Erdman - MSC Flashcards
TETRACYCLINES and TETRACYCLINE ANALOGS
- four linearly annelated six membered rings
MOA: inhibit bacterial protein synthesis by
reversibly binding to the ___ ribosome
usually ___ in action, but may
be bactericidal in high concentrations or against highly susceptible organisms
- 30S
- bacteriostatic
TETRACYCLINES and TETRACYCLINE ANALOGS
MOR
1. Decreased accumulation of tetracycline within the bacteria due to either altered ___ or the presence of tetracycline-specific ___ pumps
2. Decreased access of the tetracycline to the ribosome due to the presence of ribosomal ___ proteins.
3. Enzymatic ___ of the tetracycline
Cross-resistance is usually observed among the tetracycline antibiotics; however, ___ may retain susceptibility against some organisms (especially Staphylococcus spp)
___ , ___ , and ___ (TOE) retain activity against many tetracycline-resistant bacteria because they do NOT appear to be affected by the 2 major tetracycline resistance mechanisms
- permeability, efflux
- protective
- inactivation
- minocycline
- Tigecycline, omadacycline, eravacycline
TETRACYCLINES
SOA
Gram-Positive Aerobes – ___ and ___ most active
- Some Group and Viridans Streptococcus
- Streptococcus pneumoniae (PSSP, doxycycline ~85% susceptible)
- Some Enterococcus spp.
- Some Staphylococcus aureus (primarily ___ , 80% susceptible)
- Bacillus, Listeria, Nocardia
Gram-Negative Aerobes –were initially useful, but many Enterobacteriaceae are relatively resistant
- Haemophilus influenzae (90% susceptible)
- Haemophilus ducreyi (chancroid)
- Campylobacter jejuni
- Helicobacter pylori
- Acinetobacter baumannii (minocycline IV)
minocycline, doxycycline
MSSA
TETRACYCLINES
SOA
Anaerobes
- Gram-positive: Actinomyces, Propionibacterium spp
MSC
- Bartonella, Bordetella, Brucella, Pasteurella
- Atypical bacteria such as ___ , ___ and psittaci 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
- Legionella pneumophila
- Chlamydophila pneumoniae
TETRACYCLINE ANALOGS
SOA
___ , ___ , and ___ (TOE) are 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
Gram-Positive Aerobes
- Group streptococci including S. pyogenes and S. agalactiae
- Viridans streptococci
- Enterococcus faecalis (VSE and some VRE)
- ___ and ___
- Listeria monocytogenes
Gram-Negative Aerobes (erava with some activity against ESBL-, AmpC- and KPC-producing bacteria)
- Acinetobacter baumannii (omadacycline MICs higher)
- Aeromonas hydrophila
- Citrobacter freundii and koseri
- Enterobacter cloacae and aerogenes
- Escherichia coli
- Klebsiella pneumoniae and oxytoca
- Serratia marcescens
- Stenotrophomonas maltophilia (omadacycline MICs higher)
Anaerobes
Gram-Positive: Actinomyces, Propionibacterium, Peptostreptococcus, Clostridium perfringens
Gram-Negative: Bacteroides spp., Prevotella spp
Miscellaneous organisms
Atypical bacteria (eravacycline and omadacycline), Pasteurella multocida and Mycobacterium fortuitum, chelonae, abscessus
Tetracycline analogs are NOT active against ___ or ___
- Tigecycline, eravacycline, omadacycline
MSSA, MRSA - Proteus mirabilis,
Pseudomonas aeruginosa
TETRACYCLINES and TETRACYCLINE ANALOGS
Tetracyclines are absorbed best when taken on an ___ stomach
- Absorption of the oral tetracyclines and omadacycline is impaired by the
concurrent ingestion of ___ products, aluminum hydroxide gels, ___ , magnesium, iron, ___ , and bismuth subsalicylate due to chelation with divalent or trivalent cations
Only ___ amounts of tetracyclines and tetracycline analogs diffuse into the CSF
- empty
- dairy
- Ca, Zn
- small
TETRACYCLINES Elimination
- ___ and ___ are excreted unchanged mainly in the urine by glomerular filtration, and require dosage adjustment in renal insufficiency
- ___ and ___ are excreted mainly by nonrenal routes, and do not require dosage adjustment in renal insufficiency
- Demeclocycline, tetracycline
- Doxycycline, minocycline
T or F: tetracycline analogs require dosage adjustment in patients with renal impairment or in patients undergoing hemodialysis
FALSE
they do no require renal dosing adjustments
- Dosage adjustments of tigecycline and eravacycline are required in patients with severe hepatic impairment
CLINICAL USES - tetracyclines
the tetracyclines are primarily used for the treatment of outpatient CAP (doxycycline) or infections due to unusual organisms
- Mild to moderate outpatient community-acquired ___ (doxycycline) – due to PSSP, Mycoplasma spp, Chlamydophila spp
- ___ infections including psittacosis, lymphogranuloma venereum, and nongonococcal urethritis* (doxycycline)
- pneumonia
- Chlamydial
CLINICAL USES - tetracycline analogs
Tetracycline analogs ($$$) have an expanded spectrum of activity and are (rarely) used for the treatment of ___ infections caused by susceptible bacteria (NOT ___ spp. or ___ spp.)
- polymicrobial
- Proteus, Pseudomonas
TETRACYCLINE AEs
GI
Dermatologic - ___
Pregnancy Category D - all tetracyclines and tetracycline analogs are not recommended to be used during pregnancy/lactation and in children < 8 years of age because they cause permanent discoloration of primary dentition (yellow- gray-brown) in children with developing ___ and form a complex in bone forming tissue, leading to ___ bone growth.
- photosensitivity
- teeth, decreased
TRIMETHOPRIM-SULFAMETHOXAZOLE (SULFONAMIDES)
Sulfamethoxazole: a sulfonamide that competitively inhibits the incorporation of ___ into folic acid by inhibiting ___ synthetase, which inhibits the formation of dihydrofolic acid
Trimethoprim: competitively inhibits the activity of bacterial ___ reductase to prevent the reduction of dihydrofolate to tetrahydrofolate
Together, these two agents produce sequential inhibition of the synthesis of ___ , which is necessary for microbial production of DNA, producing a synergistic ___ effect against many Gram-positive and Gram-negative aerobic bacteria that may not be present with each agent alone.
- PABA, dihydropteroate
- dihydrofolate
- folate, bacteriocidal
TRIMETHOPRIM-SULFAMETHOXAZOLE (SULFONAMIDES)
MECHANISMS OF RESISTANCE
- Bacterial resistance is mediated by ___ mutations in ___ synthase and/or altered production or sensitivity of bacterial ___ reductase
- point, dihydropteroate
- dihydrofolate
TRIMETHOPRIM-SULFAMETHOXAZOLE (SULFONAMIDES)
SOA
Gram-Positive Aerobes: S. aureus (including some ___ , especially ___ ), 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, Serratia spp., ampicillin-resistant H. influenzae, H. ducreyi, N. gonorrhoeae, and ___
NOT active against ___ or ___
Other Organisms: ___ / ___ (DRUG OF CHOICE)
- MRSA, CA-MRSA
- Stenotrophomonas maltophilia
- anaerobes, P. aeruginosa
- Pneumocystis carinii/jirovecii
TRIMETHOPRIM-SULFAMETHOXAZOLE (SULFONAMIDES)
Steadystate serum concentrations of 1:20 (TMP:SMX) are achieved by using a fixed oral
or intravenous combination of __ : __ (TMP:SMX)
Distribution
- penetrates the ___
- found in ___ and uninflamed ___ tissue
Elimination
Doses should be adjusted in patients with CrCl < __ ml/min
1:5
- CSF
- urine, prostatic
- 30
TRIMETHOPRIM-SULFAMETHOXAZOLE (SULFONAMIDES) CLINICAL USES
- Acute, chronic or recurrent infections of the urinary tract
- Acute or chronic bacterial prostatitis
- ___ ___ / ___ pneumonia – TMP-SMX is the drug of choice for both treatment and prophylaxis
- Skin and soft tissue infections due to ___
- ___ infections
- Pneumocystis carinii/jirovecii
- CA-MRSA
- Stenotrophomonas maltophilia
TRIMETHOPRIM-SULFAMETHOXAZOLE AE
Hematologic: ___
Hypersensitivity: ___
Others: ___ insufficiency , ___ , hyper ___
should not be used in lactating or pregnant women, especially during the ___ trimester (may cause ___ due to bilirubin displacement)
DRUG INTERACTIONS
- ___ – potentiated anticoagulant effects
- leukopenia
- rash
- renal, crystalluria, hyperkalemia
- 3rd, kernicterus
- warfarin
POLYMYXIN B and COLISTIN (Polymyxin E)
MECHANISM OF ACTION
- Polymyxins are cationic detergents that bind to the anionic lipopolysaccharide molecules
of the outer cell membrane of Gram ___ bacteria causing displacement of ___
and __ , which normally stabilize the cell membrane. This action leads to changes in cell wall permeability, leakage of cellular contents, and subsequent cell death
- Polymyxins display ___ -dependent bactericidal activity
- negative, Ca, Mg
- concentration
POLYMYXIN B and COLISTIN (Polymyxin E)
MECHANISM OF RESISTANCE
- Alteration of the outer cell membrane – decreased ___ content, reduction in __ and __ content, decreased outer membrane proteins
- ___ exists between polymyxin B and colistin
- lipopolysaccharide, Ca, Mg
- cross-resistance
POLYMYXIN B and COLISTIN (Polymyxin E)
SPECTRUM OF ACTIVITY
- no activity against gram positives and anaerobes
Gram-Negative Aerobes
- ___ spp. and ___ (both including MDR strains)
Polymyxins are NOT active against ___ spp., ___ spp., ___ spp., ___ spp., and ___ spp
- Acinetobacter, Pseudomonas aeruginosa
- Burkholderia, Proteus, Providencia, Serratia, Brucella
POLYMYXIN B and COLISTIN (Polymyxin E)
Metabolism/Elimination
- Polymyxin B and colistin are primarily eliminated by nonrenal routes and do not require dose adjustments for ___ dysfunction
- However, ~ 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)
- ___ requires dosage adjustment in the presence of renal insufficiency when the creatinine clearance is < 80 ml/min
- renal
- CMS
current references do NOT recommend dosage adjustment in renal insufficiency (although the manufacturer labeling does….
CLINICAL USES - POLYMYXIN B and COLISTIN (Polymyxin E)
Infections caused by Gram ___ bacteria (including ___ and ___ ) that are resistant to other available antibiotics, including bacteremia, pneumonia, UTI, etc - polymyxin B is preferred for ___ infections; colistin preferred for ___
negative
- P. aeruginosa, A.
baumannii
- systemic, UTIs
CLINICAL USES - POLYMYXIN B and COLISTIN (Polymyxin E)
ADVERSE EFFECTS
- ___ – acute tubular necrosis manifested by an increase in serum creatinine and decrease in creatinine clearance; dose-dependent; usually reversible
- ___ – dizziness, weakness, facial and peripheral paresthesias, dose-dependent; reversible
- nephrotoxicity
- neurotoxicity
Clindamycin MECHANISM OF ACTION
- Clindamycin inhibits protein synthesis by exclusively binding (reversibly) to the ___ 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 ____ , but can display ___ -dependent bactericidal activity depending on the infecting bacteria
- 50S
- bacteriostatic, time
Clindamycin MECHANISM OF RESISTANCE
- Alteration of the ___ 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 ___ efflux pumps, and strains that are resistant to macrolides by this mechanism remain susceptible to clindamycin
- ribosomal
- macrolide
Clindamycin SOA
Gram-Positive Aerobes
- Group streptococci
- Viridans streptococci
- Streptococcus pneumoniae (PSSP)
- Staphylococcus aureus ( ___ and ___ )
Anaerobes – clindamycin is active against many Gram-positive and Gram-negative anaerobes, but is most useful for anaerobes ___ the diaphragm
- NOT ___
- MSSA, CA-MRSA
- above
C. diff
Clindamycin
Distribution
- Clindamycin penetrates into most body tissues and fluids including sputum, bile,
pleural fluid and ___
- Clindamycin does NOT penetrate the ___ , even in the presence of inflamed meninges
- bone
CSF
Clindamycin CLINICAL USES
- Infections due to ___ (including B. fragilis) ___ THE CNS – ___ infections, intraabdominal infections, pelvic infections, ___ foot infections, decubitus ulcers
- Treatment of mild to moderate skin and soft tissue infections due to staphylococci and streptococci, including ___
- Alternative agent for the treatment of infections due to gram-positive aerobes in
patients allergic to ___ (cellulitis, septic arthritis, osteomyelitis)
- anaerboes
- OUTSIDE
- pulmonary
- diabetic
- CA-MRSA
- PCN
Clindamycin AE
Gastrointestinal
- Nausea, vomiting, diarrhea – 3 to 4%
- ____ colitis ( ___ colitis or antibiotic-
associated diarrhea)
- clindamycin is one of the worst inducers
___ - elevation of transaminases
- C. diff, pseudomembranous
- hepatotoxicity
METRONIDAZOLE MECHANISM OF ACTION
- Metronidazole is a ___ 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 ___ anion
- damage bacterial ___ (inhibit nucleic acid
synthesis) and subsequently cause cell death – metronidazole is rapidly ___ in a ___ -dependent manner
- prodrug, radicals
- DNA, bacteriocidal, concentration
METRONIDAZOLE
Clinical resistance to metronidazole is well documented in Trichomonas, Giardia, and
a variety of anaerobic bacteria, but is relatively uncommon
- Altered ___ requirements – organism grows in higher local oxygen concentrations causing decreased activation of metronidazole and futile recycling of the active drug
- Altered levels of ___ – reduced transcription of the ferredoxin gene
- growth
- ferredoxin
METRONIDAZOLE SoA
Metronidazole is extremely active against a wide variety of anaerobic protozoal parasites
and obligate/strict ___ bacteria. It is the antianaerobic agent most reliably
active against ___
Gram-Negative Anaerobes
- ___
- Bacteroides distasonis, ovatus, thetaiotamicron, bivius (B. fragilis group ___ organisms)
- Fusobacterium
- Prevotella spp. and Veillonella spp.
- Helicobacter pylori (an obligate anaerobe)
Gram-Positive Anaerobes
- Clostridium spp. (INCLUDING ___ )
- Peptostreptococcus
- anaerobic, Bacteroides fragilis
- Bacteroides fragilis
- DOT
- C. diff
T or F: Metronidazole is inactive against all common aerobic and facultatively anaerobic
bacteria
TRUE
Metronidazole
T or F: Metronidazole does not penetrate the CSF
FALSE
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
Metronidazole
- Metronidazole is metabolized by the ___ 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 ___
- liver
- feces
Metronidazole CLINICAL USES
Infections due to ___ . Many serious anaerobic infections are ___ and additional antibiotics are necessary for coverage of ___ bacteria
- Pseudomembranous colitis due to ___
- ___
- Diarrhea due to ___
- anaerobes, polymicrobial, aerobic
- C. diff
- Trichomonas vaginalis
- Giardia
Metronidazole
Gastrointestinal – nausea, diarrhea, anorexia, ___ taste, stomatitis, pancreatitis
Central nervous system – most serious; rare unless large doses are utilized or therapy is prolonged
- Seizures, encephalopathy, cerebellar dysfunction, peripheral ___
- Use with caution in patient with CNS disorders
Mutagenicity and Carcinogenicity
- Metronidazole may be ___ – should be avoided during the first trimester and during breastfeeding (Pregnancy Category B)
DRUG INTERACTIONS
- ___ - Increased anticoagulant effect
- ___ - Disulfiram reaction
- metallic
- neuropathy
- teratogenic
- warfarin
- alcohol
