with pre-existing lung disease], neuropathy, autoimmune hepatitis—these complications are seen with prolonged use [greater than 1 month]
▪ Those with impaired renal function—should not take this drug—as it increases the chance of ADEs
▪ Not effective in pyelonephritis
▪ Do not prescribe in those with calculated GFR <35 cc/minute