miscellaneous antibiotics

Question 1

tetracyclines

Answer 1

tetracycline, doxycycline, minocycline

Question 2

glycylcyclines

Answer 2

tigecycline

Question 3

sulfonamides

Answer 3

sulfamethoxazole-trimethoprim

Question 4

polymyxin

Answer 4

colistin

Question 5

lincosamides

Answer 5

clindamycin

Question 6

nitromidazoles

Answer 6

metronidazole

Question 7

tetracycline chemistry

Answer 7

The name “tetracycline” refers to antibiotics of either natural or semisynthetic origin that are comprised of a system of four* linearly annelated six-membered rings. Tigecycline, a glycylcycline antibiotic, contains a glycylamido moiety attached to the 9-position of minocycline, which imparts enhanced activity against many tetracycline-resistant bacteria.

Question 8

tetracycline MOA

Answer 8

Tetracyclines and glycylcyclines inhibit bacterial protein synthesis by reversibly* binding to the 30S* ribosome, blocking binding of amino-acyl tRNA to the acceptor (A) site on the mRNA-ribosomal complex. This prevents the addition of amino acid residues to the elongating peptide chain and inhibits protein synthesis.
Tetracyclines and glycylcyclines are usually bacteriostatic** in action, but may be bactericidal in high concentrations or against highly susceptible organisms.

Question 9

tetracycline MOR

Answer 9

There are 3 main mechanisms of resistance to the tetracycline antibiotics:
-Decreased accumulation of tetracycline within the bacteria due to either altered permeability or the presence of tetracycline-specific efflux* pumps.
-Decreased access of the tetracycline to the ribosome due to the presence of ribosomal protection proteins.
-Enzymatic inactivation of the tetracycline.
Tigecycline does NOT appear to be affected by the 2 major tetracycline resistance mechanisms, namely tetracycline-specific efflux and ribosomal protection.
Cross-resistance is usually observed among the tetracycline antibiotics, but minocycline may retain susceptibility against some organisms (especially Staphylococcus spp.). Also, tigecycline displays activity against many tetracycline-resistant bacteria.

Question 10

tetracycline SOA overview

Answer 10

The tetracyclines display activity against Gram-positive and Gram-negative aerobic bacteria, as well as unusual bacteria. However, the emergence of resistance to tetracyclines in conjunction with the introduction of new and improved antibiotics has limited the therapeutic usefulness of the tetracyclines.

Question 11

tetracyclines vs gram positive aerobes

Answer 11

minocycline and doxycycline most active
Some Group and Viridans Streptococcus
Streptococcus pneumoniae (PSSP, doxycycline ∼ 85% susceptible)
Some Enterococcus spp.
Some Staphylococcus aureus (primarily MSSA***, 80% susceptible)
Bacillus, Listeria, Nocardia

Question 12

tetracyclines vs gram-negative aerobes

Answer 12

were initially useful for Gram-negative aerobes, but many Enterobacteriaceae are relatively resistant 
Haemophilus influenzae (90% susceptible)
Haemophilus ducreyi (chancroid)
Campylobacter jejuni
Helicobacter pylori

Question 13

tetracyclines vs anaerobes

Answer 13

Gram-positive: Actinomyces, Propionibacterium spp.

Question 14

tetracyclines vs misc organisms

Answer 14

Bartonella, Bordetella, Brucella, Pasteurella,
Atypical bacteria such as Legionella pneumophila, Chlamydophila pneumoniae and psittaci (macrolide and FQ better); Chlamydia trachomatis, Mycoplasma hominis and pneumoniae, Ureaplasma spp.
Spirochetes including Borrelia, Leptospira, and Treponema
Rickettsia such as Rickettsia, Coxiella
Doxycycline and tetracycline display activity against Mycobacterium fortuitum

Question 15

tigecycline SOA

Answer 15

is active against a broad range of Gram-positive and Gram-negative aerobic and anaerobic bacteria, with an expanded spectrum that includes many tetracycline-resistant strains

Question 16

Tigecycline vs gram positive aerobes

Answer 16

Group streptococci including S. pyogenes and S. agalactiae
Viridans streptococci
Enterococcus faecalis (vancomycin susceptible isolates only)
Staphylococcus aureus (MSSA** and MRSA**) - never used in serious infections
Listeria monocytogenes

Question 17

tigecycline vs gram negative aerobes

Answer 17

Acinetobacter baumannii			
Aeromonas hydrophila			
Citrobacter freundii and koseri
Enterobacter cloacae and aerogenes
Escherichia coli
Klebsiella pneumoniae and oxytoca
Serratia marcescens
Stenotrophomonas maltophilia**
***Tigecycline is NOT active against Proteus mirabilis or Pseudomonas aeruginosa

Question 18

tigecycline vs anaerobes

Answer 18

Gram-Positive: Actinomyces, Propionibacterium, Peptostreptococcus, Clostridium perfringens
Gram-Negative: Bacteroides spp., Prevotella spp.

Question 19

tigecycline vs miscellaneous organisms

Answer 19

Pasteurella multocida and Mycobacterium fortuitum, chelonae, abscessus

Question 20

absorption of tetracyclines

Answer 20

tigecycline is only available IV; doxycycline is available IV and PO, tetracycline and minocycline are only available PO
Tetracycline, demeclocycline – 60 to 80% absorbed from the GI tract
Doxycycline, minocycline – 90 to 100% absorbed from the GI tract
Tetracyclines are absorbed best when taken on an empty stomach**.
Absorption of the oral tetracyclines is impaired by the concurrent ingestion of dairy products, aluminum hydroxide gels, calcium, magnesium, iron, zinc, and bismuth subsalicylate due to chelation with divalent or trivalent cations. - ZICAM

Question 21

distribution of tetracyclines

Answer 21

Tetracyclines and tigecycline are widely distributed into body tissues and fluids including pleural fluid, bronchial secretions, sputum, saliva, ascitic fluid, synovial fluid, aqueous and vitreous humor, and prostatic* and seminal fluids.
Only small amounts of tetracyclines diffuse into the CSF.

Question 22

elimination of tetracyclines

Answer 22

Demeclocycline and tetracycline are excreted unchanged mainly in the urine by glomerular filtration, and require dosage adjustment in renal insufficiency.
Tetracycline half-life = 6 to 12 hours
Demeclocycline half-life = 16 hours
Doxycycline and minocycline are excreted mainly by nonrenal routes, and do not require dosage adjustment in renal insufficiency – elimination half-lives ranges from 16 to 18 hours
Tigecycline is mainly eliminated by biliary/fecal excretion of unchanged drug and its metabolites (59%), with only 20% of the dose excreted as unchanged drug in the urine. The half-life of tigecycline = 27 to 42 hours. Dosage adjustments of tigecycline are required in patients with severe hepatic impairment*** (Child Pugh C), but are not required in patients with renal impairment or in patients undergoing hemodialysis.
Tetracyclines and tigecycline are not appreciably removed during hemodialysis or peritoneal dialysis.

Question 23

Clinical uses of tetracyclines

Answer 23

the tetracyclines are primarily used for the treatment of outpatient CAP** (doxycycline) or infections due to unusual organisms
The emergence of bacterial resistance and the availability of more potent and useful antibiotics have limited the therapeutic usefulness of the tetracyclines in the treatment of Gram-positive and Gram-negative infections.
-Mild to moderate outpatient community-acquired pneumonia* (doxycycline*) – due to penicillin-susceptible S. pneumoniae, Mycoplasma spp, Chlamydophila spp.
-Treatment of rickettsial infections including Rocky Mountain spotted fever, epidemic and endemic typhus, Brill-Zinsser disease, scrub typhus, Q fever (Coxiella burnetti), rickettsial pox (doxycycline, tetracycline)
-Chlamydial infections including psittacosis, lymphogranuloma venereum, and nongonococcal urethritis** (doxycycline)
-Brucellosis, bartonellosis (doxycycline)
-Acne (minocycline)
-Useful as either primary or alternative therapy for the treatment of Plague (Yersinia pestis), Tularemia, Chancroid, Pertussis, Clostridial infections, Anthrax, Listeria, Syphilis, Lyme disease, H pylori, Ehrlichia, Cholera, prevention of Malaria (doxycycline)
-Chronic syndrome of inappropriate antidiuretic hormone secretion – SIADH (demeclocycline)
Because of an expanded spectrum of activity, tigecycline** is approved for the treatment of polymicrobial infections caused by susceptible bacteria (NOT Proteus spp. or Pseudomonas spp.):
-Complicated skin and skin structure infections
-Complicated intra-abdominal infections

Question 24

tetracycline AEs

Answer 24

Gastrointestinal – nausea (up to 29% with tigecycline), vomiting (up to 19% with tigecycline), diarrhea, flatulence, epigastric burning, oral candidiasis, antibiotic-associated pseudomembranous colitis
Hypersensitivity - rash, pruritus, urticaria, angioedema, anaphylaxis, serum sickness, Stevens-Johnson syndrome
Dermatologic* – photosensitivity**, manifested as exaggerated sunburn - most severe with demeclocycline, less frequently with doxycycline, tetracycline, and oxytetracycline, rarely with minocycline and tigecycline
Renal - Fanconi-like syndrome with ingestion of outdated tetracycline; reversible dose-related diabetes insipidus with demeclocycline
Hepatic - elevation of transaminases
Central Nervous System - lightheadedness, dizziness, vertigo, ataxia, headache
Other - vaginal candidiasis, thrombophlebitis with IV administration
Pregnancy Category D - all tetracyclines and tigecycline are contraindicated for use during pregnancy and in children less than 8 years of age because they cause permanent discoloration of primary dentition (yellow-gray-brown) in children with developing teeth and form a complex in bone-forming tissue, leading to decreased bone growth.

Question 25

tetracycline dosing

Answer 25

PO

250 to 500 mg every 6 hours

Question 26

doxycycline dosing

Answer 26

PO and IV

100 mg every 12 hours

Question 27

minocycline dosing

Answer 27

PO

100 mg every 12 hours

Question 28

Tigecycline dosing

Answer 28

IV

100 mg followed by 50 mg every 12 hours

Question 29

SMX-TMP MOA

Answer 29

TMP and SMX produce sequential blockade of microbial folic acid synthesis
Sulfamethoxazole: a sulfonamide that competitively inhibits the incorporation of p-aminobenzoic acid (PABA) into folic acid by inhibiting dihydropteroate synthetase, which inhibits the formation of dihydrofolic acid
Trimethoprim: competitively inhibits the activity of bacterial dihydrofolate reductase* to prevent the reduction of dihydrofolate to tetrahydrofolate
Together, these two agents produce sequential inhibition of the synthesis of folate, which is necessary for microbial production of DNA, producing a synergistic bactericidal** effect against many Gram-positive and Gram-negative aerobic bacteria that may not be present with each agent alone.

Question 30

SMX-TMP MOR

Answer 30

Resistance to trimethoprim-sulfamethoxazole occurs, but appears to develop more slowly to the combination than to each individual agent.
Resistance has been reported in E. coli, Klebsiella spp., Proteus mirabilis, H. influenzae, Salmonella spp., and Staphylococcus aureus.
Bacterial resistance is mediated by point mutations in dihydropteroate synthase and/or altered production or sensitivity of bacterial dihydrofolate reductase.

Question 31

SMX-TMP SOA

Answer 31

Gram-Positive Aerobes: S. aureus (including some MRSA, especially CA-MRSA), S. pyogenes (marginal), and Nocardia
Gram-Negative Aerobes: most Enterobacteriaceae including Acinetobacter baumannii, Enterobacter spp., E. coli (75-80%), K. pneumoniae, P. mirabilis, Salmonella, Shigella, ampicillin-resistant H. influenzae, H. ducreyi, N. gonorrhoeae, and Stenotrophomonas maltophilia
-TMP-SMX is NOT active against P. aeruginosa*
Anaerobes: no activity
Other Organisms: Pneumocystis carinii/jirovecii (DRUG OF CHOICE)***

Question 32

SMX-TMP pharmacology

Answer 32

The optimal synergistic ratio of trimethoprim (TMP) to sulfamethoxazole (SMX) in serum and tissues against most susceptible bacteria is approximately 1:20. Steady-state serum concentrations of 1:20 (TMP:SMX) are achieved by using a fixed oral or intravenous combination of 1:5 (TMP:SMX).
Absorption
-Co-trimoxazole is rapidly and well absorbed after oral administration.
-Peaks are higher and more predictable after parenteral administration.
Distribution
-TMP-SMX concentrates in most tissues, including the CSF in the presence of inflamed meninges. CSF concentrations are 30 to 50% (TMP) and 20% (SMX) of concomitant plasma concentrations.
-TMP-SMX concentrates well into saliva, breast milk, urine, uninflamed prostatic tissue, seminal fluid, inflamed lung tissue, and bile.
-Sulfamethoxazole is 70% protein bound.
Elimination
-About 60% of TMP and 25 to 50% of SMX is excreted in the urine in 24 hours.
-In patients with normal renal function, the half-lives of TMP and SMX are 11 and 9 hours, respectively.
-Doses should be adjusted in patients with CrCl under 30 ml/min.

Question 33

clinical uses of SMX-TMP

Answer 33

Acute, chronic or recurrent infections of the urinary tract*
Acute or chronic bacterial prostatitis*
Acute bacterial exacerbations of chronic bronchitis (ABECB)
Pneumocystis carinii/jirovecii pneumonia* – TMP-SMX is the drug of choice* for both treatment and prophylaxis
Skin and soft tissue infections due to CA-MRSA*
Salmonella, Shigella, enteric fever, infantile diarrhea caused by enteropathogenic E. coli, traveler’s diarrhea prophylaxis
Acute otitis media (sulfisoxazole), sinusitis (co-trimoxazole)
Nocardia infections – sulfisoxazole or TMP-SMX
Stenotrophomonas maltophilia infections***
Toxoplasmosis – sulfadiazine (with pyrimethamine)

Question 34

SMX-TMP AEs

Answer 34

Gastrointestinal: nausea, vomiting, anorexia, glossitis, abdominal pain, diarrhea
Hematologic: leukopenia, thrombocytopenia, eosinophilia, megaloblastic anemia, acute hemolytic anemia, aplastic anemia, agranulocytosis - may require d/c of therapy
Hypersensitivity reactions: rash, urticaria, pruritus, epidermal necrolysis, Steven’s Johnson syndrome, erythema multiforme, exfoliative dermatitis, drug fever, malaise, serum sickness
CNS: headache, insomnia, depression, fatigue, aseptic meningitis, seizures, tremor, hallucinations
Others: chills, myalgias, hepatitis (cholestatic and hepatic necrosis), renal insufficiency, crystalluria** (especially with older, less soluble sulfonamides), hyperkalemia (high doses)
Pregnancy Category C - should NOT be used in pregnant women (especially during the third trimester or at term) or lactating women because it may cause kernicterus in the newborn due to bilirubin displacement from protein binding sites

Question 35

SMX-TMP DIs

Answer 35

warfarin - potentiated anticoagulant effects d/t inhibition of metabolism and possible displacement from protein binding sites

Question 36

SMX-TMP dosgin

Answer 36

Oral tablets:
Single Strength (SS) = 80mg TMP and 400mg SMX
Double Strength (DS) = 160mg TMP and 800mg SMX
Oral Suspension = 40mg TMP and 200mg SMX per 5 ml
IV solution = 16mg TMP and 80mg SMX per ml
UTI, prostatitis, GI infections - one DS tablet BID
skin and soft tissue infections d/t CA-MRSA - two DS tablets BID
pneumocystis cainii/jirovecii pneumonia:
-Treatment: 15 to 20 mg/kg TMP daily divided every 6 to 8 hours (PO or IV)
-Prophylaxis: One DS tablet daily

Question 37

colistin chemistry

Answer 37

Colistin is derived from Bacillus colistinus and is a cationic cyclic decapeptide linked to a fatty acid chain by an α-amide linkage. Two forms of colistin, or polymyxin E, are commercially available: colistin sulfate (used orally) and colistimethate sodium (CMS, also known as colistin methanesulfate; used parenterally and by inhalation). CMS is available for use in the US and is a prodrug that is less potent and less toxic than colistin sulfate. CMS undergoes hydrolysis in aqueous solutions to colistin and to a complex mixture of partially sulfomethylated derivatives.

Question 38

Colistin MOA

Answer 38

Colistin is a cationic detergent that binds to the anionic lipopolysaccharide molecules of the outer cell membrane of Gram-negative bacteria causing displacement of calcium and magnesium, which normally stabilize the cell membrane. This action leads to changes in cell wall permeability, leakage of cellular contents, and subsequent cell death.
Colistin displays concentration-dependent bactericidal** activity.

Question 39

colistin MOR

Answer 39

Alteration of the outer cell membrane – decreased lipopolysaccharide content, reduction in calcium and magnesium content, decreased outer membrane proteins

Question 40

colistin SOA

Answer 40

Gram-Positive Aerobes – colistin is inactive** against aerobic Gram-positive bacteria
Gram-Negative Aerobes – colistin displays excellent activity against most Gram-negative aerobic bacilli
-Acinetobacter spp.** (including MDR strains)
-Citrobacter spp.
-Enterobacter spp.
-Escherichia coli
-Haemophilus influenzae
-Klebsiella spp.
-Pseudomonas aeruginosa** (including MDR strains)
-Salmonella spp.
-Shigella spp.
-Stenotrophomonas maltophilia (83-88% susceptible)
*Colistin is NOT active against Burkholderia spp., Proteus spp., Providencia spp., Serratia spp., and Brucella spp.
Anaerobes – colistin is inactive against anaerobes

Question 41

colistin pharmacology

Answer 41

Older colistin PK data was derived using microbiologic methods, which could not differentiate between CMS and colistin concentrations. More accurate methods for CMS and colistin serum concentration determination have been developed to facilitate PK characterization of these agents. Colistin displays extensive interpatient variability and a narrow therapeutic window – TDM may be needed for dose optimization.
Absorption – Colistin is not absorbed from the gastrointestinal tract, and must be administered parenterally (IV) or by inhalation in the US for the treatment of systemic infections.
Distribution
-Vd of colistin = 0.5 L/kg (indicating limited extravascular distribution)
-Older literature suggests that colistin demonstrates poor penetration into the pleural cavity, lung parenchyma, bone, and the CSF. However, a recent study demonstrated colistin CSF concentrations were approximately 25% of simultaneous serum concentrations.
Metabolism/Elimination
-Approximately 50% of CMS is excreted unchanged in the urine by glomerular filtration (efficiency of this elimination pathway impacts the amount of CMS available for conversion to colistin); colistin is extensively eliminated by non-renal routes.
-CMS half-life is approximately 2 to 3 hours, which is prolonged in the presence of renal dysfunction. Colistin half-life = 14.4 hours.
-CMS requires dosage adjustment in the presence of renal insufficiency when the creatinine clearance is under 80 ml/min.

Question 42

colistin clinical uses

Answer 42

*Infections caused by Gram-negative bacteria (including P. aeruginosa and A. baumannii) that are resistant to other available antibiotics, including bacteremia, urinary tract infections, pneumonia, etc. Colistin is usually administered intravenously for the treatment of systemic infections, but may be administered by inhalation (aerosolized) for the treatment of patients with cystic fibrosis and as adjunctive treatment for pneumonia.

Question 43

colistin AEs

Answer 43

why we don’t use
**Nephrotoxicity – acute tubular necrosis manifested by an increase in serum creatinine and decrease in creatinine clearance; dose-dependent; usually reversible
**Neurotoxicity – dizziness, weakness, facial and peripheral paresthesias, dose-dependent; reversible
Chest tightness, bronchospasm – inhalation

Question 44

colistin dosage and administration

Answer 44

Oral – colistin sulfate (not available in the US)
Parenteral – colistimethate sodium (Coly-Mycin M Parenteral®); each vial contains colistimethate sodium, which is equivalent 150 mg colistin base activity
-Adult dose: 2.5 to 5 mg/kg colistin base per day in 2 to 4 divided doses (typical dose is 2.5 mg/kg/dose colistin base every 12 hours) in patients with normal renal function; USE LBW*** for dosing; doses must be adjusted in renal insufficiency according to the manufacturer’s guidelines:
-CrCl (ml/min) over 80: 2.5 mg/kg/dose every 12 hours
-CrCl (ml/min) 50 to 79: 1.25 to 1.9 mg/kg/dose every 12 hours
-CrCl (ml/min) 30 to 49: 1.25 mg/kg/dose every 12 hours
-CrCl 10 to 29: 1.5 mg/kg every 36 hours
-Hemodialysis - ?? 2 mg/kg after each HD
Inhalation – 80 to 160 mg colistin base every 8 to 12 hours

Question 45

clindamycin MOA

Answer 45

Clindamycin inhibits protein synthesis by exclusively binding (reversibly) to the 50S ribosomal subunit.
Although clindamycin, the macrolides, the streptogramins, and chloramphenicol are not structurally related, they all act at sites within close proximity on the 50S ribosome and may competitively inhibit the action of each other.
Clindamycin is primarily bacteriostatic, but can display time-dependent bactericidal activity depending on the infecting bacteria, inoculum of bacteria, and concentration of antibiotic at the site of infection.

Question 46

clindamycin MOR

Answer 46

Alteration of the ribosomal binding site** – ribosomal methylation by erm-encoded enzymes; cross-resistance with macrolides and streptogramins occur in the presence of this enzyme (MLSb resistance)
Clindamycin is NOT a substrate for macrolide efflux pumps, and strains that are resistant to macrolides by this mechanism remain susceptible to clindamycin.

Question 47

clindamycin SOA

Answer 47

Gram-Positive Aerobes – clindamycin is active against many Gram-positive aerobes
-Group streptococci
-Viridans streptococci
-Streptococcus pneumoniae (PSSP)
-Staphylococcus aureus (MSSA** and CA-MRSA)
Anaerobes – clindamycin is active against many Gram-positive and Gram-negative anaerobes, but is most useful for anaerobes above the diaphragm
-Gram positive anaerobes: peptostreptococcus spp., Clostridium spp. (not C. difficile*), Actinomyces, propionibacterium
-Gram negative anaerobes: Bacteroides spp., Prevotella, Fusobacterium
Other Atypical Bacteria:
-Pneumocystis carinii/jirovecii
-Toxoplasmosis gondii
-Plasmodium falciparum and vivax (malaria)

Question 48

clindamycin pharmacology

Answer 48

Absorption – clindamycin is rapidly and almost completely absorbed after oral administration; bioavailability approaches 90%; food has minimal effect on the absorption of clindamycin
Distribution
-Good serum concentrations are achieved by the oral, intramuscular or intravenous route.
-Clindamycin penetrates into most body tissues and fluids including sputum, bile, pleural fluid and bone**.
-Clindamycin does NOT penetrate the CSF, even in the presence of inflamed meninges.
Metabolism/Elimination
-Clindamycin is primarily metabolized by the liver (85%) to metabolites with varying antimicrobial activity, which are eliminated in the urine.
-Enterohepatic circulation of clindamycin and its metabolites can lead to prolonged antimicrobial presence in the stool.
-Half-life = 2.5 to 3 hours, which is prolonged in the presence of liver dysfunction.
-Clindamycin is NOT removed by hemodialysis or peritoneal dialysis.

Question 49

clindamycin clinical uses

Answer 49

Infections due to anaerobes (including B. fragilis) OUTSIDE THE CNS – pulmonary infections, intraabdominal infections, pelvic infections, diabetic foot infections, decubitus ulcers.*
Alternative to penicillin in the treatment of infections due to C. perfringens.
Treatment of mild to moderate skin and soft tissue infections due to staphylococci and streptococci, including CA-MRSA.**
Alternative agent for the treatment of infections due to gram-positive aerobes in patients allergic to penicillin* (cellulitis, septic arthritis, osteomyelitis).
Alternative for the treatment of encephalitis due to Toxoplasmosis gondii in AIDS patients (with pyrimethamine).
Alternative for the treatment of Pneumocystis carinii/jirovecii pneumonia in AIDS patients allergic to sulfonamides (with primaquine).
Treatment of bacterial vaginosis (vaginal cream).

Question 50

clindamycin AEs

Answer 50

Gastrointestinal
-Nausea, vomiting, diarrhea – 3 to 4%
-Clostridium difficile colitis (pseudomembranous colitis or antibiotic-associated diarrhea)*
—Incidence 0.01 to 10% - clindamycin is one of the worst inducers
—Caused by toxin produced by C. difficile
—Ranges from mild and self-limiting to life-threatening
—Can occur with oral, intravenous, or topical
-Other – abdominal distention, metallic taste
Hepatotoxicity** – elevation in transaminases
Hypersensitivity – rash, drug fever, eosinophilia
Other – neutropenia, thrombocytopenia (rare)

Question 51

clindamycin dosage and administration

Answer 51

Oral – available as 75mg, 150mg and 300mg capsules; 75mg per 5ml oral solution
-Adult dose = 150 mg to 450 mg PO every 6 hours (dose depends on the severity of infection)
-Pediatric dose = 8 to 25 mg/kg/day in 3 to 4 divided doses
Parenteral – higher doses for more severe infections
-Adult dose = 300 mg to 900 mg IV every 8 hours (dose depends on the
severity of infection – up to 1200 mg every 6 hours for Toxoplasmosis gondii encephalitis)
-Pediatric dose = 15 to 40 mg/kg/day in 3 to 4 divided doses

Question 52

metronidazole MOA

Answer 52

Metronidazole is a prodrug that is activated by a reductive process. Its selective toxicity towards anaerobic and microaerophilic bacteria is due to the presence of electron transport components such as ferredoxins within these bacteria. Ferredoxins are small Fe-S proteins that donate electrons to metronidazole to form a highly reactive nitro radical anion.
These short-lived activated metabolites damage bacterial DNA (inhibit nucleic acid synthesis) and subsequently cause cell death – metronidazole is rapidly bactericidal in a concentration-dependent manner.***
Metronidazole is catalytically recycled when loss of the electron from the active metabolite regenerates the parent compound.
Increased levels of oxygen inhibit metronidazole-induced cytotoxicity since oxygen competes with metronidazole for generated electrons.

Question 53

metronidazole MOR

Answer 53

Clinical resistance to metronidazole is well documented in Trichomonas, Giardia, and a variety of anaerobic bacteria, but is relatively uncommon**.

• Altered growth requirements – organism grows in higher local oxygen concentrations causing decreased activation of metronidazole and futile recycling of the active drug
• Altered levels of ferredoxin – reduced transcription of the ferredoxin gene

Question 54

metronidazole

Answer 54

Metronidazole is extremely active against a wide variety of anaerobic protozoal parasites and obligate/strict anaerobic bacteria. It is the antianaerobic agent most reliably active against Bacteroides fragilis.*
Gram-Negative Anaerobes – highly active against cocci and bacilli
-Bacteroides fragilis**
-Bacteroides distasonis, ovatus, thetaiotamicron, bivius (B. fragilis group DOT** organisms)
-Fusobacterium
-Prevotella spp. and Veillonella spp.
-Helicobacter pylori (an obligate anaerobe)
Gram-Positive Anaerobes – active against cocci (variably) and sporulating bacilli
-Clostridium spp. (INCLUDING Clostridium difficile**)
-Peptostreptococcus
Other organisms: Trichomonas vaginalis, Entamoeba histolytica, Giardia lamblia, Gardnerella vaginalis
Metronidazole is inactive* against all common aerobic and facultatively anaerobic bacteria.

Question 55

metronidazole pharmacology

Answer 55

Absorption
-Metronidazole is rapidly and almost completely absorbed (F = 90 to 100%) after oral administration, achieving peak concentrations within 0.25 to 3 hours.
-Food does not affect the absorption of metronidazole, but may delay the Tmax.
-Serum concentrations are similar after equivalent intravenous and oral doses. Rectal absorption is adequate but delayed, and vaginal absorption is minimal.
Distribution
-Metronidazole is well distributed into body tissues and fluids, including vaginal secretions, seminal fluids, saliva, and breast milk. Repeated dosing results in some accumulation of the drug.
-Metronidazole DOES penetrate into the CSF and brain tissue*** achieving 50 to 100% of simultaneous serum concentrations in the CSF depending on the degree of meningeal inflammation.
Metabolism/Elimination
-Metronidazole is metabolized by the liver to several active metabolites; accounting for over 50% of the systemic clearance of metronidazole.
-Metronidazole and its metabolites are primarily excreted in the urine; only 10% is recovered as unchanged drug in the urine; 6-15% of a dose is excreted in the feces.
-The elimination half-life in normal renal and hepatic function is 6 to 8 hours for the parent drug, and 12 to 15 hours for some metabolites. The half-life is prolonged in the presence of renal or hepatic dysfunction, so that dosage adjustments are required.
-Metronidazole is removed during hemodialysis

Question 56

metronidazole clinical uses, dosages and administration

Answer 56

available orally as 250mg and 500 mg tablets; 500 mg for parenteral use; intravaginal gel
Infections due to anaerobes** (including serious infections) such as skin and soft tissue infections, bone and joint infections, intraabdominal and pelvic infections or abscesses, brain abscesses, diabetic foot infections, etc. Many serious anaerobic infections are polymicrobial and additional antibiotics are necessary for coverage of aerobic bacteria.
-Oral: 250 mg to 500 mg every 6 to 8 hours
-Parenteral: typical adult dose is 500 mg every 6 hours; maximum dose is 4 grams daily*
Pseudomembranous colitis due to Clostridium difficile – DRUG OF CHOICE**
-Metronidazole (PO or IV) is the drug of choice for mild to moderate C. difficile colitis because it is less expensive than oral vancomycin with similar treatment outcomes and causes less impact on microbial ecology in the intestinal tract.
-Oral or parenteral therapy may be used: 250 mg to 500 mg every 6 to 12 hours
Bacterial vaginosis due to Gardnerella vaginalis – oral (500 mg twice daily for 7 days) or intravaginal therapy (5 g twice daily for 5 days)
Trichomonas vaginalis – 2 grams orally as a single dose; 500 mg PO twice daily for 5 days; 250 mg PO every 8 hours for 7 days
Diarrhea due to Giardia** - 500mg PO every 12 hours for 5 to 7 days
Amebiasis (intestinal or extraintestinal) – 750 mg PO or IV every 8 hours for 10 days
Other: H. pylori (250 mg to 500 mg PO every 8 hours with other meds); Crohn’s disease (intestinal bacterial overgrowth); acne rosacea; gingivitis

Question 57

metronidazole AEs

Answer 57

Gastrointestinal – nausea, diarrhea, anorexia, metallic taste, stomatitis, pancreatitis
Central nervous system – most serious; rare unless large doses are utilized or therapy is prolonged
-Seizures, encephalopathy, cerebellar dysfunction, peripheral neuropathy
-Use with caution in patient with CNS disorders
-If neurologic symptoms develop, the drug should be discontinued immediately
Other: reversible neutropenia, dark brown urine, local vaginal reactions
Mutagenicity and Carcinogenicity
-Carcinogenic in rodents, especially female rats; concern about the promotion of cancer in humans (long term effects of high-dose prolonged therapy have not been studied)
-Metronidazole may be teratogenic – should be avoided during the first trimester and during breastfeeding (Pregnancy Category B)

Question 58

metronidazole drug interactions

Answer 58

warfarin - increased anticoagulant effect, alcohol- disulfram effect