Antibiotics: Agents Interfering with Bacterial Protein, and DNA Synthesis Flashcards by Joel Glotfelty

Which type of antibacterial agents inhibit DNA replication?

DNA Gyrase & Topo IV Inhibitors

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What is an example of a DNA gyrase and topo IV inhibitor?

Fluoroquinolones

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Which type of antibacterial agents inhibit protein synthesis?

50S Inhibitors and 30S inhibitors

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What are 4 examples of 50S Inhibitors

Macrolides, Clindamycin, Streptogramins, and Linezolid

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Which type of antibacterial agents inhibit cell wall synthesis?

Penicillins, Cephalosporins, Carbapenems, Monobactams, and Vancomycin

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Which type of antibacterial agents inhibit folate metabolism?

Sulfonamides and Trimethoprim

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What are two types of 30S inhibitors?

Aminoglycosides and Tetracyclines

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Exploit differences between bacterial 70S and mammalian 80S ribosomes

Protein synthesis inhibitors

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Inhibits the 30S ribosonal subunit in Streptomycin, Gentamicin, Tobramycin, Amikacin, Neomycin, and Kanamycin

Aminoglycosides

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Inhibits the 30S ribosomal subunit in Tetracycline, Demeclocycline, Minocycline, Doxycycline, Oxytetracycline, and Tigecycline

Tetracyclines

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Inhibits the 50S subunit in Erythromycin, Clarithromycin, Azithromycin, and Telithromycin

Macrolides

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Inhibit the 50S ribosomal subunit of Clindamycin

Lincosamide

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Inhibits the 50S ribosomal subunit of Quinupristin/Dalfopristin

Streptogramins

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Inhibits the 50S ribosomal subunit of Linezolid

Oxazolidinone

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Bind to the 30S subunit and irreversibly interfere with protein synthesis in 3 ways

Aminoglycosides

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They are rapidly bactericidal vs. many aerobic Gram-negative bacteria

Aminoglycosides

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Aminoglycosides also exhibit a significant

-antibacterial activity persists beyond the time that measurable drug is present

Postantibiotic effect

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Mainly used as a second-line agent for the treatment of tuberculosis

Streptomycin

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For this application, it should be used in combination with other agents (e.g., INH and rifampin) to prevent emergence of resistance

Streptomycin

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Mainly used in cases of severe infection (e.g., sepsis and pneumonia) caused by Gram-negative bacteria that are likely to be resistant to other drugs

Tobramycin and Gentamicin

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Tobramycin and gentamicin are often used in combination with a

B-lactam

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Tobramycin and gentamicin are often used in combination with a B-lactam antibiotic to take advantage of synergistic effects and to prevent the emergence of

Resistance

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Often preferred over tobramycin due to its reduced cost

Gentamicin

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A semisynthetic derivative of kanamycin that is less toxic than the parent molecule

Amikacin

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It is resistant to many enzymes that inactivate gentamicin and tobramycin, and can thus be employed against microorganisms resistant to the latter drugs

Amikacin

They are used on infected surfaces (skin or eyes) or injected into joints, the pleural cavity, tissue spaces, and abscess cavities where infection is present -Both are primarily limited to topical use

Neomycin and Kanamycin

The primary adverse reaction of aminoglycosides is that all aminoglycosides are

Nephrotoxic

More likely to occur when therapy is continued for >5 days, at higher doses, in the elderly, and in cases of renal insufficiency

Nephrotoxicity

What are the three most nephrotoxic aminoglycosides

Neomycin, tobramycin, and gentamicin

Another adverse effect of aminoglycosides, is that all aminoglycosides are

Ototoxic

Like the nephrotoxic effects, is more likely to occur when therapy is continued for >5 days, at higher doses, and in the elderly

Ototoxicity

Can be manifested either as auditory damage (e.g., tinnitus, highfrequency hearing loss) or as vestibular damage (e.g., vertigo, ataxia)

Ototoxicity

Which 3 aminoglycosides cause the most auditory damage?

Neomycin, kanamycin, and amikacin

Which two aminoglycosides cause the most vestibular damage?

Streptomycin and gentamicin

Tend to be irreversible, even upon discontinuation of therapy

Ototoxicity

Bind to the 30S ribosomal subunit and prevent aminoacyl-tRNA binding to the A-site, thereby blocking peptide elongation

Tetracyclines

Bacteriostatic for many aerobic and anaerobic Gram-positive and Gram-negative bacteria, including rickettsiae, chlamydiae, and mycoplasmas

Tetracyclines

Tetracyclines are also active against some

Protozoa

Antibacterial activities of most tetracyclines are similar, with differences in clinical efficacy being due primarily to differences in

PK properties

Absorption of orally administered tetracyclines is impaired by food except for

Doxycycline and Minocycline

Chelate multivalent cations (Ca2+, Mg2+, Fe2+, and Al3+)

Tetracyclines

Tetracycline absorption is therefore also impaired by these

Cations

Poorly absorbed orally and must be administered IV

Tigecycline (a glycylcycline)

Has a longer half-life than the other tetracyclines

Tigecycline (a glycylcycline)

What 4 things are tetracyclines used for?

Rickettsial Infections, Sexually Transmitted Infections, Respiratory Tract Infections, and Skin and Soft-Tissue Infections

Used in the treatment and prevention of anthrax and malaria, as well as for the treatment of Lyme disease

Doxycycline

Used for treatment of community-acquired pneumonia, intra-abdominal, skin, and soft tissue infections caused by MDR bacteria, including

Tigecycline

Which tetracycline is used to treat infections caused by multidrug-resistant (MDR) bacteria

Tigecycline

Nausea, vomiting, and diarrhea are the most common reasons for discontinuing

Tetracycline use

Bind calcium that is deposited in newly formed teeth and bone in young children

Tetracyclines

The drug can be deposited in teeth (including fetal teeth during pregnancy), causing fluorescence, discoloration, and enamel dysplasia

Tetracyclines

Tetracyclines can also be deposited in bone, where it may cause deformity or

Growth inhibition

Another major adverse reaction of tetracyclines is

Photosensitization

Tetracyclines are contraindicated during pregnancy because of susceptibility to

Liver disturbances

Bind the 50S ribosomal subunit and inhibit the translocation step of protein synthesis

Macrolides

Generally bacteriostatic vs. aerobic Gram-positive and some Gramnegative bacteria

Macrolides

Clarithromycin, azithromycin, and telithromycin (a ketolide) are semi-synthetic derivatives of

Erythromycin

Active against many macrolide-resistant bacterial strains

Telithromycin

Antibacterial activities of the macrolides are similar, with differences in clinical properties being due primarily to differences in

PK properties

The longer t½ values of clarithromycin, telithromycin, and azithromycin allow

Less frequent dosing

Used for community-acquired pneumonia, acute exacerbations of chronic bronchitis

Macrolides

Useful as a penicillin-substitute in penicillinallergic individuals with susceptible Staph infections

Macrolides

What are the two primary adverse effects of Macrolides?

GI effects and Liver toxicity

Anorexia, nausea, vomiting, and diarrhea occasionally accompany oral administration of

Macrolides

GI intolerance caused by direct stimulation of gut motility is less so for

Clarithromycin and azithromycin

Can produce acute cholestatic hepatitis, probably as a hypersensitive reaction

Macrolides

The liver toxicity effect has caused the approved use of telithromycin to be limited only to

Community-acquired pneumonia

50S inhibitor that is used for the treatment of skin and soft-tissue infections caused by aerobic and anaerobic Gram-positive bacteria

Clindamycin (Lincosamide)

Combination (IV only) approved for treatment of infections caused by vancomycin-resistant Enterococcus faecium and complicated skin infections caused by methicillin-sensitive S. aureus (MSSA)

Quinupristin/dalfopristin (Streptogramins)

The newest synthetic antibiotic approved for treatment of infections caused by MDR Gram-positive bacteria, including MRSA, VRE, and penicillinresistant streptococci

Linezolid (Oxazolidinone)

What are the two functional classes of DNA synthesis inhibitors?

1. ) Antifolate Drugs | 2. ) DNA Gyrase/Topo IV Inhibitors

Inhibit bacterial biosynthesis of purine bases and thus DNA.

Antifolate drugs (Sulfonamides and Trimethoprim)

Block bacterial DNA replication by inhibiting bacterial topoisomerase II (DNAgyrase) and topoisomerase IV

DNA Gyrase/Topo IV Inhibitors -Fluoroquinones

Unlike mammals, sulfonamide-susceptible microorganisms cannot use exogenous folate, but must synthesize it from

p-aminobenzoic acid (PABA)

PABA analogs that act as competitive inhibitors of dihydropteroate synthase, which converts PABA to dihydrofolic acid

Sulfonamides

Bacteriostatic when administered as single agents

Sulfonamides

Combination with a dihydrofolate reductase inhibitor produces synergistic activity, due to inhibition of sequential steps in

Folate synthesis

The combination is typically

Bactericidal

Used almost exclusively to treat urinary tract infections (UTIs), but rarely as monotherapy due to resistance

The Sulfonamides sulfisoxazole and sulfamethoxazole

Widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease

Sulfasalazine

All sulfonamides are considered to be partially

Cross-allergic

Most common unwanted effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, and diarrhea

Sulfonamides

May precipitate in the urine, producing crystalluria, hematuria, or even obstruction

Sulfonamides

Selectively inhibits bacterial dihydrofolate reductase, which converts dihydrofolate to tetrahydrofolate

Trimethoprim

~50,000 times less efficient at inhibiting mammalian dihydrofolate reductase

Trimethoprim

Trimethoprim is typically combined with sulfamethoxazole to make

TMP-SMX (Bactrim®, Septra®).

Used for uncomplicated UTIs, pneumocystis jiroveci pneumonia, and acute exacerbations of chronic bronchitis

TMP-SMX

The most common adverse effect with short courses (<5 days) of TMP-SMX treatment is allergy to the -occurs in up to 10% of patients

Sulfonamide component

Longer courses of treatment (>5 days) can result in more serious adverse effects typical of antifolates, including

Magaloblastic anemia and leukopenia

Block DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV

Fluoroquinolones

Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for

DNA replication

Interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division

Inhibition of topoisomerase IV

Bactericidal against both Gram-negative (gyrase is the primary target) and Gram-positive (topo IV is the primary target) bacteria

Fluoroquinolones (FQ's)

Ciprofloxacin, lomefloxacin, levofloxacin, and ofloxacin make up a group of similar agents with excellent

Gram Negative activity (moderate Gram-positive)

Gemifloxacin and moxifloxacin make up a 2nd group with improved activity against

Gram-positive organisms

Effective in UTIs, even when caused by MDR bacteria

FQ's

The drug of choice for prophylaxis and treatment of anthrax (caused by B. anthracis)

Ciprofloxacin

Dubbed the “respiratory FQs,” and are effective and used increasingly for treatment of upper and lower respiratory tract infections

Levofloxacin, gemifloxacin, and moxifloxacin

May damage growing cartilage and cause arthropathy, and, thus, are not routinely recommended for patients under 18 years of age

FQ's

However, the arthropathy is reversible and there is a growing consensus that in some cases, FQs may be used in

Children