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Flashcards in Miscellaneous Antibiotics lecture Deck (61):
1

Tetracyclines first and second generation

First Generation
Tetracycline

Second Generation
Doxycycline, Minocycline

2

Glycylcycline

Tigecycline

3

Tetracyclines/Glycylcyclines Mechanism of action

Reversibly binds to the 30S ribosomal subunit
Inhibit the binding of aminoacyl transfer-RNA to the acceptor (A) site on the mRNA-ribosomal complex, which prevents addition of amino acid residues on elongating peptide chain


Bacteriostatic
Bactericidal when present at high concentrations against very susceptible organisms

4

Tetracyclines/Glycylcyclines mechanism of resistance

• Efflux Pumps
decreased accumulation of tetracycline within bacteria
• Ribosomal protection proteins
Cytoplasmic proteins that protects ribosomes from 1st and 2nd generation tetracyclines
• Enzymatic inactivation

Cross-resistance observed between tetracyclines, except for minocycline

Tigecycline resistant to these mechanisms

5

which drug is not susceptable to the resistance mechanisms against tetracyclines/glycocyclins

Tigecycline

6

tigecyline spectrum of activity

very broad, gram + and gram - aerobes plus some anaerobes

***not active against: Proteus spp or Pseudomonas aeruginosa***

not for bacteremias or UTIs bc you cannot maintain good levels in the blood/urine

7

which Tetracyclines/Glycylcyclines
 is available po and IV

doxycycline is available PO and IV

8

What affects Tetracyclines/Glycylcyclines absorption?

Absorbed best on an empty stomach
Absorption impaired by di- and trivalent cations (dietary supplements, Ca2+)

9

Tetracyclines/Glycylcyclines
 distribution

Widely distributed with good penetration into synovial fluid, prostate, seminal fluid (prevents high concentrations in the blood)
Minimal CSF penetration
poor distribution to the bladder- no UTI use

10

Demeclocycline/tetracycline
 elimination

excreted unchanged in the urine
**dosage adjustment required in renal insufficiency

Tetracycline half-life = 6 to 12 hours; demeclocycline half-life = 16 hours

11

Doxycycline, minocycline elimination

metabolized (excreted mainly by non-renal routes)

Half-lives = 16-18 hours (doxy, mino) but dosed every 12 hrs

12

tigecycline elimination

biliary - does not need adjustment for renal insufficiency but does for liver disease

13

The Clinical Uses of Tetracyclines/Glycylcyclines

Respiratory infections
Community-acquired pneumonia (doxy)
Acute exacerbation of chronic bronchitis
Pertussis

STDs –Chlamydia, Syphilis, gonorrhea

Treatment or prophylaxis of malaria

The Others:
**Rocky Mountain Spotted Fever, Q Fever, Lyme
Brucellosis, Bartonellosis, plague, Tularemia, chancroid, anthrax, H. pylori

Polymicrobial infections (Tigecycline)
Complicated skin and soft tissue infections
Intraabdominal infections

Acne

SIADH (demeclocycline)

14

Pertussis treatment with tetracyclines/glycylcyclines

decreased colonization and therefore spread but does not significantly reduce symptoms

15

Tetracycline/Tigecycline 
Adverse Effects

Gastrointestinal
Nausea, vomiting – high incidence with tigecycline (29%)
Diarrhea, pseudomembranous colitis

Hypersensitivity
Rash, pruritus, urticaria, angioedema, anaphylaxis

**Photosensitivity
Exaggerated sunburn (hands and face)

Renal
Fanconi-like syndrome with outdated tetracycline
Reversible dose-related diabetes insipidus (demeclocycline)

Other
Hepatic enzyme elevation

16

why is tigecycline not well tolerated

many pts have severe nausea and vomiting

17

why is it important to check tetracyclines expiration dates

expired tetracycline causes Fanconi-like syndrome (renal disease)

18

can you give Tetracycline/Tigecycline
 to a pregnant woman?

NO - Pregnancy Category D
Discoloration of permanent teeth and decreased bone growth in children

19

Sulfonamides mechanism of action

** Inhibits dihydropteroate synthetase –
Inhibits incorporation of p-aminobenzoic acid (PABA) into tetrahydropteroic acid

Bacteriostatic

20

long acting sulfonamides

Sulfadoxine
Combined with pyrimethamine (Fansidar)

21

Trimethoprim mechanism of action

Bacteriostatic

Inhibits dihydrofolate reductase
Interferes with conversion of dihydrofolate to tetrahydrofolate

22

Trimethoprim-Sulfamethoxazole 
(TMP-SMX, Bactrim®) advantages

Bactericidal in combination with synergistic activity

Broader spectrum of activity

Decreased emergence of resistance

work at 2 different placed on the same pathway to prevent the production purines

23

Sulfonamide resistance

• Resistance widespread
(Streptococci, Staphylococci, Enterobacteriacae, Neisseria sp., Pseudomonas sp., Shigella, Salmonella)
• PABA overproduction
• Structural change of Dihydropteroate synthetase
• Plasmid mediated production of drug resistant DHPS or decreased bacterial cell wall permeability to sulfonamides

24

Trimethoprim resistance

Chromosomal or plasmid mediated

Plasmid-mediated production of dihydrofolate reductase resistant to trimethoprim

Changes in cell permeability

25

TMP-SMX
 Spectrum of Activity

good gram + including S. aureus and good gram - including Stenotrophomonas maltophilia

No ANAEROBE activity

26

TMP-SMX
 absorption

Absorption – available IV and PO
Rapidly and completely absorbed (F > 90%)
Peaks are higher and more predictable with IV administration

use oral unless a pt cannot take it

27

TMP-SMX distribution

Good distribution – lungs, urine, prostate, etc
Penetrates the CSF – TMP (30-50%), SMX (20%)
SMX is 70% protein bound

28

TMP-SMX
 elimination

Both are eliminated by the liver and kidney

require dose adjustment if creatine clearence is less than 30ml/min - and follow renal function

29

TMP-SMX 
Clinical Uses

** Acute, chronic, or recurrent infections of the urinary tract

** Acute or chronic bacterial prostatitis

** Skin infections due to CA-MRSA

Bacterial Sinusitis

Nocardia

30

the treatment of choice for nocardia is

TMP-SMX

31

some common uses for TMP-SMX

Pneumocystis carinii pneumonia

Stenotrophomonas

Toxoplasmosis

Listeria monocytogenes

Nocardia

32

TMP-SMX 
Adverse Effects - hematologic and GI

Gastrointestinal
• Nausea, vomiting, diarrhea, glossitis
• Jaundice
• Hepatic necrosis

Hematologic
• **Leukopenia, **thrombocytopenia, eosinophilia
• Acute hemolytic anemia, aplastic anemia, agranulocytosis
• Megaloblastic anemia (impaired folate usage with prolonged administration)

33

TMX-SMX hypersensivity

*Rash, urticaria, epidermal necrolysis, Stevens-Johnson, drug fever

34

TMP-SMX 
Adverse Effects - CNS, Renal and other

• CNS
Headache, aseptic meningitis, seizures

• Renal toxicity
Tubular necrosis
Interstitial nephritis

• Drug-induced lupus

• Serum sickness-like syndrome

• Other - crystalluria**

35

Chloramphenicol
 - general information

Isolated from mulched field and compost
Streptomyces venezuelae
Introduced into use in U.S. in 1949
Due to significant adverse events, this agent is not used in the U.S.
Use is common in the developing world

36

Chlorampenicol
 Mechanism of action

Binds to 50s subunit of 70s ribosome
Prevents peptide bond formation

Static activity except for:
Haemophilus influenza
Streptococcus pneumoniae
Neisseria meningitidis

37

Chloramphenicol 
Resistance mechanism(s)

1. Reduced permeability or uptake
2. Ribosomal mutation
3. Acetyltransferase inactivation
Responsible for widespread outbreaks of typhoid fever and Shigella dysentery in Central and South America, Vietnam, India

38

Chloramphenicol absorption

Well absorbed by the GI tract
IV administration – peak level approximately 70% of peak following oral administration

39

Chloramphenicol distribution

Distribution
Lipid soluble
Not highly protein bound (25-50%)
CSF levels 30-50% of serum levels

40

Chloramphenicol
 elimination

Elimination
Metabolized by the liver
Enterohepatic circulation
Excreted by the kidneys

Decrease dose in liver failure
Does adjustment not required in renal failure

41

Chloramphenicol 
Antimcrobial spectrum

Gram Positives
Unreliable against Staph aureus and not active against enterococci

Gram Negatives
Not active against P. aeruginosa

Anaerobes (Gram negative and Gram positive)

42

specific types of bacteria chloramphenicol is used for in other countries

Rickettsiae sp.
Spirochetes
Chlamydia
Mycoplasma

43

clinical uses of chloramphenicol

Pneumonia
Bacterial meningitis
Typhoid fever

Rocky mountain spotted fever

44

Chloramphenicol
 adverse effects

Hematologic
Reversible bone marrow suppression
Aplastic anemia (1 in 24,500 – 40,800)

Gray baby syndrome (neonates)
Optic neuritis
Hypersensitivity reaction
Anaphylaxis
GI intolerance (vomiting, diarrhea)
Stomatitis
porphyria

45

grey baby syndrome

due to use of chloramphenicol during pregnancy or given to a baby

Abdominal distention
Vomiting
Flaccidity
Cyanosis
Circulatory collapse/Death

46

Urinary Tract Agents

Nitrofurantoin and Methenamine

47

Nitrofurantoin mechanism of action

Poorly understood
Binds to ribosomal proteins
Inhibits translation
Inhibits bacterial respiration and pyruvate metabolism

48

Methenamine mechanism of action

Converted in acid pH to ammonia and formaldehyde

Formaldehyde – non-specific denaturant of proteins and nucleic acids

not really an antibiotic more of a denaturant

49

Nitrofurantoin mechanisms of resistnace

Poorly understood
Development of resistance while on treatment rare
E. coli – Chromosomal or plasmid-mediated production of nitrofuran reductase

50

methenamine mechanisms of resistance

Alkaline urine
No bacterial resistance to formaldehyde described

51

both nitrofurantoin and methenamine are given

orally

52

nitrofurantoin absorption

40-50% absorption following oral administration
Occurs in small intestine
Enhanced with food

53

Methenamine absorption

Rapid absorption after oral administration
May be partially degraded by gastric acid

54

Nitrofurantoin distribution

Large urine concentrations
Low/undetectable serum concentration
Therapeutic concentrations not attained in prostate

(bc it doesn't accumulate anywhere else it is only useful for UTIs)

55

methenamine distribution

Rapid absorption following oral dose
Broad distribution in tissue

56

Nitrofurantoin elimination

Eliminated in the urine
Glomerular filtration
Tubular secretion
Tubular reabsorption
Biliary excretion: minor
Serum half life

57

methenamine elimination

Renal excretion
Half-life 3-4 hours with normal renal function

58

clinical uses of Nitrofurantoin

Acute, uncomplicated UTIs (commonly used for E. coli among many others)

Do not use for:
Pyelonephritis
Complicated UTi

59

clinical uses of Methenamine

Suppression or prophylaxis against recurrent UTIs

Do not use for:
Established infections
Prophylaxis against catheter-associated UTI

60

Nitrofurantoin
 Adverse reactions

• GI intolerance
• Rashes
• Acute pulmonary symptoms – reversible hypersensitivity phenomenon
- Weeks to months after drug exposure
- Rapid onset of fever, cough, dyspnea, myalgia
- Peripheral blood eosinophilia and lower lobe pulmonary infiltrates
• Subacute and chronic pulmonary reaction
- Gradual onset of progressive, non-productive cough and dyspnea
- Interstitial infiltrate on CXR
- Reversible but may lead to pulmonary fibrosis
- May have + antinuclear antibodies
- Bronchiolitis obliterans and organizing pneumonia reported

61

Methenamine 
Adverse reactions

Generally well-tolerated
GI (nausea, vomiting)
Rash
Pruritis
Bladder irritation
Hemorrhagic cystitis (higher doses)
Peripheral sensory neuropathy
Hepatitis
Hemolytic anemia
Leukopenia
Aplastic anemia
Megaloblastic anemia (folic acid responsive)
Eosinophilia