Download ANTIMICROBIAL DRUGS

β-Lactam antibiotics
Antimicrobial Drugs
 As a class, they are one of the most frequently used as well as
misused drugs.
 Drugs in this class differ from all others in that they are
designed to inhibit/kill the infecting organism and to have
no/minimal effect on the recipient.
 This type of therapy is generally called chemotherapy.
 Chemotherapy is a treatment of systemic infections with
specific drugs that selectively suppress the infecting
microorganism without significantly affecting the host.
 Due to analogy between the malignant cell and the pathogenic
microbes, treatment of neoplastic diseases with drugs is also
called ‘chemotherapy’.
General Considerations
Antibiotics
 These are substances produced by microorganisms,
which selectively suppress the growth of or kill other
microorganisms at very low concentrations.
Chemotherapeutic agent
 Initially this term was restricted to synthetic
compounds, but now since many antibiotics and their
analogues have been synthesized, this criterion has
become irrelevant;
Antimicrobial agent (AMA)
 includes synthetic as well as naturally obtained drugs
that attenuate microorganisms.
PROBLEMS THAT ARISE WITH
THE USE OF AMAs
 Toxicity
 Hypersensitivity reactions
 Drug resistance (Natural / Acquired resistance )
 Superinfection
 Nutritional deficiencies
 Masking of an infection
Beta-Lactam Antibiotics
These are antibiotics having a β-lactam ring.
 Penicillins
 Cephalosporins
 Monobactams
 Carbapenems
PENICILLINS
 All β-lactam antibiotics inhibit the
synthesis of bacterial cell wall→
bacterial lysis occurs → bactericidal
action
 Rapid cell wall synthesis occurs when the
organisms are actively multiplying; βlactam antibiotics are more lethal in this
phase.
 High sensitivity to the gram-positive
(Gr+) bacteria.
Penicillins
 Natural penicillins
 Semisynthetic penicillins
Natural penicillins
 Benzylpenicillin (penicillin
G, the original penicillin found
in 1928),
 Procaine benzylpenicillin
(procaine penicillin)
 Benzathine benzylpenicillin
(benzathine penicillin)
 Phenoxymethylpenicillin
(penicillin V)
intravenous use
intramuscular use
the same antibacterial activity
as benzylpenicillin but act for
a longer period of time
oral use
Antibacterial spectrum
 Narrow spectrum antibiotics; activity is limited primarily
to GR+ bacteria, few GR- ones and anaerobes.
Cocci:
 Streptococci, pneumococci, etc.
 Staph. Aureus - now absolutely resistant
Gram negative cocci:
 Neisseria gonorrhoeae
Gram-positive bacilli:
 Corynebacterium diphtheriae,
 all Clostridia (tetani and others),
 Listeria
 Spirochetes (Treponema pallidum, Leptospira, and others)
Bacterial resistance
 The primary mechanism of acquired resistance is
production of penicillinase.
 Penicillinase -it is a narrow spectrum β-lactamase which
opens the β-lactam ring and inactivates penicillin.
 Some bacteria become penicillin tolerant and not
penicillin destroying due to acquired low affinity.
 The methicillin-resistant Staph. aureus (MRSA) have
acquired a PBP which has very low affinity for β-lactam
antibiotics.
SEMISYNTHETIC PENICILLINS
CLASSIFICATION
Penicillinase-resistant penicillins (β-lactamase-resistant)
Methicillin
Nafcillin
Oxacillin
Cloxacillin
Dicloxacillin.
Aminopenicillins (broad spectrum penicillins):
 Ampicillin
 Amoxicillin
 Bacampicillin
Carboxypenicillins:
β-lactamase inhibitors :
 Carbenicillin
Clavulanic acid
 Ticarcillin
Sulbactam
Ureidopenicillins:
Tazobactam
 Piperacillin
 Mezlocillin
PENICILLINASE-RESISTANT PENICILLINS
Methicillin, Cloxacillin, Dicloxacillin
 They have side chains that protect the β-lactam ring from attack by penicillinase. However, this
also partially protects the bacteria from the β-lactam ring.
 Their only indication is infections caused by penicillinase
producing Staphylococci, for which they are the drugs of
choice.
 MRSA (methicillin resistant Staph. Aureus) have emerged in many areas.
These are insensitive to all penicillins and to other βlactams as well as to erythromycin, aminoglycosides,
tetracyclines, etc.
Broad spectrum penicillins
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Ampicillin, Amoxicillin
None is resistant to penicillinase or to other βlactamases.
These semisynthetic penicillins are active against a
variety of :
Gr- bacilli- H. influenzae, E. coli, Proteus, Salmonella,
Shigella and Helicobacter pylori
Gr+- as natural penicillins
Carboxypenicillins
Carbenicillin,Ticarcillin
 The special feature of this group is its activity against
Pseudomonas aeruginosa.
 P. aeruginosa has association with serious illnesses – especially nosocomial
infections such as ventilator-associated pneumonia and various sepsis
syndromes.
 The indications for carbenicillin are—serious
infections caused by Pseudomonas, e.g. burns, urinary
tract infection, septicaemia.
Ureidopenicillins
Piperacillin, Mezlocillin
 This antipseudomonal penicillins is about 8 times more
active than carbenicillin.
 It is frequently employed for treating serious
pseudomonal infections in
neutropenic/immunocompromised or burn patients.
Uses
 1. Streptococcal infections like bronchitis, sinusitis,
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pharyngitis, otitis media, scarlet fever, rheumatic
fever, urinary tract infections,
2. Pneumococcal infections for empirical therapy
of pneumococcal (lobar) pneumonia and
meningitis
3. Meningococcal infections are still mostly
responsive; meningitis and other infections may
be treated with intravenous injection of high
doses.
4. Gonorrhoea
5. Syphilis- T. pallidum has not shown any
resistance and penicillin is the drug of choice.
6. Diphtheria (Antitoxin therapy is of prime
importance).
7. Tetanus and gas gangrene (Antitoxin and other
measures are more important; adjuvant value.)
8. Penicillin is the drug of choice for rare infections
like anthrax, actinomycosis, rat bite fever and
those caused by Listeria monocytogenes,
Pasteurella multocida.
Adverse effects
Penicillin is one of the most nontoxic antibiotics.
 Hypersensitivity/ anaphylaxis
 Allergy
 Diarrhoea
BETA-LACTAMASE INHIBITORS
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Clavulanic acid, sulbactam,tazobactam
β-lactamases are a family of enzymes produced by
many gram-positive and gram-negative bacteria that
inactivate β-lactam antibiotics by opening the βlactam ring.
AUGMENTIN: Amoxicillin + clavulanic acid
UNASYN: Ampicillin + sulbactam
Piperacillin + tazobactam
CEPHALOSPORINS
 All cephalosporins are bactericidal and have the same
mechanism of action as penicillin, i.e. inhibition of
bacterial cell wall synthesis.
 They are divided into 5 generations. This division has a
chronological sequence of development, but more
importantly, takes into consideration the overall
antibacterial spectrum as well as potency.
CEPHALOSPORINS
 1st Generation
Parenteral
Cefazolin
 2nd Generation
Parenteral
Cefuroxime
Cefoxitin
Oral
Cephalexin
Cefadroxil
Oral
Cefaclor
Cefuroxime axetil
Cefprozil
 3rd Generation
 Cefixime,
 Ceftriaxone,
 Ceftazidime,
 Cefoperazone,
 Cefotaxime
 4th Generation (Pseudomonas)
 Cefepime
 Cefpirome
 5th Generation
 Ceftaroline
 Ceftolozane
Generations
1st Gen- high activity against Gr+ bacteria.
2nd Gen-These are more active against Gr- organisms,. They
are weaker than the 1st generation against Gr+bacteria.
 Don’t inhibit P. aeruginosa
3rd Gen – high activity against Gr-.
 Inhibit Pseudomonas.
4th Gen- high activity against Gr-.
 against Gr+bacteria (weaker than the 1st generation)
 High activity against Pseudomonas aeruginosa
 Is indicated for the treatment of serious and resistant hospital-acquired infections
including septicaemias, lower respiratory tract infections, etc.
5th Gen- powerful antipseudomonal characteristics and
appears to be less susceptible to development of resistance.
The first cephalosporin with antimicrobial activity against
MRSA.
Uses
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They cover a wide range of Gr+ and Gr- (but not MRSA) → one of the most commonly used antibiotics.
 1. As alternatives to penicillins (1st gen ).
 2. Respiratory, urinary and soft tissue infections caused by Gr
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organisms(2nd gen)
3. Penicillinase producing staphylococcal infections (3-5th gen).
4. Septicaemias
5. Surgical prophylaxis
6. Meningitis
7. Gonorrhoea
8. Hospital acquired infections, especially respiratory and other
infections in intensive care units, resistant to commonly used
antibiotics (3rd or 4th gen)
9. Prophylaxis and treatment of infections in neutropenic
patients(3rd gen).
Adverse effects
 Diarrhoea
 Hypersensitivity reactions
 Nephrotoxicity
 Neutropenia and
thrombocytopenia
 Pain after i.m. injection
 Thrombophlebitis of
injected vein
MONOBACTAMS
Aztreonam
 Spectrum: Only against aerobic Gr- bacteria (e.g.,
Neisseria, Pseudomonas )
 Reserve drug
 The main indications of aztreonam are hospital-
nosocomial infections originating from urinary, biliary,
gastrointestinal and female genital tracts.
 Adverse effects: skin rash
CARBAPENEMS
Imipenem, Meropenem
 Spectrum: Gr+,Gr-, anaerobes
 Inhibit Pseudomonas
 Reserve drug for the treatment of serious nosocomial
respiratory, urinary, abdominal, pelvic, skin and soft
tissue infections
 ADR: hypersensitivity reactions
TETRACYCLINES
 Tetracyclines inhibite practically all types of pathogenic microorganisms → name ‘broadspectrum antibiotic’.
 Classification:
- natural (tetracycline);
- semisynthetic (doxycycline).
In world practice for the systemic action is used primarily doxycycline.
 Mechanism of action: inhibition of bacterial protein synthesis by interfering with ribosomes
of bacteria
 Action: bacteriostatic
 Activity: as drugs with a broad spectrum of antimicrobial activity, but in the process of their
long-term use, many bacteria have acquired resistance to them.
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Gr+ flora: Streptococcus pneumoniae, but resistant to tetracycline, many strains of S. pyogenes, and
nosocomial strains of staphylococci and most enterococci.
Gr - flora: the meningococcus and M. catarrhalis; many gonococci are resistant. Tetracyclines are also active
against Listeria monocytogenes, H. influenzae, Yersinia (including Yersinia pestis), Campylobacter
(including H. pylori), Brucella, bartonellas, vibrios (including cholera), agents of inguinal granuloma,
anthrax, tularemia, spirochetes, Leptospira, Borrelia (including the causative agents of Lyme disease),
Rickettsia (including pathogens I spotted fever of the Rocky mountains. and of typhus), chlamydia,
Mycoplasma (including the causative agents of atypical pneumonia), actinomyces, Clostridium (except C.
difficile), fuzobakterii, P. acnes, Entamoeba histolytica. Most strains of E. coli, Salmonella, Shigella,
Klebsiella, Enterobacter bacteroids sustainable.
 Specific adverse reactions: tooth/ bones damage(because of the affinity to Ca2+ and
formation of complexes, which leads to demineralization of bone tissue).
Adverse effects:
 Teeth and bones
 Tetracyclines are deposited in developing teeth and bones →
brown discolouration, ill-formed teeth which are more
susceptible to caries.
 Tetracyclines given between 3 months and 6 years of age affect
the crown of permanent anterior dentition.
 Suppression of bone growth + deformities +reduction in
height
 Tetracyclines should not be used during pregnancy, lactation
and in children.
 Irritative effects (epigastric pain, nausea,vomiting and
diarrhoea)
 Hepatotoxicity
 Phototoxicity
Uses
Tetracyclines are the first choice drugs:
 Venereal diseases:
 Chlamydial nonspecific urethritis/endocervicitis
 Lymphogranuloma venereum
 Granuloma inguinale.
 Atypical pneumonia
 Cholera
 Brucellosis
 Plague: Tetracyclines are highly effective in both bubonic and
pneumonic plague. They are preferred for blind/mass treatment
of suspected cases during an epidemic.
 Relapsing fever: due to Borrelia
 Rickettsial infections: typhus, rocky mountain spotted fever, Q
fever, etc. respond dramatically.
 Anthrax
AMPHENICOLS
Chloramphenicol
 Mechanism of action: inhibition of bacterial protein synthesis by interfering with
ribosomes of bacteria
 Action: bacteriostatic
 Activity: broad spectrum of antimicrobial activity, but in the process of long use,
many bacteria have become resistant. The level of resistance to it in economically
developed countries is quite good, because for a long time strictly limited to the
application.
 Among Gr+ flora most sensitive to the drug pneumococcus, (stable penicillin-resistant strains), H.
influenzae (including ampicillinresistant strains), E. coli, Salmonella, Shigella, diphtheria, anthrax,
brucellosis, plague. Enterococci are not sensitive. From G - flora most sensitive meningococci.
The drug has a high activity against spore-forming and asporogenous anaerobes, including B.
fragilis.
 Uses: In all developed countries, their use is strictly limited, mainly meningitis or
some other life-threatening infections (e.g., salmonellosis, rickettsial), resistant to
other drugs.
 SIDE EFFECTS: aplastic anemia, bone marrow depression and other disorders of
hematopoiesis, pancytopenia, “gray baby syndrome”.
Gray baby syndrome
 The baby stopped feeding, vomited, became hypotonic
and hypothermic, abdomen distended, respiration
became irregular; cyanosis (gray body) developed in
many, followed by cardiovascular collapse and death.
 It occurs because of inability of the newborn to
adequately metabolize and excrete chloramphenicol.
 Chloramphenicol blocks electron transport in the liver,
myocardium and skeletal muscle, resulting in the
above symptoms.
MACROLIDE ANTIBIOTICS
 Macrolides and azalides - first place in the application and importance in serious nosocomial
infections.
 Azithromycin is the most widely used antibiotic in the world.
 Classification
- with 14 – membered ring: erythromycin, clarithromycin, roxithromycin;
- with 15 - membered ring (azalides): azithromycin;
- with 16 - membered ring: spiramycin, josamycin.
 Mechanism of action: inhibition of bacterial protein synthesis by interfering with ribosomes
of bacteria
 Action: bacteriostatic (azithromycin taken in high doses, has a bactericidal effect;
clarithromycin has bactericidal effect on Helicobacter pylori)
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Activity:
Gr- flora: Neisseria, Bordetella pertussis, Legionella, Helicobacter pylori, Haemophilus;
Gr+ flora Str. pyogenes, Str.pneumoniae, Str.faecalis.
Also effective against Chlamydia, Mycoplasma, Ureaplasma. It is very important that
they act on intracellular organisms.
 Specific adverse reactions: dyspepsia reactions, QT prolongation, hepatotoxicity (more
common in erythromycin)
As a first choice drug for:
1. Atypical pneumonia caused by Mycoplasma, Chlamydia, Ureaplasma
2. Whooping cough
LINCOSAMIDE ANTIBIOTICS
Lincomycin, Clindamycin
 Mechanism of action: inhibition of bacterial protein
synthesis by interfering with ribosomes of bacteria
Action: bacteriostatic
Activity:
 Anaerobes: Bacteroides (B. fragilis);
 Gr+ flora: staphylococci, Bacillus anthracis,
Corynebacterium diphtheriae.
Side effects :
 diarrhoea and pseudomembranous enterocolitis due to
Clostridium difficile superinfection which is potentially fatal.
The drug should be promptly stopped and oral metronidazole
or vancomycin given to treat it.
GLYCOPEPTIDE ANTIBIOTICS
Vancomycin
 Mechanism of action: inhibition of cell wall synthesis
 Action: bactericidal
 Activity: very Gr+ (aerobic+anaerobic) Staphylococcus spp. Streptococcus spp., Enterococcus
spp. Clostridium difficile.
 !!!Reserve drugs for the treatment of infections caused by staphylococci (including
MRSA, MRSE)!!!!
 To treat antibiotic- related pseudomembranous enterocolitis and diarrhoea
 Specific adverse reactions:
 nephrotoxicity,
 ototoxicity,
 Red man syndrome (red neck syndrome)- Rapid i.v. injection has caused chills, fever,
urticaria and intense flushing.
 Note: In concomitant use with Amphotericin b, Aminoglycosides, Colistimethate sodium –
increased risk of development and severity of nephrotoxicity, ototoxicity.
 The use with furosemide - increased risk of ototoxicity ( for all – OTO - and nephro-toxicity).
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Aminoglycosides
 Mechanism of action :They act by interfering with
bacterial protein synthesis.
 Action: All are bactericidal
 Activity: All are active against aerobic Gr- bacilli and
do not inhibit anaerobes.
 All exhibit ototoxicity and nephrotoxicity.
 With cephalosporins may increase the risk of development and severity of
nephrotoxicity.
 With Amphotericin b, Vancomycin, Colistimethate sodium – increased risk of
nephrotoxicity, ototoxicity.
 With furosemide– increased risk of the ototoxic actions.
Aminoglycosides
Classification
I Generation : Streptomycin, Kanamycin, Neomycin
 Mostly Gr - aerobic flora: Enterobacteriaceae, including Escherichia coli, Klebsiella
spp., Salmonella spp. Shigella spp. Proteus spp. Serratia spp. Enterobacter spp.
 Active against M. tuberculosis (streptomycin - the drug of 1st line, kanamycin – 2nd
line drug for the treatment of tuberculosis) and some atypical mycobacteria.
 NO effect on Pseudomonas aeruginosa.
II Generation : Gentamicin
 Gr - aerobic flora,
 Active against P. aeruginosa (but at present, many strains are resistant)
 No effect on M. tuberculosis.
III Generation : Amikacin, Netilmicin, Tobramycin
 Gr - aerobic flora
 Active against Pseudomonas aeruginosa.
 A reserve antibiotic in case of resistance to therapy with gentamicin
IV Generation : Isepamicin
 Gr - that are resistant to other aminoglycosides
Uses
 Tuberculosis (only 1st gen)
 Bacterial endocarditis
 Plague
 Tularemia
 Peritonitis
 Septicaemias
OXAZOLIDINONES
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Linezolid
Mechanism of action: inhibition of bacterial protein
synthesis by interfering with ribosomes of bacteria
Action: bactericidal against streptococci, C. perfringens,
B. fragilis; bacteriostatic against staphylococci and
enterococci.
Activity: Gr+ flora: streptococci, enterococci (including
VRE), staphylococci (including MRSA and MRSE)
For treatment of MRSA or VRE infections
Specific adverse reactions: depression of bone
marrow function, thrombocytopenia, peripheral
neuropathy, lactic acidosis
POLYPEPTIDE ANTIBIOTICS
 All are powerful bactericidal agents, but not used
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systemically due to toxicity.
Mechanism of action: violation of the integrity of
microbial cell membrane
Action: bactericidal
Against Gr- bacteria only
Polymyxin B: a Very toxic drug (nephrotoxicity,
neurotoxicity), however, highly effective for the treatment
of diseases caused by Pseudomonas aeruginosa → reserve
drug.
Colistin (polymyxin E). Practically not absorbed in the
intestine, and therefore is used for selective intestinal
decontamination of sensitive microorganisms
Rifamycins
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Rifampicin, Rifabutin
Mechanism of action: disrupts synthesis of RNA in bacterial
cells(inhibits the transcription of RNA). Human RNA does not
act.
Action: bactericidal
Activity: Mycobacterium tuberculosis (rifampicin – a 1st line,
rifabutin – 2nd line)
Rifampicin is also effective for Brucella spp. Chlamydia
trachomatis, Legionella pneumophila, Rickettsia typhi,
Mycobacterium leprae, Staph. spp. Str. spp. Clostridium spp.
Bacillus anthracis, Neisseria meningitidis, Neisseria
gonorrhoeae and Gr - flora.
Specific adverse reactions: hepatotoxicity
note: Due to the rapid development of resistance, drug’s usage
should be limited to tuberculosis.
MRSA
The drug of choice:
 Vancomycin
Also could be used:
 Linezolid
 Ceftaroline
 Doxycycline
 Clindamycin (for osteomyelitis)