Misc. Antibiotics: Tetracyclines, Sulfonamides, Chloramphenicol and UTI Agents 9/11/15 Flashcards
List the first and second generation tetracyclines.
First = Tetracycline (PO)
Second = Doxycycline (IV/PO), Minocycline (PO)
“Toast, then Drink More”
What is the prototypical drug of Glycylcyclines and why was it developed?
Tigecycline
- Improve spectrum of activity
- Overcome resistance mechanisms
What is the MOA of Tetracyclines/Glycylcyclines, and are they bacteriostatic or cidal?
Inhibits protein synthesis
Bacteriostatic (cidal at high concentrations)
What are some mechanisms of resistance against Tetracyclines/Glycylcyclines?
Efflux Pumps
Ribosomal protection proteins
Enzymatic inactivation
***Tigecycline resistant to these mechanisms
List the Spectrum of activity for the Tetracyclines.
Misc:
Rickettsia/Coxiella
Chlamydia
Mycoplasma
Spirochetes: Borrelia, Treponema, Leptospira
Gram Positive Aerobes:
- MSSA
- PSSP
- Bacillus, Listeria, Nocardia
Gram Negative Aerobes:
- Neisseria
- H. flu
- Burkholderai pseudomallei
What is the spectrum of activity for Tigecycline?
Gram Negative Aerobes:
- E. coli
- Klebsiella spp
- Citrobacter spp
- Serratia marcescens
NOT PROTEUS or P. AERUGINOSA
Gram Positive Aerobes:
- S. aureus (MSSA, MRSA)
- Enterococcus spp (VRE, VSE)
NOT for BACTEREMIA or UTIs
Anaerobes:
-C. perfringens, Bacteroides spp
What impairs absorption of Tetracyclines/Glycylcyclines, and describe their distribution?
Di/Trivalent Cations = Mg, Ca, Fe
Wide distribution = synovial fluid, prostate, seminal fluid, minimal CSF
How are the following drugs eliminated, and which of them require adjustments for disease states:
- tetracycline
- doxycycline
- minocycline
- tigecyclin
tetracycline = kidneys = adjust dose in RI
doxy/minocycline = metabolized
tigecycline = biliary = adjust dose with liver disease
ALL = minimally removed during HD
What are clinical uses for Tetracyclines/Glycylcyclines?
Respiratory Infections:
-Community acquired pneumonia (doxy)
STDs:
-CHLAMYDIA, Syphilis, Gonorrhea (no doxy)
Malaria prophylaxis
Others:
-RMSF, Q Fever, Lyme
Polymicrobial Infections:
-Complicated skin/soft tissue infections (tigecycline)
What are the major AEs of the Tetracyclines?
GI problems
Photosensitivity (esp doxy)
Hepatotoxicity (esp doxy)
Discolored teeth (pregnancy category D: if exposed in utero/childhood)
Fanconi Syndrome (if outdated): renal problems
What are the major AEs of Tigecycline?
GI problems = nausea, vomiting
What do sulfonamides inhibit, and are they bactericidal or static?
Inhibit dihydropteroate synthetase
Bacteriostatic
What does Trimethoprim inhibit and is it bacteriostatic or cidal?
Inhibits dihydrofolate reductase
Bacteriostatic
Why was Trimethoprim combined with Sulfamethoxazole (TMP-SMX = IV/PO)?
Static + Static = Cidal
Synergistic activity
Broader spectrum of activity (SOA)
Decreased emergence of resistance
List some mechanisms of resistance to Sulfonamides and Trimethoprim.
Sulfonamides:
PABA Overproduction
Structural change of Dihydropteroate synthetase (D.S.)
Decreased cell wall permeability
Trimethoprim:
Dihydrofolate reductase resistance
Changes in cell wall permeability
What is the SoA for TMP-SMX?
Gram Positive:
- Staph aureus (MRSA)
- Nocardia
Gram Negative:
- Stenotrophomonas maltophilia
- Haemophilus spp
- Shigella
- Salmonella
Anaerobes = NO ACTIVITY
Other:
-Pneumocystis carinii (esp in HIV pts)
Describe the A and D of TMP-SMX.
Absorption = rapidly/completely absorbed
Distribution = Good = lungs, urine, prostate and CSF
SMX = 70% protein bound
How is TMP-SMX eliminated?
Liver and kidney = adjust dose for RI
What are some clinical uses for TMP-SMX?
UTI (acute, chronic, recurrent)
Bacterial prostatitis (acute, chronic)
Skin infections (CA-MRSA)
Pneumocystis carinii pneumonia
Stenotrophomonas
Nocardia
What are some major AEs of TMP-SMX?
GI + Jaundice/Hepatic necrosis
Hematologic = leukopenia/thrombocytopenia/anemia
Hypersensitivity = rash, epidermal necrolysis
CNS = aseptic meningitis, seizure
Renal Toxicity = tubular necrosis/crystalluria
Drug-induced lupus
What drug interactions occur with TMP-SMX?
Phenytoin = increase phen levels
Warfarin = increase anticoagulation
Methotrexate = decrease renal clearance
Describe MOA for Chloramphenicol.
Prevents protein synthesis = no peptide bond formation
Bacteriostatic EXCEPT against:
H. flu, Strep pneumo, N. meningitidis
What are the mechanisms of resistance (MoR) for Chloramphenicol?
Reduced permeability/uptake
Ribosomal mutation
Acetyltransferase inactivation = responsible for widespread outbreaks of typhoid fever/Shigella in developing countries
Describe A, D and E for Chloramphenicol.
Absorption:
Well absorbed by GI tract
Distribution:
Lipid soluble
Not highly protein bound
Distributes to CSF
Elimination:
Metabolized by liver = decrease dose in liver failure
Excreted by kidneys: dose adjustment NOT required in RI
What is the SoA for Chloramphenicol?
Gram Positive: NOT active against S. aureus and Enterococci
Gram Negative: NOT active against P. aeruginosa
IS active against:
- Rickettsiae spp
- Spirochetes
- Chlamydia
- Mycoplasma
“Rocky Mountain Spotted Cold”
List the clinical uses for Chloramphenicol.
NONE in U.S.
Developing World = pneumonia, bacterial meningitis, typhoid fever, RMSF
What are the major AEs of Chloramphenicol?
Gray Baby Syndrome:
- flaccidity
- cyanosis
- circulatory collapse/death
Hematologic = reversible bone marrow suppression and aplastic anemia
Anaphylaxis
Porphyria
What are the UTI agents and what are their MOAs?
Nitrofurantoin:
- Inhibits translation
- Inhibits bacterial respiration/pyruvate metabolism
Methenamine:
- NOT an antibiotic persay
- Converted in acidic pH to ammonia/formaldehyde
- Formaldehyde = denaturant of proteins/nucleic acid
Describe the absorption of the UTI Agents.
Nitrofurantoin:
40-50% absorbed after oral administration
Occurs in small intestine
Enhanced with food
Methenamine:
Rapid absorption after oral administration
May be partially degraded by gastric acid
What are the differences in distribution of Nitrofurantoin and Methenamine?
Nitrofurantoin = Large urine concentration, Low serum concentration
Methenamine = Broad distribution in tissues
Explain the differences in excretion of Nitrofurantoin and Methenamine.
Nitrofurantoin = eliminated in urine with minor biliary excretion, shorter half-life
Methenamine = renal excretion, longer half-life
What are the indications and contraindications for Nitrofurantoin?
IND: Acute, uncomplicated UTIs
CONTRA: Pyelonephritis, complicated UTIs
What are the IND and CONTRAIND for Methenamine?
IND: Suppression/prophylaxis against recurrent UTIs
CONTRA: Established infections, prophylaxis against catheter-associated UTI
What is the SoA for Nitrofurantoin?
Active against:
- E. coli
- Staph saprophyticus
- Enterococcus/VRE
- Group B strep
NOT active against:
- P. aeruginosa
- Proteus
- Providencia
“The Three P’s”
List the major AEs of Nitrofurantoin.
GI intolerance
Rash
Acute pulmonary symptoms:
- weeks to months after exposure
- rapid onset of fever, cough, dyspnea, myalgia
- eosinophilia/lower lobe lung infiltrates
Subacute/chronic pulmonary reaction:
- gradual onset of non-productive cough and dyspnea
- Interstitial infiltrate on CXR
List the major AEs of Methenamine.
- Generally well-tolerated
- Hepatitis
- Leukopenia
- Hemorrhagic Cystitis (higher dose)
- Neuropathy
- Anemia
