Tetracyclines and Chlorampenicol

Question 1

Because of overuse, tetracycline and macrolide resistance is common. Except for____________ these antibiotics are usually administered orally.

Answer 1

tigecycline and the streptogramins,

Question 2

_________ are crystalline amphoteric substances of low solubility. They are available as hydrochlorides, which are more soluble. Such solutions are acid and, with the exception of chlortetracycline, fairly stable. These chelate divalent metal ions, which can interfere with their absorption and activity.

A newly approved analog, tigecycline, is a glycylcycline and a semisynthetic derivative of minocycline.

Answer 2

Free tetracyclines

Question 3

Mechanism of Action & Antimicrobial Activity

Tetracyclines

Answer 3

broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis.

Tetracyclines enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport. Susceptible organisms concentrate the drug intracellularly. Once inside the cell, tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNAribosome complex ( Figure 44–1 ). This prevents addition of amino acids to the growing peptide.

NMEMONICS : Buy AT 30

Aminoglycoside

Tetracycline

Cells at 50

Clindamycin

Erythromycin (Macrrolides)

Linozelid ( Oxazoladinones)

chloramphenicoL

Streptogramines

Question 4

Tetracyclines are active against

.

Answer 4

many gram-positive and gramnegative bacteria, including certain anaerobes, rickettsiae, chlamydiae, and mycoplasmas

Question 5

The antibacterial activities of most tetracyclines are similar except that tetracycline-resistant strains may be susceptible to________________ all of which are poor substrates for the efflux pump that mediates resistance. Differences in clinical efficacy for susceptible organisms are minor and attributable largely to features of absorption, distribution, and excretion of individual drugs.

Answer 5

doxycycline, minocycline, and tigecycline,

Question 6

Resistance Three mechanisms of resistance to tetracycline analogs have been described:

Answer 6

(1) impaired influx or increased efflux by an active transport protein pump;
(2) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome; and
(3) enzymatic inactivation

Question 7

. The most important of these resistance mechanisms are_____________

Answer 7

production of an efflux pump and ribosomal protection.

Question 8

Tet(AE) efflux pump-expressing gram-negative species are resistant to the older tetracyclines, doxycycline, and minocycline. They are susceptible, however, to ______________-, which is not a substrate of these pumps.

Answer 8

tigecycline

Question 9

Similarly, the Tet(K) efflux pump of ___________confers resistance to tetracycline, but not to doxycycline, minocycline, or tigecycline, none of which are pump substrates.

Answer 9

staphylococci

Question 10

The Tet(M) ribosomal protection protein expressed by ___________produces resistance to tetracycline, doxycycline, and minocycline, but not to tigecycline, which because of its bulky t -butylglycylamido substituent, has a steric hindrance effect on Tet(M) binding to the ribosome.

Answer 10

gram-positives

Question 11

____________ is a substrate of the chromosomally encoded multidrug efflux pumps of Proteus sp and Pseudomonas aeruginosa , accounting for their intrinsic resistance to all tetracyclines including tigecycline.

Answer 11

Tigecycline

Question 12

Pharmacokinetics

Tetracyclines differ in their absorption after oral administration and in their elimination.

Absorption after oral administration is approximately 30% for chlortetracycline;

60–70% for tetracycline, oxytetracycline, demeclocycline, and methacycline; and

95–100% for ___________________

Answer 12

doxycycline and minocycline.

Question 13

_______________is poorly absorbed orally and must be administered intravenously.

Answer 13

Tigecycline

Question 14

A portion of an orally administered dose of tetracycline remains in the gut lumen, alters intestinal flora, and is excreted in the feces. Absorption occurs mainly in the upper small intestine and is impaired by food _____________); by divalent cations (Ca 2+ , Mg 2+ , Fe 2+ ) or Al 3+ ; by dairy products and antacids, which contain multivalent cations; and by alkaline pH.

Specially buffered tetracycline solutions are formulated for intravenous administration.

Tetracyclines are 40–80% bound by serum proteins. Oral dosages of 500 mg every 6 hours of tetracycline hydrochloride or oxytetracycline produce peak blood levels of 4–6 mcg/mL.

Intravenously injected tetracyclines give somewhat higher levels, but only temporarily. Peak levels of 2–4 mcg/mL are achieved with a 200-mg dose of doxycycline or minocycline. Steady-state peak serum concentrations of tigecycline are 0.6 mcg/mL at the standard dosage.

Answer 14

(except doxycycline and minocycline

Question 15

TETRACYCLINES

Absorption occurs mainly in the upper small intestine and is impaired by __________________

Answer 15

food; by divalent cations (Ca 2+ , Mg 2+ , Fe 2+ ) or Al 3+ ; by dairy products and antacids, which contain multivalent cations; and by alkaline pH.

Question 16

NOTE :

Tetracyclines are distributed widely to tissues and body fluids except for ___________, where concentrations are 10–25% of those in serum.

Answer 16

cerebrospinal fluid

Question 17

_____________- reaches very high concentrations in tears and saliva, which makes it useful for eradication of the meningococcal carrier state.

Answer 17

Minocycline

Question 18

Tetracyclines cross the placenta to reach the fetus and are also excreted in milk. As a result of chelation with calcium, tetracyclines are ___________

Answer 18

bound to—and damage—growing bones and teeth

Question 19

may shorten the half-life of doxycycline 50% by induction of hepatic enzymes that metabolize the drug.

Answer 19

. Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion

Question 20

Tetracyclines are classified as

Answer 20

short-acting

intermediate-acting

long-acting

Note : based on serum half-lives of 6–8 hours,

12 hours,

and 16–18 hours, respectively.

Question 21

What are you short acting Tetracyclines?

Answer 21

short-acting

• (chlortetracycline,
• tetracycline,
• oxytetracycline),

i

Question 22

What are your intermediate acting Tetracyclines?

Answer 22

intermediate-acting

• (demeclocycline and
• methacycline), or

Question 23

What are your long acting Tetracyclines?

Answer 23

long-acting (doxycycline and minocycline)

Question 24

______________ has a half-life of 36 hours.

Answer 24

Tigecycline

Question 25

The almost complete absorption and slow excretion of _________________allow for once-daily dosing for certain indications, but by convention these two drugs are usually dosed twice daily.

Answer 25

doxycycline and minocycline

Question 26

Clinical Uses

A tetracycline is the drug of choice in the treatment of infections caused by____________________. Tetracyclines are also excellent drugs for the treatment of Mycoplasma pneumonia , chlamydiae, and some spirochetes.

They are used in combination regimens to treat gastric and duodenal ulcer disease caused by Helicobacter pylori.

They may be used in various gram-positive and gram-negative bacterial infections, including vibrio infections, provided the organism is not resistant.

Answer 26

rickettsiae

Question 27

In cholera,____________rapidly stop the shedding of vibrios, but resistance has appeared during epidemics.

Answer 27

tetracyclines

Question 28

Tetracyclines remain effective in most______________including sexually transmitted infections.

NOTE : Tetracyclines are no longer recommended for treatment of gonococcal disease because of resistance.

Answer 28

chlamydial infections,

Question 29

A tetracycline—in combination with other antibiotics— is indicated for_______________

Answer 29

plague, tularemia, and brucellosis.

Question 30

Tetracyclines are sometimes used in the treatment or prophylaxis of __________,

NOTE :Other uses include treatment of acne, exacerbations of bronchitis, community-acquired pneumonia, Lyme disease, relapsing fever, leptospirosis, and some nontuberculous mycobacterial infections (eg, Mycobacterium marinum ). Tetracyclines formerly were used for a variety of common infections, including bacterial gastroenteritis and urinary tract infections. However, many strains of bacteria causing these infections are now resistant, and other agents have largely supplanted tetracyclines.

Answer 30

protozoal infections

eg, those due to Plasmodium falciparum (see Chapter 52 ).

Question 31

__________ 200 mg orally daily for 5 days, can eradicate the meningococcal carrier state, but because of side effects and resistance of many meningococcal strains, rifampin is preferred.

Answer 31

Minocycline,

Question 32

__________ inhibits the action of antidiuretic hormone in the renal tubule and has been used in the treatment of inappropriate secretion of antidiuretic hormone or similar peptides by certain tumors (see Chapter 15 ).

Answer 32

Demeclocycline

Question 33

________________ , the first glycylcycline to reach clinical practice, has several unique features that warrant its consideration apart from the older tetracyclines.

Many tetracycline-resistant strains are susceptible to this because the common resistance determinants have no activity against it. Its spectrum is very broad.

Coagulase-negative staphylococci and Staphylococcus aureus , including methicillin-resistant, vancomycin-intermediate, and vancomycin-resistant strains; streptococci, penicillin-susceptible and resistant; enterococci, including vancomycin-resistant strains; gram-positive rods; Enterobacteriaceae; multidrug-resistant strains of Acinetobacter sp; anaerobes, both gram-positive and gramnegative; rickettsiae, Chlamydia sp, and Legionella pneumophila; and rapidly growing mycobacteria all are susceptible.

Answer 33

Tigecycline

Question 34

Species resistant to Tigecycline

Answer 34

Proteus sp and P aeruginosa , however, are intrinsically resistant.

Question 35

Tigecycline, formulated for intravenous administration only, is given as a 100-mg loading dose, then 50 mg every 12 hours. As with all tetracyclines, tissue and intracellular penetration is excellent; consequently, the volume of distribution is quite large and peak serum concentrations are low. Elimination is primarily biliary, and no dosage adjustment is needed for patients with renal insufficiency.

In addition to the tetracycline class effects, the chief adverse effect of tigecycline is________, which occurs in up to one third of patients, and occasionally vomiting. Neither nausea nor vomiting usually requires discontinuation of the drug.

Tigecycline is Food and Drug Administration (FDA)-approved for treatment of skin and skin-structure infection, intra-abdominal infections, and community-acquired pneumonia.

Because active drug concentrations in the urine are relatively low, tigecycline may not be effective for urinary tract infections and has no indication for this use.

Because it is active against a wide variety of multidrug-resistant nosocomial pathogens (eg, methicillinresistant S aureus , extended- spectrum β-lactamase-producing gram-negatives, and Acinetobacter sp, tigecycline is a welcome addition to the antimicrobial drug group. However, its clinical efficacy in infections with multidrug-resistant organisms, compared with other agents, is largely unknown.

Answer 35

Nausea

Question 36

A. Oral Dosage

The oral dosage for rapidly excreted tetracyclines, equivalent to tetracycline hydrochloride, is _____________

. For severe systemic infections, the higher dosage is indicated, at least for the first few days.

The daily dose is 600 mg for demeclocycline or methacycline, 100 mg once or twice daily for doxycycline, and 100 mg twice daily for minocycline.

Answer 36

0.25–0.5 g four times daily for adults and 20–40 mg/kg/d for children (8 years of age and older)

Question 37

_________________ is the oral tetracycline of choice because it can be given twice daily, and its absorption is not significantly affected by food. All tetracyclines chelate with metals, and none should be orally administered with milk, antacids, or ferrous sulfate. To avoid deposition in growing
bones or teeth, tetracyclines should be avoided in pregnant women
and children younger than 8 years.

Answer 37

Doxycycline

Question 38

B. Parenteral Dosage Several tetracyclines are available for intravenous injection in doses of 0.1–0.5 g every 6–12 hours (similar to oral doses) but_____________ is the usual preferred agent, at a dosage of 100 mg every 12–24 hours. Intramuscular injection is not recommended because of pain and inflammation at the injection site.

Answer 38

doxycycline

Question 39

Adverse Reactions TETRACYCLINE

Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines are____________

Answer 39

** uncommon. **

Question 40

Most adverse effects of Tetracyclineare due to ________________________

Answer 40

direct toxicity of the drug or to alteration of microbial flora

Question 41

Most adverese effect of tetracyclines are

Answer 41

a. GIT
b. Bony structure and teeth

Question 42

. A. __________- are the most common reasons for discontinuing tetracycline medication.

Answer 42

Gastrointestinal Adverse Effects Nausea, vomiting, and diarrhea:

Note : These effects are attributable to direct local irritation of the intestinal tract. Nausea, anorexia, and diarrhea can usually be controlled by administering the drug with food or carboxymethylcellulose, reducing drug dosage, or discontinuing the drug.

Tetracyclines alter the normal gastrointestinal flora, with suppression of susceptible coliform organisms and overgrowth of pseudomonas, proteus, staphylococci, resistant coliforms, clostridia, and candida.

This can result in intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis, or Clostridium difficile- associated colitis.

Question 43

B. Bony Structures and Teeth

Tetracyclines are readily bound to calcium deposited in newly formed bone or teeth in young children. When a tetracycline is given during pregnancy, it can be deposited in the fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia; it can also be deposited in bone, where it may cause deformity or growth inhibition.

Because of these effects, tetracyclines are generally avoided in pregnancy.

If the drug is given for long periods to children younger than____________, similar changes can result.

Answer 43

** 8 years**

Question 44

C. Other Toxicities Tetracyclines can impair hepatic function, especially during pregnancy, in patients with preexisting hepatic insufficiency and when high doses are given intravenously.

Hepatic necrosis has been reported with daily doses of 4 g or more intravenously. Renal tubular acidosis and other renal injury resulting in nitrogen retention have been attributed to the administration of outdated tetracycline preparations.

Tetracyclines given along with diuretics may produce __________.

Tetracyclines other than doxycycline may accumulate to toxic levels in patients with impaired kidney function. Intravenous injection can lead to venous thrombosis. Intramuscular injection produces painful local irritation and should be avoided.

Answer 44

nitrogen retention

Question 45

Systemically administered tetracycline, especially _____________can induce sensitivity to sunlight or ultraviolet light, particularly in fair-skinned persons. Dizziness, vertigo, nausea, and vomiting have been noted particularly with doxycycline at doses above 100 mg. With dosages of 200–400 mg/d of minocycline, 35–70% of patients will have these reactions.

Answer 45

demeclocycline,

Question 46

Mechanism of Action & Antimicrobial Activity

_____________is a potent inhibitor of microbial protein synthesis.

It binds reversibly to the 50S subunit of the bacterial ribosome ( Figure 44–1 ) and inhibits peptide bond formation (step 2).

This is a bacteriostatic broad-spectrum antibiotic that is active against both aerobic and anaerobic gram-positive and gramnegative organisms.

It is active also against Rickettsiae but not Chlamydiae.

Most gram-positive bacteria are inhibited at concentrations of 1–10 mcg/mL, and many gram-negative bacteria are inhibited by concentrations of 0.2–5 mcg/mL

. H influenzae, Neisseria meningitidis , and some strains of bacteroides are highly susceptible, and for these organisms, this may be bactericidal.

Low-level resistance to thisl may emerge from large populations of chloramphenicol-susceptible cells by selection of mutants that are less permeable to the drug.

Answer 46

Chloramphenicol

Question 47

Clinically significant resistance is due to production of ______________-, a plasmid-encoded enzyme that inactivates the drug.

Answer 47

chloramphenicol acetyltransferase

Question 48

Pharmacokinetics

The usual dosage of chloramphenicol is 50–100 mg/kg/d.

After oral administration, crystalline chloramphenicol is rapidly and completely absorbed.

A 1-g oral dose produces blood levels between 10 and 15 mcg/mL.

____________is a prodrug that is hydrolyzed in the intestine to yield free chloramphenicol.

The parenteral formulation is a prodrug, ____________________, which hydrolyzes to yield free chloramphenicol, giving blood levels somewhat lower than those achieved with orally administered drug.

Answer 48

Chloramphenicol palmitate

chloramphenicol succinate

Question 49

Chloramphenicol is widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid, such that the concentration of chloramphenicol in brain tissue may be equal to that in serum.

The drug penetrates cell membranes readily.

Most of the drug is inactivated either by conjugation with glucuronic acid (principally in the liver) or by reduction to inactive aryl amines.

Active chloramphenicol (about 10% of the total dose administered) and its inactive degradation products (about 90% of the total) are eliminated in the urine.

A small amount of active drug is excreted into bile and feces. The systemic dosage of chloramphenicol need not be altered in renal insufficiency, but it must be reduced markedly in hepatic failure.

Newborns less than a week old and premature infants also clear chloramphenicol less well, and the dosage should be reduced to 25 mg/kg/d.

Question 50

Clinical Uses

Because of potential toxicity, bacterial resistance, and the availability of many other effective alternatives, chloramphenicol is rarely used in the United States.

It may be considered for treatment of serious __________________ It is an alternative to a β-lactam antibiotic for treatment of __________________-

The dosage is 50–100 mg/kg/d in four divided doses. ***Chloramphenicol is used topically in the treatment of eye infections because of its broad spectrum and its penetration of ocular tissues and the aqueous humor.
It is ineffective for chlamydial infections.

Answer 50

• rickettsial infections such as typhus and Rocky Mountain spotted fever.
• bacterial meningitis occurring in patients who have major hypersensitivity reactions to penicillin.

Question 51

Adverse Reactions Adults occasionally develop gastrointestinal disturbances, including nausea, vomiting, and diarrhea. This is rare in children

. Oral or vaginal candidiasis may occur as a result of alteration of normal microbial flora.

Chloramphenicol commonly causes a _________________________

Answer 51

**dose-related reversible suppression of red cell production at dosages exceeding 50 mg/ kg/d after 1–2 weeks. **

Question 52

_____________, a rare consequence (1 in 24,000 to 40,000 courses of therapy) of chloramphenicol administration by any route, is an idiosyncratic reaction unrelated to dose, although it occurs more frequently with prolonged use.

It tends to be irreversible and can be fatal.

Answer 52

Aplastic anemia

Question 53

Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol.

Consequently, when infants are given dosages above 50 mg/kg/d, the drug may accumulate, resulting in the ____________ , with vomiting, flaccidity, hypothermia, gray color, shock, and vascular collapse.

Answer 53

gray baby syndrome

Note: To avoid this toxic effect, chloramphenicol should be used with caution in infants and the dosage limited to 50 mg/kg/d (or less during the first week of life) in full-term infants more than 1 week old and 25 mg/kg/d in premature infants.

Question 54

Chloramphenicol inhibits ___________that metabolize several drugs.

Half-lives of these drugs are prolonged, and the serum concentrations of __________________ are increased. Like other bacteriostatic inhibitors of microbial protein synthesis, chloramphenicol can antagonize bactericidal drugs such as penicillins or aminoglycosides.

Answer 54

hepatic microsomal enzymes

phenytoin, tolbutamide, chlorpropamide, and warfarin