ANTIMICROBIAL DRUGS

Definition

ANTIMICROBIAL DRUGS
are chemical substances that can kill or suppress the
growth of microorganisms without harming the cells
of the host

ANTIBIOTICS
are soluble compounds that are derived from certain
microorganisms and that inhibit the growth of other
organisms
eg. Penicillin from Penicillium notatum
 Selection of Antimicrobial Drugs

Selection of the most appropriate antimicrobial drugs

requires knowledge of:
• Organism's Identity
• Sensitivity to particular drug
• Site of Infection
• Safety of the Drug
• Patient Factor
• Cost of Therapy

However, some critically ill patients require empiric

therapy
 Empiric Therapy

• or Presumptive therapy

• Immediate administration of drug(s) covering

infections by both gram positive and gram negative
microorganisms

• Use of drugs before microorganism identification

• Based on experience
 Indication of Empirical Therapy

• Significant risk of morbidity

• Public health reasons

• Ensure cure and further transmission of infection

 Bacteriostatic vs Bactericidal drugs

Bacteriostatic
• arrest the growth and replication of bacteria
• protein synthesis inhibitor
Bactericidal
• kills bacteria
• cell wall synthesis inhibitor

Chloramphenicol
static: gram (-) rods
cidal: Pneumococci
Minimum Inhibitory concentration (MIC)
-the lowest concentration of antibiotic that inhibits
bacterial growth.

Minimum Bactericidal concentration (MBC)

-the minimum concentration of antibiotic that kills
the bacteria under investigation.
-99.9% decline in colony count
 2 groups of Bactericidal Drugs

A. Concentration dependent killing

eg. Aminoglycosides & Quinolones

• rate and extent of killing ↑ with ↑ concentration

B. Time dependent killing

eg. β-lactams & Vancomycin

• bactericidal activity continues as long as serum conc.

are greater than minimum bactericidal conc.
Bacteriostatic Drugs Bactericidal Drugs
Chloramphenicol Aminoglycosides
Clindamycin Bacitracin
Ethambutol β-lactam antibiotics
Macrolides Isoniazid
Nitrofurantoin Metronidazole
Novobiocin Polymyxins
Oxazolidinones Pyrazinamide
Sulfonamides Quinolones
Tetracycline Quinupristin-dalfopristin
Trimethoprim Rifampin
Vancomycin
 Chemotherapeutic Spectra

=refers to the species of organisms affected by a

particular drug

A. NARROW SPECTRUM
• single or a limited group of microbes
eg. Isoniazid only for Mycobacteria

B. EXTENDED SPECTRUM
• gram (+) and some gram (-)
eg. Ampicillin
 Chemotherapeutic Spectra

C. BROAD SPECTRUM
• affect wide variety of microbial species
• can alter nature of normal flora and can precipitate
superinfection
eg. Tetracycline & Chloramphenicol
 Combinations of Antimicrobial Drugs

=Single agent that is most specific for the infecting

organism
• ↓ possibility of superinfection
• ↓ resistance
• ↓ toxicities

= Drug combinations benefit in some situations

eg. Tuberculosis
 Reasons of Drug Combination

• Broad-spectrum empirical therapy

• Treat polymicrobial infection
• Synergism
• ↓ resistant strain
• ↓ dose related toxicity
• Enhanced inhibition or killing
 Inappropriate Use of Combination

• Antagonism between antimicrobial drugs

• ↑ number or severity of ADR

• ↑ cost
 Indication of Drug Combination

• Mixed infection

• Risk of developing resistant organisms

• Greatest antimicrobial coverage is desirable

Enterococcal endocarditis = PCN + Streptomycin

Mycobacterium tuberculosis = RIPES
Cryptococcal meningitis = Amphotericin B + Flucytosine
 Drug Resistance

• If their growth is not halted by the maximal level of

an antibiotic

• organisms have adapted through spontaneous

mutation and become more virulent

• emergence or resistant strains has been ascribed to

the Imprudent and Inappropriate use of antibiotics
 Drug Resistance

A. Genetic alterations
1. undergo spontaneous mutation
2. R factor (plasmid) move from one organism to
another

B. Altered expression of proteins

1. decreased permeability of drugs
2. presence of antibiotic-inactivating enzymes
 Prophylactic Antibiotics

• For prevention rather than treatment

• Restricted to clinical situation in which benefits

outweigh the potential risks

• Proper selection is of utmost importance

 Complication of Antibiotic Therapy

HYPERSENSITIVITY
-state of altered reactivity in which the body
reacts with an exaggerated immune response to
what is perceived as a foreign substance.

Ex. Penicillin
– urticaria (hives) to anaphylactic shock
Mechanisms of action of antimicrobial agents

Penicillins, Cephalosporins,
Cell Wall Synthesis Bacitracin, Vancomycin

Chloramphenicol, Tetracyclines,
Protein Synthesis Aminoglycosides, Macrolides,
Lincosamides, Pleuromutilins

Polymyxin, Aminoglycosides,
Cell Membrane Amphotericin, Imidazoles vs fungi

Nitroimidazoles, Nitrofurans,
Nucleic acid function Quinolones, Rifampin

Intermediary metabolism Sulfonamides, Trimethoprim

CELL WALL
INHIBITORS
CELL WALL INHIBITORS
 Definition of terms

• BETA-LACTAM ANTIBIOTICS
Drugs with structure containing a beta-lactam ring:
Penicillins, cephalosporins and carbapenems. This ring
must be intact for antimicrobial action

• BETA-LACTAMASES
Bacterial enzymes that hydrolyze the beta-lactam ring
(penicillinases, cephalosporinases)
 Definition of terms
• BETA-LACTAMASE INHIBITORS
Potent inhibitors of some bacterial beta-lactamases
used in combinations to protect hydrolyzable
penicillins from inactivation

• MINIMUM INHIBITORY CONCENTRATION

Minimum amount required of a drug to inhibit the
growth of bacteria

• MINIMUM BACTERICIDAL CONCENTRATION

Minimum amount required of a drug to kill bacteria
 Definition of terms

• PENICILLIN BINDING PROTEINS (PBPs)

Bacterial cytoplasmic membrane proteins that act as
the initial receptors for penicillins & other beta-
lactam antibiotics

• PEPTIDOGLYCAN
Chains of polysaccharides and polypeptides that are
cross-linked to form the bacterial cell wall
 Definition of terms

• SELECTIVE TOXICITY
More toxic to the invader than to the host

• TRANSPEPTIDASES
Bacterial enzymes involved in the cross-linking
of linear peptidoglycan chains, the final step in
cell wall synthesis
 PENICILLINS
• most widely effective

• increased resistance has limited their use

• only effective against rapidly growing organisms that

synthesize a peptidoglycan cell wall.

• they are inactive against organisms devoid of this

structure, such as mycobacteria, protozoa, fungi and
viruses.
 Mechanism of Action

MOA:
Interfere with the last step of bacterial cell
wall synthesis (transpeptidation or cross-
linkage), resulting in exposure of the osmotically
less stable membrane.
 Mechanism of Action
1. Penicillin-binding proteins (PBPs)
-bacterial enzymes involved in the synthesis of cell
wall and in the maintenance of the morphologic
features of the bacterium.

Exposure to penicillin can therefore not only

prevent cell wall synthesis but also lead to
morphologic changes or lysis of bacteria.
2. Inhibition of transpeptidase
-Some PBPs catalyze formation of the cross-
linkages between petidoglycan chains.

Penicillins inhibit the transpeptidase-catalized

reaction, thus hindering the formation of cross-links
essential for cell wall integrity.
3. Production of autolysins
Many bacteria, particularly the G+ cocci, produce
degradative enzymes (autolysins) that participate in the
normal remodeling of the bacterial cell wall.

In the presence of a penicillin, the degradative

action of the autolysins proceeds in the absence of cell
wall synthesis. Thus, the antibacterial effect of a
penicillin is the result of both inhibition of cell wall
synthesis and destruction of existing cell wall by
autolysins.
 NATURAL PENICILLINS

-obtained from fermentations of the mold

Penicillium chrysogenum
-susceptible to inactivation by β-lactamases(penicillinases)

1.Penicillin G (benzylpenicillin)
- prototype of subclass of penicillins
- Clinical use: cornerstone of therapy for infections caused
by a number of g+ & g- cocci, g+ bacilli, and spirochetes.
- Resistant strains: Strains of pneumococci, S. areus &
significant numbers of N. gonorrhea
 NATURAL PENICILLINS

- no longer suitable for tx of gonorrhea, Pen G remains

the DOC for Syphilis

- Activity against enterococci is enhanced by

aminoglycoside antibiotics

2. Penicillin V (Phenoxymethylpenicillin)
- orally taken penicillin because it is more acid stable
than Pen G & used mainly in
oropharyngeal infections
 Antistaphylococcal penicillins
Penicillinase-resistant Penicillins
1. Methicillin (prototype)
2. Oxacillin
3. Nafcillin
4. Dicloxacillin

- their use is restricted to the treatment of infections

caused by penicillinase-producing staphylocci, including
methicillin sensitive S. aureus (MSSA)
-have no activity versus gram negative infections
 Antistaphylococcal penicillins
Note:
Because of its toxicity (interstitial nephritis),
Methicillin is not used clinically except to identify
resistant strains of S. aureus.

Methicillin resistant staphylococcus aureus (MRSA)

-currently a source of serious community and
nosocomial infections. This organism is usually
susceptible to vancomycin.
 Extended-spectrum Penicillins
1. Ampicillin
2. Amoxicillin

- have an antibacterial spectrum similar to that of

penicillin G but are more effective against
gram-negative bacilli
- remains susceptible to penicillinases
- Clinical use: indication is similar to Pen G as well as
Listeria monocytogenes, E. coli, Proteus mirabilis,
Haemophilus influenzae & Moraxella catarrhalis
1. Ampicillin
-DOC for Listeria monocytogenes
2. Amoxicillin
-commonly used for prophylaxis

• Clavulanic acid & Sulbactam

– β-lactamase inhibitor
Preparation:
Ampicillin + Sulbactam (Unasyn)
Amoxicillin + clavulanic acid (Augmentin)
 Antipseudomonal penicillins

1. Carbenicillin
2. Ticarcillin
3. Piperacillin –most potent

- effective against many g- rods, including Pseudomonas

aeruginosa, Enterobacter & in some cases Klebsiella
species

- frequently used in combination with an

aminoglycoside or fluoroquinolone for
pseudomonal infections outside the urinary tract.
Preparations:
Piperacillin + Tazobactam (Piptaz)
Ticarcillin + clavulanic acid (Timentin)
 Adverse Reactions

Generally well tolerated, and unfortunately, this

encourages their misuse and inappropriate use.
• Hypersensitivity - includes urticaria, severe pruritus,
fever, joint swelling, hemolytic anemia, nephritis and
anaphylaxis.
Antigenic determinants include degradation product
of penicillins such as penicilloic acid.
Complete cross-allergenicity between different
penicillins should be assumed
• Gastrointestinal disturbances - Nausea & Diarrhea,
GI upsets
 CEPHALOSPORINS

• Cephalosporins are similar to penicillins, but more

stable to many bacterial β lactamases due to
structure differences and therefore have a broader
spectrum of activity.

• not active against enterococci & L. monocytogenes.

• Mainly excreted in urine except for Cefoperazone

and Ceftriaxone that are excreted mainly in the bile.
 Mechanism of Action and Resistance

• Mechanism of action is similar to those of the

penicillins

• Resistance can also result from decreases in

membrane permeability to cephalosporins and from
changes in PBPs

• Methicillin-resistant staphylococci are also resistant

to cephalosporins
 Generations of Cephalosporins

Beta-lactamase
Gen. Members Gram + Gram - stability

1st Cephalexin, Cefazolin +++ +/- easily hydrolyzed

cefotetan, cefoxitin,
2nd cefamandole, cefuroxime, ++ + +
cefaclor

ceftazidime, cefoperazone,
3rd cefotaxime + ++ ++

4th Cefepime, Cefpirome +/- +++ +++

5th Ceftaroline, Ceftobiprole

 Adverse Reaction

• hypersensitivity reactions that are identical to those

of penicillins
• Cross sensitivity is assumed
• May cause pain at intramuscular injection sites and
phlebitis
• may increase the nephrotoxicity of aminoglycosides
• Drugs containing a methylthiotetrazole group (eg,
cefamandole, cefoperazone, cefotetan) may cause
hypoprothrombinemia and disulfiram-like reactions
with ethanol.
 OTHER BETA-LACTAM DRUGS

Aztreonam
- a monobactam that is resistant to beta-lactamases
produced by certain gram (-) rods
- no activity against Gram (+) bacteria & anaerobes

Mechanism of action:
- preferentially binding to a specific penicillin-binding
protein (PBP3)

- synergistic with aminoglycosides

 OTHER BETA-LACTAM DRUGS

• Administered intravenously and is eliminated via

renal tubular secretion
• Adverse effects:
gastrointestinal upset with possible superinfection,
vertigo and headache, and rarely hepatotoxicity
• No cross-allergenicity with penicillins
 OTHER BETA-LACTAM DRUGS

Carbapenems
Imipenem (1st drug in this class)
Doripenem
Meropenem
Ertapenem

- chemically different from PCNs but retains the beta-

lactam ring with low susceptibility to beta-
lactamases
- wide activity against gram (+) cocci, gram (-) rods, and
anaerobes
- active against P aeruginosa and Acinetobacter species
except for Ertapenem
- For pseudomonal infections, they are often used in
combination with an aminoglycoside
- Co-drugs of choice for infections caused by
Enterobacter, Citrobacter, and Serratia species
- Imipenem is rapidly inactivated by renal
dehydropeptidase I and is administered in fixed
combination with cilastatin, an inhibitor of this
enzyme.
- other carbapenems are not significantly degraded by
the kidney
Adverse reactions
• Imipenem-cilastatin include gastrointestinal distress,
skin rash, and, at very high plasma levels, CNS
toxicity
• Partial cross-allergenicity with the penicillins
Beta-lactamase inhibitors
Clavulanic acid
Sulbactam
Tazobactam
- used in fixed combinations with certain hydrolyzable
penicillins

- most active against plasmid-encoded beta-lactamases

produced by;
gonococci, streptococci, E coli, and H influenzae
Vancomycin
- prevents elongation of the peptidoglycan chain and
interferes with crosslinking

- narrow spectrum of activity and is used for serious

infections caused by drug-resistant gram-positive
organisms

- backup drug for treatment of infections caused by

Clostridium difficile
Administration:
Oral
- not absorbed in the GI
- given for bacterial enterocolitis

Parenteral
- penetrates most tissues
- eliminated unchanged in the urine
 Adverse Reaction

• chills
• fever
• phlebitis
• ototoxicity
• nephrotoxicity (needs dose adjustments)
• Rapid intravenous infusion may cause diffuse
flushing from histamine release
(“red man syndrome”)
 Quiz #2

Penicillins Cephalosporins Carbapenems Tetracyclines

Beta-
Beta-lactam Beta-lactam Beta-
lactamase
antibiotics ring lactamase
inhibitor
PBP Transpeptidase Pen G Pen V
Anti-
Penicilloic
Vancomycin Aztreonam staphylococcal
acid
antibiotics
Clavulanic
1st Gen 5th Gen Sulbactam
acid
 PROTEIN
SYNTHESIS
INHIBITORS
 Tetracyclines

Tetracycline, Doxycycline, Minocycline, Tigecycline

• broad-spectrum bacteriostatic antibiotics with
activity against:
gram (+)
gram (-) bacteria
species of Rickettsia
Chlamydia
Mycoplasma
some protozoa
 Clinical uses:

Primary uses
Mycoplasma pneumoniae (in adults), chlamydiae,
rickettsiae, vibrios, and some spirochetes
Secondary uses
Alternative drugs for syphilis, tx for respiratory
infections, leptospirosis & acne
Selective uses
Tetracycline - tx for GI ulcers caused by H. pylori
Doxycycline - tx for Lyme disease & amebiasis,
prevention of malaria
Minocycline - meningococcal carrier state
Demeclocycline - inhibits the renal actions of
antidiuretic hormone (ADH) and is used in the
management of patients with ADH secreting tumors

Tigecycline (IV only)

• Organisms resistant to standard tetracyclines
• Methicillin resistant gram (+) cocci (MRSA strains)
• Vancomycin (VRE strains)
• Beta-lactamase–producing gram-negative bacteria
• anaerobes, chlamydiae, and mycobacteria.
Adverse Reactions
 Adverse Reactions

• Gastrointestinal disturbances
From mild nausea and diarrhea to severe, possibly
life-threatening enterocolitis. Disturbances in the
normal flora.
• Bony structures and teeth
Fetal exposure causes tooth enamel dysplasia and
irregularities in bone growth.
In younger children may cause enamel dysplasia and
crown deformation when permanent teeth appear.
• Hepatic toxicity
High doses of tetracyclines may impair liver function
and lead to hepatic necrosis.
• Renal toxicity
One form of renal tubular acidosis, Fanconi’s
syndrome, has been attributed to the use of
outdated tetracyclines.

• Photosensitivity
Especially demeclocycline, may cause enhanced skin
sensitivity to UV light.

• Vestibular toxicity
Dose-dependent reversible dizziness and vertigo
have been reported with doxycycline and
minocycline
 Macrolides

Erythromycin, Azithromycin, and Clarithromycin

• drugs have good oral bioavailability, but azithromycin
absorption is impeded by food
• Erythromycin: active against the same organism as
Pen G
• Azithromycin and clarithromycin: similar to
Erythromycin but include greater activity against
species of Chlamydia, Mycobacterium avium
complex, Toxoplasma, Legionella, & Moraxella
• Complete cross resistance
Clinical use
Adverse reactions
 Ketolide

Telithromycin
- ketolide structurally related to macrolides
- same mechanism of action as erythromycin
- similar spectrum of antimicrobial activity
- some macrolide-resistant strains are susceptible to
telithromycin
 OTHERS

• Chloramphenicol
• Clindamycin – Dalacin C
• Linezolid – Zyvox
• Quinupristin/Dalfopristin - Synercid
 Chloramphenicol

Chloramphenicol
• active against a wide range of G+ and
G- organisms
•bind to the 50S subunit and block
transpeptidation
•SE: Bone marrow toxicity
•Restricted for life-threatening infections
where no alternative exists.
 Spectrum

• Broad spectrum antibiotic

• Active against bacteria, Rickettsia

• Excellent activity against anaerobes

• Both bactericidal and bacteriostatic

 Adverse effects

• Haemolytic anemia
• Gray Baby Syndrome
• Bone marrow depression

INTERACTIONS:
blocks the metabolism of warfarin,
phenytoin, tolbutamide &
chlopropamide = increased effects of
the drugs
 CLINDAMYCIN

CLINDAMYCIN
•Mechanism of action same as erythromycin

•Treatment of infections caused by

anaerobic bacteria- Bacteriodes fragilis
(infections associated with trauma) & MRSA

•Resistance same as erythromycin

SIDE EFFECTS:
Fatal pseudomembraneous colitis
 Quinupristin/Dalfopristin

Quinupristin/Dalfopristin
•Reserved for Vancomycin-resistant
Enterococcus faecium (VRE)
•Active against G+ cocci including those
resistant to other antibiotics,including MRSA
•Primary use treatment of E.faecium
infections + VRE strains
LINEZOLID
 NUCLEIC
ACID
INHIBITORS
 QUINOLONES

• Not recommended for children

• May prolong QT interval, not to be used in
patients with arrhythmias
• Limited therapeutic utility and rapid
development of resistance
• Interfere with absorption
-antacids contg. Al or Mg
-dietary substances contg. Fe or Zn
-Calcium, milk or yogurt
 Newer compounds
• Ciprofloxacin & Ofloxacin
-greater potency
-broader spectrum of antimicrobial
activity
-greater efficacy against resistant
organisms
-active against G- bacilli & cocci,
mycobacteria, mycoplasmas & Rickettsia
-Some cases better safety profile than
older quinolones
 Respiratory Quinolones

• Levofloxacin & Moxifloxacin

-active against G+, typical, atypical &
anaerobic pathogens
 CELL
MEMBRANE
INHIBITORS
 SULFONAMIDES
SULFONAMIDES
-seldom prescribed on their own
-resistance limits spectrum of
antimicrobial activity
AE: Nephrotoxicity
Hypersensitivity
Hemopoetic disturbances
Kernicterus
Displaces warfarin & Methotrexate from
binding sites
Sulfamethoxazole + Trimethoprim (Cotrimoxazole)

USES:
Pneumocystis jiroveci pneumonia
-common opportunistic infection complicating
AIDS. Cotrimoxazole is the most effective
therapy.
ANTIMYCOBACTERIAL
S
Drugs used to treat tuberculosis
•Rifamycins
•Isoniazid (INH)
•Pyrazinamide
•Ethambutol
Rifampin
AE: Hepatitis, GI upset, rash, flu-like
syndrome

Isoniazid
AE: Hepatic enzyme elevation,
Hepatitis, peripheral neuropathy
Pyrazinamide
AE: Nausea, hepatitis, hyperuricemia,
rash, joint ache, gout (rare)

Ethambutol
AE: Optic neuritis w/ blurred vision, red-
green color blindness