Misc. Antibiotics: Tetracyclines, Sulfonamides, Chloramphenicol and UTI Agents 9/11/15 Flashcards by Laquita Brown

List the first and second generation tetracyclines.

First = Tetracycline (PO)

Second = Doxycycline (IV/PO), Minocycline (PO)

“Toast, then Drink More”

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What is the prototypical drug of Glycylcyclines and why was it developed?

Tigecycline

Improve spectrum of activity
Overcome resistance mechanisms

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What is the MOA of Tetracyclines/Glycylcyclines, and are they bacteriostatic or cidal?

Inhibits protein synthesis

Bacteriostatic (cidal at high concentrations)

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What are some mechanisms of resistance against Tetracyclines/Glycylcyclines?

Efflux Pumps

Ribosomal protection proteins

Enzymatic inactivation

***Tigecycline resistant to these mechanisms

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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

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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

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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

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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

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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)

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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

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What are the major AEs of Tigecycline?

GI problems = nausea, vomiting

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What do sulfonamides inhibit, and are they bactericidal or static?

Inhibit dihydropteroate synthetase

Bacteriostatic

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What does Trimethoprim inhibit and is it bacteriostatic or cidal?

Inhibits dihydrofolate reductase

Bacteriostatic

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Why was Trimethoprim combined with Sulfamethoxazole (TMP-SMX = IV/PO)?

Static + Static = Cidal

Synergistic activity

Broader spectrum of activity (SOA)

Decreased emergence of resistance

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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

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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 "**R**ocky **M**ountain **S**potted **C**old"

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