Chapter 44

Chloramphenicol and Tetracyclines

Objectives
• The major pharmacological effects and clinical
applications of chloramphenicol and tetracyclines
• The major adverse reactions of chloramphenicol and
tetracyclines
Characterization of chloramphenicol and tetracyclines
Chloramphenicol and tetracyclines are active against
both aerobic and anaerobic gram-positive and gram-negative
organisms, they are called as bacteriostatic broad-spectrum
antibiotics.
Chloramphenicol
Spectrum of activity
Chloramphenicol has a broad spectrum of bacteriostatic
activity for
• bacteria (especially salmonella)
• rickettsiae（立克次体）,
• chlamydiae（衣原体)
• spirochetes (螺旋体)
• mycoplasmas（支原体）
Chloramphenicol
Mechanism of action of Chloramphenicol
• Chloramphenicol inhibits protein synthesis by acting on
the 50s ribosomal subunit and inhibiting peptidyl
transferase.
• The drug is primarily bacteriostatic, although it may be
bactericidal to some strains.

chloramphenicol(50S)

P A Peptidyl P A
transferase
Resistance of chloramphenicol
Almost all microorganisms could develop resistance to
chloramphenicol. The resistance usually is caused by a
plasmid-encoded acetyltransferase that inactivates the drug.
After chloramphenicol is acetylated, it fails to bind to
bacterial ribosomes.
Therapeutic applications of Chloramphenicol
• Potentially severe toxicity limits the use of
choramphenicol. If an agent is as efficacious
as chloramphenicol and potentially less toxic,
the other agent should be used instead.
• Chloramphenicol could be used to treat typhoid fever(first
choice), bacterial meningitis, anaerobic infections, and other
rickettsial diseases.
Adverse reaction of Chloramphenicol
• Bone marrow disturbances
• Reversible anemia is apparently dose-related
and occurs concomitantly with period of treatment.
（reversible suppression of red cell production)
Aplastic anemia is idiosyncratic（特异质） and
usually fatal, which is not related to dose and therapy
(develop in one of every 24,000-40,000 patients who
have taken the drug..）
Adverse reaction of Chloramphenicol
• Gray-baby syndrome
1) This condition is seen in
neonates, especially premature infants who have been
given relatively large doses of chloramphenicol;
2) Vomiting, hypothermia, gray color, respiratory
irregularities and shock are often observed.
3) The condition develops because of the immature
hepatic conjugating mechanism and the inadequate
mechanism for renal excretion in neonates.
• Gastrointestinal disorders
Nausea, vomiting and diarrhea develop in adult
patients.
 Tetracyclines 四环素类
Tetracyclines are derivatives of the naphthacene (并四苯) .
The tetracyclines include
tetracycline (四环素),
terramycin (土霉素),
doxycycline (脱氧土霉素, 多西环素).
Minocycline（米诺环素）
Tigecycine （替加环素）
Antibacterial activity of Tetracyclines
• Tetracyclines have a broad-spectrum ranging from
aerobic and anaerobic gram-positive to gram-negative
bacteria.
Rickettsiae（立克次体）, chlamydiae(衣原体）, and
mycoplasmas （支原体）, even some spirochetesare
sensitive to the tetracyclines.
• Tetracyclines are generally bacteriostatic but not
bactericidal.
Mechanism of action of Tetracyclines
Tetracyclines are potent inhibitors of microbial protein
synthesis by binding to the 30S subunit of the bacterial
ribosome.

P A P A

,A ine
0S cl
(3 acy

)
tr
te
Therapeutic applications of Tetracyclines
• Tetracycline is the drug of choice for the infections
caused by Mycoplasma pneumonia, Chlamydiae(衣原体）,
Rickttsiae, and some Spirochetes.
• Tetracycline remains effective in most gram-negative
bacterial infections.
• The drug is usually used in combination with an
aminoglycoside.
 Pharmacokinetics of Tetracyclines
• Tetracyclines are adequately but incompletely
absorbed from the gastrointestinal tract. Absorption is
impaired by food, milk, milk products, aluminum
hydroxide gels, calcium and magnesium salts.
• Tetracyclines diffuse readily into body fluids but
concentrations in the cerebrospinal fluid is low.
• Tetracyclines are metabolized in the liver and
excreted mainly by the bile and urine.
Adverse reactions of Tetracyclines
• Gastrointestinal side effects
Nausea, vomiting, and diarrhea
• Superinfection (double infection, 二重感染)
Superinfection is caused by overgrowing of resistant
organism and yeasts in respiratory and gastrointestinal
tract. Superinfection is a significant problem which
can result in staphylococcal enterocolitis, intestinal
candidosis, and pseudomembranous colitis. These
superinfections should be treated with vancomycin
and other drugs.( intestinal flora )
• Effects on calcified tissue
Tetracyclines are attracted to
embryonic and growing osseous
tissue where they form a tetracycline-calcium
orthophophate complex. The danger is greatest from
midpregnancy to 3 years of age. Children receiving
either short-or long-term tetracycline therapy may
develop yellow-brown discolorations of their teeth and
suffer depressed bone growth.
• Hepatic toxicity
Tetracylines may cause liver damage that is sometimes
associated with Pancreatitis, particular when large doses
(>2g daily) are iv administered.
• Other adverse reactions
Other adverse reactions include delay of blood
coagulation, hypersensitivity, photosensitivity.
 Chapter 45
Macrolides, Clindamycin,
Polymyxins, and Vancomycin
Macrolides (大环内酯类）
The macrolides are a group of antibiotics with a
macrocyclic lactone ring. Which include
Erythromycin （红霉素）
Medemycin (麦迪霉素)
Spiramycin (螺旋霉素)

Roxithromycin (罗红霉素）
Clarithromycin（克拉霉素）
Azithromycin (阿奇霉素）
 chemical structure

Erythromycin （14） Azithromycin（15） Spiramycin（16）

20
Mechanism of action
Macrolides inhibit microbial protein synthesis by binding
reversibly to 50S ribosome subunit.
Erythromycin can decrease the antibacterial activity of
chloramphenicol or Lincomycin as erythromycin interferes
with the binding of chloramphenicol to the same site.

macrolides(50S)

P A Peptidyl P A
transferase
Antibacterial activity
Erythromycin is usually bacteriostatic, and bactericidal
at higher concentrations for some very susceptible
organisms. Aerobic gram-positive cocci and bacilli are
most susceptible, e.g., Pneumococci, Streptococci,
Staphylococci.
It is not very active against most gram-negative bacilli.
Therapeutic applications
• Erythromycin is the drug of first choice in Mycoplasma
Pneumonia infections, Legionnaires’ disease, diphtheria.
• Macrolides are also useful as a penicillin substitute in
penicillin-allergic (resistant) persons.
Adervse reactions of Erythromycin
Erythromycin has a very low incidence of serious
side effects.
• Epigastric distress can occur.
• Hypersensitivity reactions include allergic
cholestatic hepatitis; This reaction occurs primarily
with the estolate form of the drug.
Vancomycin
Mechanism of action
Vancomycin is a rapid bactericidal agent for dividing
microorganisms. It inhibits the synthesis of the cell wall
in sensitive bacteria.
Antibacterial activities
Vancomycin is primarily active against gram-positive bacteria
and its antibacterial spectrum is narrow. But strains resistant to
methicillin, even methicillin(甲氧西林）-resistant S. aureus
(MRSA), are sensitive to vancomycin.
Therapeutic applications
Vancomycin should be only employed to treat
serious infections, especially in the treatment of
infections due to MRSA.
 Lincomycins
lincomycin and Clindamycin
• Pharmacological effects
The antibacterial activity of clindamycin(克林霉素）is similar
to that of macrolides. Pneumonococci, S. pyogenes, Viridans
Streptococci (绿色链球菌）and streptococci, including some
macrolide-resistant, are susceptible to clindamycin;
anaerobe strains.
Similar mechanism with macrolides；inhibit 50S subunit
Clinical uses
• aerobic G+ cocci infection
• severe anaerobic infections and against other anaerobes that
participate in mixed infections
Polymyxins 多粘菌素类
•There are five polymyxins. A, B, C, D, E,
•Polymyxin E, 多粘菌素E (Colistin,抗敌素)
is frequently used in clinics.
Spectrum of activity of polymyxins
Polymyxins are active mainly against gram-negative
bacilli, particulary pseudomonas and coliform organisms.
Mechanism of action of polymyxins
Polymyxins act by attaching to the cell membranes of
bacteria and other membranes rich in
phosphatidylethanolamin (磷脂酰乙醇胺) and
disrupting the osmotic properties and transport
mechanisms of the membrane. This results in
leakage of macromolecules and death of the cell.
Adverse reactions
The severe adverse reaction is nephrotoxicity.
Give a true or false choice to each of the following
statements
1. Aplastic anemia caused by chloramphenicol is related to
dose and therapy.
2. MRSA are sensitive to vancomycin , so vancomycin can be
used widely in clinic.
3. Erythromycin is the drug of first choice in Mycoplasma
Pneumonia infections, Legionnaires’ disease