Chapter 41 Antimicrobial Agents

General Consideration

Gao Dongyan 高东雁

Email: gaody1975@163.com
WeChat: gdy1975
 Chemotherapy refers to the treatment of disease by chemicals that kill
cells, specifically those of microorganisms or cancer.

Chemotherapy index (CI) （化疗指数）

To evaluate the safety of chemotherapeutic drugs,
the value is LD50/ED50 or LD5/ED95.

The relationship of Host-Drug-Pathogen in chemotherapy

 • Neisseria
• Pseudomonas
Chemotherapy aeruginosa （假单
胞菌）
• Escherichia coli
• bacteria （细菌） • gram-negative • Legionella （军团
• chlamydia （衣原体） bacteria 菌）
• mycoplasma （支原体） • gram-positive • ....
rickettsia （立克次体） bacteria • Staphylococcus （葡
• spirochetes （螺旋体） 萄球菌）
• Streptococcus （链
• protozoa （原虫） 球菌）
pathogenic • actinomyces （放线菌） • Corynebacterium
microorganisms diphtheria ( 白喉杆
• coccus ( 球菌） 菌）
• viruses
• bacillus （杆 • Bacillus
菌） anthracis （炭疽杆
• fungi
菌）
• parasite • Tetanus bacillus
（破伤风杆菌）
• cancer cells • ....
Classification of chemotherapeutic drugs
according to the actions against the type of organism
• bacteria （细菌）
• chlamydia （衣原体）
• mycoplasma （支原体）
rickettsia （立克次体）
• spirochetes （螺旋体）
• protozoa （原虫）
• actinomyces （放线菌）

• viruses

• fungi
• parasite
• cancer cells
• Professional terms

Antibacterial drug: any drug that destroys bacteria or inhibits their growth

– Synthetic Antimicrobial Drugs

– Antibiotic
A drug used to treat infections caused by bacteria and other
microorganisms. Originally, an antibiotic was a substance produced by
one microorganism that selectively inhibits the growth of another.
• Bacteriostatic drugs
arrest the growth or replication of the microorganism.
• Bactericidal drugs
The agents which can kill the microorganisms are called bactericidal
drugs ; a drug may be bacteriostatic for one organism but
bactericidal for another.
• Minimal inhibitory concentration (MIC)
MIC is the lowest concentration of antimicrobial agents that prevents
visible bacterial growth in 18-24 hours incubation.
• Minimum bacteriocidal concentration (MBC)
MBC is the lowest concentration of a drug that kills a particular
pathogen.
• Post-antibiotic effect (PAE) is defined as the time of an antimicrobial
drug to inhibit the growth of bacteria after removal of the drug from
the culture
Antimicrobial spectrum ( 抗菌谱）
Antimicrobial spectrum of a drug means the species of
microorganisms that the drug can inhibit or kill.
• Narrow spectrum
The agents act against a single or limited group of microorganisms
(isoniazid: mycobacteria )
• Extended spectrum
The agent that are effective against gram-positive organisms and also
against a number of gram-negative bacteria (ampilcillin ).
• Broad spectrum
The agent affect a wide variety of microbial species (tetracycline)
Mechanism of
action of
antimicrobial
agents

PABA
↓
DHFA
↓
THFA
Folic acid
metabolism
Sulfonamides
trimethonprim
Antimicrobial agents’ resistance
• Enzymic inactivation
The ability to destroy or inactivate the antimicrobial agents can confer
resistance. For example, β-lactamase destroy many penicillins and
cephalosporins
• Modification (alteration) of target sites penicillin binding protein,
PBP
• Decreased accumulation
Antibiotics are unable to gain access to the site of action due to the
presence of an efflux system that pumps out the drug
• Genetic mutations
Classification of Quinolones
• First generation
nalidixic acid
• Second generation
ciprofloxacin
norfloxacin
• Third generation
sparfloxacin
levofloxacin
• Fourth generation
moxifloxacin
delafloxacin
 Chapter 42 Synthetic Antimicrobial Drugs

Objectives
• Understanding the antibacterial spectrum and mechanisms of
quinolones and sulfonamides.
• Beware of the antibacterial activities, therapeutic applications of
metronidazole
Quinolones
 Antibacterial activity of Quinolones
• First generation
• narrow antibacterial spectrum
• G- bacterium, such as Escherichia coli
except against Pseudomonas aeruginosa
• poor absorption
• only used for urinary tract infections
• Second generation
• better G- and part of G+ bacterium
• For urinary and intestinal tract infections
 Antibacterial activity of Quinolones
• Third generation
• broad antimicrobial activity
• much higher activity against
• G- (E. coli, Salmonella, Shigella, Enterobacter,Campylabacter,
Neisseria ， Pseudomonas aeruginosa, Legionella, Brucella)
• some G+ (S. pneumoniae, staphylococci)
• chlamydia （衣原体）
• mycoplasma （支原体）
• mycobacteria ( 结核分枝杆菌）
• Fourth generation
• extensive activity against G- and G+
including resistant strains and anaerobic bacteria.
Structure-activity relations of Quinolone core substitutions
Mechanism of action of Quinolones
Quinolones exert their bactericidal effect by inhibiting topoisomerase II
(DNA gyrase, DNA 回旋酶 ) and topoisomerase IV.
• DNA gyrase is a heterotetramer composed of two A subunits and two
B subunits. The enzyme introduces negative superhelical twists （负
超螺旋） into bacterial DNA and this is essential for replication and
transcription.
Mechanism of action of Quinolones

1st to 3rd- generation quinolones → Gram-negative bacteria

Mechanism of action of Quinolones
• Topoisomerase IV is composed of two C subunits and two E subunits .
Inhibition of topoisomerase Ⅳprobably interferes with separation of replicated
chromosomal DNA into the respective daughter cells during cell division.

4th- generation quinolones

→ Gram-negative bacteria
→ Gram-positive bacteria
Mechanism of action of Quinolones
Pharmacokinetics
The fluoroquinolones were well absorbed after oral administration and
distributed widely in body fluids and tissues.
Resistance to quinolones may develop
via
(a) mutations in the bacterial
chromosomal genes
encoding DNA gyrase or topoisomerase
Ⅳ
(b) a change in the permeability of the
organism
(c) active transport of the drug out of the
bacteria.
Therapeutic Uses
• Urinary Tract Infections, even caused by multidrug resistant bacteria, eg,
pseudomonas.
Sexually Transmitted Diseases
• Gastrointestinal and abdominal infections
• Respiratory tract infections
• Bone, Joint, and soft tissue infections
• Ciprofloxacin and ofloxacin are second-line agents for treatment of
tuberculosis.
Adverse Reactions
1 The most common adverse reactions are nausea, vomiting, and abdominal
discomfort.
2. Photosensitivity has been reported with lomefloxacin ( 洛美沙星） and
sparfloxacin( 斯帕沙星）
3.Central nervous system adverse effect: headache, dizziness, insomnia
4. Quinolones can produce arthropathy （ arthritis) in some species of
immature animals, so they should be used with caution in children and
adolescent.
 Sulfonamides

The discovery of sulfonamides

• Sulfonamides were the first effective chemotherapeutic
agents systemically for the treatment of bacterial infections
in 1930s
Antimicrobial Activities of sulfonamides
Sulfonamides inhibit a wide range of microorganisms
including Streptococcus pyogenes, Streptococcus pneumoniae,
Haemophilus influenzae, Nocardia, Chlamydia trachomatis( 沙眼衣原体 ),
and some protozoa. Some enteric bacteria, such as E coli, salmonella, and
shigella （志贺菌） are inhibited.
 Mechanisms of Action of sulfonamides
• Susceptible microorganisms require extracellular para-aminobenzoic acid (PABA)
（对氨基苯甲酸） in order to form dihydrofolic acid, an essential step in the
production of purines and the synthesis of nucleic acids.
• The structures of sulfonamides are similar to PABA
• Sulfonamides competitively inhibit dihydropteroate synthase （二氢叶酸合成酶）
and prevent normal bacterial utilization of PABA.
• Sulfonamides are bacteriostatic . Sulfonamides do not affect mammalian cells since
they require preformed folic acid .

Sulfonamide PABA
Mechanisms of Action of sulfonamides

Sulfonamides

PABA dihydroteroate synthase dihydrofolic acid

Dihydrofolate
reductase

TMP

DNA purines tetrahydrofolic acid

Trimethoprim (TMP, 甲氧苄啶 )
• Trimethoprim (TMP, 甲氧苄啶 ), inhibits bacterial dihydrofolic acid
reductase （二氢叶酸还原酶） .
• Trimethoprim given together with sulfonamides, produces sequential
blocking of folic acid synthesis, resulting in marked enhancement
(synergism) of the bacteriostatic activity.
• The combination of the two drugs is often bactericidal, compared to
the bacteriostatic activity of a sulfonamide used alone. (SMZ+ TMP)
Mechanisms of Action of trimethoprim

Sulfonamides

PABA dihydroteroate synthase dihydrofolic acid

Dihydrofolate
reductase

TMP

DNA purines tetrahydrofolic acid

• SMZ+ TMP( 复方新诺明）
1.Antibacterial spectrum↑
2. Antibacterial activity↑
double blocking of folic acid synthesis;
similar t1/2
3. Drug Resistance↓
4. Adverse reaction↓
Pharmacokinetics of sulfonamides
Sulfonamides , with the except of those poorly absorbed, are generally well
absorbed and distributed throughout the body including cerebrospinal fluid
（ CSF ，脑脊液 ) .
• They are metabolized in the liver by acetylation reaction （乙酰化反
应） .
• The largest fraction is excreted in the urine .The older insoluble
sulfonamides can cause crystalline deposits in urinary tract.
Resistance of sulfonamides

The three main resistance mechanisms include:

• lowered affinity of dihydropteroate synthase to Sulfonamides;
• decreased bacterial permeability of sulfonamides;
• an alterative metabolic pathway e.g. over-production of PABA.
Therapeutic applications of sulfonamides
Systemic infection
• Sulfisoxazole (SIZ, 磺胺异唔唑 ) and sulfamethoxazole (SMZ, 磺胺甲基
异唔唑 ) are often used to treat urinary tract infections.
• SMZ given together with TMP, is used widely for respiratory tract
infections, such as sinusitis and bronchitis, and enteric infection.
• Sulfadiazine (SD ，磺胺嘧啶 ) achieves therapeutic concentrations in
cerebrospinal fluid and is a first-line therapy for treatment of epidemic
cerebrospinal meningitis.
Therapeutic applications of sulfonamides
Local infection
• Sodium sulfacetamide (SA-Na ，磺胺醋酰钠） is employed effectively in
the therapy of ophthalmic infections
• Mafenide sulfamylon (SML ，磺胺米隆 ) and silver sulfadiazine (SD-Ag ，
磺胺嘧啶银 ) are used topically to prevent bacterial colonization and infection
of burn wounds.
Intestinal tract infection
Salazosulfapyridine (SASP ，柳氮磺胺吡啶 ) is poorly absorbed so it is used
for intestinal tract infections.
Adverse Reactions of sulfonamides

Urinary tract disturbances

• Crystalluria, hematuria, or even obstruction may occur in patients receiving
SD. Preventive strategies include administration of sodium bicarbonate to
alkalinize the urine and fluids to maintain adequate hydration.
Allergic reactions
Fever, skin rashes ， dermatitis （皮炎） , and urticaria （荨麻疹） may
happen.
Adverse Reactions of sulfonamides

Hematopoietic system disorders

Aplastic anemia, granulocytopenia, thrombocytopenia, or leukemoid
reactions are uncommon.
Hemolytic anemia （溶血性贫血） is related to an erythrocytic deficiency
of glucose-6-phosphate dehydrogenase.
Miscellaneous reactions
Nausea, vomiting, diarrhea, headache (1-2 % patients)
 Metronidazole
Mechanism of action
Metronidazole is a prodrug. In anaerobic bacteria and sensitive protozoas （原
虫） , metronidazole is converted into an active form by reduction of its nitro
group, and the active form binds to DNA and prevents nucleic acid formation.
It is a bacteriostatic agent.
Antimicrobial Activities of metronidazole
• Metronidazole kills trophozoites but not cysts of Entamoeba histolytica.
• It has activity against Giardia lamblia （贾第鞭毛虫） as well as
Trichomonas vaginalis （阴道滴虫） .
• Metronidazole has antibacterial activity against all anaerobic bacilli
Therapeutic applications of metronidazole
• Metronidazole effectively treats all symptomatic forms of amebiasis,
including gastrointestinal infection and liver abscess.
• It is effective for the therapy of giardiasis and trichomoniasis.
• effective for the infections with susceptible anaerobes

Adverse Effects of metronidazole

• nausea, headache, vomiting, or an unpleasant metallic taste in the mouth.
• Infrequent adverse effects include diarrhea, insomnia, weakness, dizziness,
rash, vertigo, paresthesias, and neutropenia.
Please make a judgment whether the following statement is true or not
1. Sulfadiazine(SD) is the first choice of treating meningococcal infections.
2. Quinolones inhibit DNA synthesis through inhibiting DNA polymerase.
3. TMP prevent normal bacterium synthesizing folic acid through inhibiting
dihydropteroate synthase.

Give a true or false choice to each of the following statements.

• Metronidazole can be used effectively to treat amebiasis, trichomoniasis
and anaerobic bacteria infection.
• Crystalluria, hematuria and skin rashes may occur during the treatment
with sulfonamides