postgraduate

1. Dr. ihsan edan alsaimary
Dept. microbiology – college of medicine – university of basrah - IRAQ

2. Antimicrobial Chemotherapy
 Use of drugs to combat infectious agents
 Antibacterial
 Antiviral
 Antifungal
 Antiparasitic

3. Antimicrobial Chemotherapy
 Differential toxicity: based on the concept that the
drug is more toxic to the infecting organism than to
the host
 Majority of antibiotics are based on naturally
occurring compounds
 or may be semi-synthetic or synthetic

4. What is the ideal antibiotic
 Have the appropriate spectrum of activity for the clinical
setting.
 Have no toxicity to the host, be well tolerated.
 Low propensity for development of resistance.
 Not induce hypersensitivies in the host.
 Have rapid and extensive tissue distribution
 Have a relatively long half-life.
 Be free of interactions with other drugs.
 Be convenient for administration.
 Be relatively inexpensive

5. Principles / Definitions
 Spectrum of Activity:
Narrow spectrum - drug is effective against a limited
number of species
Broad spectrum - drug is effective against a wide
variety of species
 Gram negative agent
Gram positive agent
Anti-anaerobic activity

6. Principles / Definitions
 Minimum Inhibitory Concentration (MIC)
- minimum concentration of antibiotic required to inhibit the
growth of the test organism.
 Minimum Bactericidal Concentration (MBC)
- minimum concentration of antibiotic required to kill the test
organism.
 Bacteriostatic
 Bactericidal
 Time dependent killing
 Concentration dependent killing

7. Principles / Definitions
 Treatment vs prophylaxis
 Prophylaxis - antimicrobial agents are
administered to prevent infection
 Treatment - antimicrobial agents are administered
to cure existing or suspected infection

8. Combination Therapy
 To prevent the emergence of resistance
- M.tuberculosis
 To treat polymicrobial infections
 Initial empiric therapy
 Synergy
 Why not use 2 antibiotics all the time?
 Antagonism
 Cost
 Increased risk of side effects
 May actually enhance development of resistance
inducible resistance
 Interactions between drugs of different classes
 Often unnecessary for maximal efficacy

9. What influences the choice of antibiotic?
 Activity of agent against proven or suspected organism
 Site of infection
 Mode of administration
 Metabolism and excretion
 renal and hepatic function
 Duration of treatment / frequency of dose
 Toxicity / cost
 Local rates of resistance

10. How do antimicrobial agents work?
 must bind or interfere with an essential
target
 may inhibit or interfere with essential
metabolic process
 may cause irreparable damage to cell

11. Targets of antibacterial agents
 Inhibit cell wall production
- penicillin binding proteins
 Inhibit protein synthesis
- bind 30s or 50s ribosomal subunits
 Inhibit nucleic acid synthesis
- binding topoisomerases / RNA polymerase
 Block biosynthetic pathways
- interfere with folate metabolism
 Disrupt bacterial membranes
- polymixins

12. Antimicrobial resistance
 Resistance: the inability to kill or inhibit
the organism with clinically achievable
drug concentrations
 Resistance may be innate
(naturally resistant)
 Resistance may be acquired
- mutation
- acquisition of foreign DNA

13. Antimicrobial resistance
 Factors which may accelerate the
development of resistance
1- inadequate levels of antibiotics at the
site of infection
2- duration of treatment too short
3- overwhelming numbers of organisms
4- overuse / misuse of antibiotics

14. Antimicrobial resistance
General mechanisms of resistance
1-Altered permeability
2-Inactivation / destruction of antibiotic
3-Altered binding site
4-Novel (new) binding sites
5-Efflux (pumps) mechanisms
6-Bypass of metabolic pathways

15. Antibiotic Classes
 Cell Wall Active Agents
bactericidal, time dependent killing
 B-lactams
- penicillins / cephalosporins /
- cephamycins / carbapenems
 Glycopeptides
- vancomycin / teicoplanin
- gram positive agents

16. Structure of -lactam drugs

17. Penicillins
 Penicillin G / V
- good gram positive (not Staph)
-moderate anaerobic activity
 Synthetic penicillins (Ampicillin)
- good gram positive (not Staph)
- moderate gram negative (not Pseudomonas)
 Anti-staphylococcal penicillins
- Cloxacillin
 Anti-pseudomonal penicillins
- Piperacillin

18. Cell Wall Active Agents
 B-lactams bind to “penicillin binding proteins”
(PBP)
-PBP are essential enzymes involved in cell wall
synthesis
-weakened / distorted cell wall leading to cell lysis
and death
 Glycopeptides bind to the terminal D-ala of
nascent cell wall peptides and prevents cross-
linking of these peptide to form mature
peptidoglycan ( ex ; vancomycin)

19. Vancomycin: Mechanism of Action
 Inhibit peptidoglycan synthesis in bacterial cell wall by
complexing with the D-alanyl-D-alanyl portion of the cell
wall precurser
2L-ala
2D-ala
D-ala-D-ala
UDP-L-ala-D-glu-L-lys
UDP-L-ala-D-glu-L-lys-D-ala-D-ala
pentapeptide--
racemase
ligase (ddl)
adding enzyme
--L-ala-D-glu-L-lys--D-ala-D-ala
vancomycin
-L-ala-D-glu-L-lys-D-ala-D-ala
transglycosidase
-L-ala-D-glu-L-lys-D-ala-D-ala
-L-ala-D-glu-L-lys-D-ala-D-ala
transpeptidase
-L-ala-D-glu-L-lys-D-ala-D-ala
carboxypeptidase

20. Cell Wall Active Agents
 B-lactam resistance
1. Production of a B-lactamase (most common)
2. Altered PBP (S.pneumoniae)
3. Novel PBP (MRSA)
4. Altered permeability
 Glycopeptide resistance
1- primary concern is Enterococcus / S.aureus
2- altered target
3- bacteria substitutes D-lac for D-ala
4- vancomycin can no longer bind

21. Cephalosporins
 History
 Discovered in sewage in Sardinia in
the mid 1940s.
 Cephalosporium sp was recovered
and proved a source of
cephalosporin.
 Subsequently, four generations of
cephalosporins have emerged.

22. Cephalosporins
 1st generation- mainly gram pos, some gram neg
(cefazolin)
2nd generation- weaker gram pos, better gram neg
(cefuroxime)
3rd generation - excellent gram neg, some gram
pos
(ceftriaxone)
4th generation - excellent gram neg, good gram pos
(cefepime)

23. First-Generation Cephalosporins: What
do they cover?
 Cefazolin (Kefzol) and cephalexin (Keflex)
 Activity includes:
○ Methicillin susceptible staphylococci
○ Streptococci excluding enterococci
○ E. coli, Klebsiella sp., and P. mirabilis
○ Many anaerobes excluding B. fragilis

24. Where do you think they should be used?
 Simple mixed aerobic infections.
 In penicillin allergic (not immediate) patients.
 Surgical prophylaxis.
 Convenience drug for S. aureus and
streptococci?

25. What about second generation
cephalosporins?
 Cefuroxime
 Think Haemophilus in
addition to 1st
generation specturm
 A respiratory drug
 Cefoxitin/cefotetan
 1st generation plus-
anaerobes
 A mixed, non-serious
infection surgeon drug
 Think cefazolin/metro
which is what we
would use

26. Third-Generation Cephalosporins
 Cefotaxime, ceftriaxone (IV)
 Enhanced activity against Enterobacteriaceae
 Enhanced activity against streptococci, including
penicillin resistant S. pneumoniae.
 Long half life favors ceftriaxone
 Less diarrhea favors cefotaxime
 Ceftazidime (IV)
 Active against P. aeruginosa.
 Decreased activity against gram positive cocci.

27. Fourth generation cephalosporins
 Cefepime
 Marginal improvements
 Not available at the QE II

28. Carbapenems:
What don’t they get?
 Everything except:
 MRSA and MRSE
 Enterococcus faecium
 Stenotrophomonas maltophilia
 Burkholderia cepacia

29. When to use carbapenems?
 Life threatening polymicrobial infections
 Intra abdominal sepsis in ICU esp nosocomial
in origin
 Gram negative/ nosocomial pneumonia in
intubated patient
 Monotherapy of febrile neutropenia (high
risk patients)

30. What are the beta-lactamase inhibitors?
 Clavulanate (with amoxicillin or ticarcillin)
 Tazobactam (with piperacillin)

31. What additional bugs do they cover?
 S. aureus
 H. influenzae
 Neisseria sp.
 Bacteroides fragilis
 E. coli and Klebsiella
 Not better for Pseudomonas or
Enterobacter

32. Inhibitors of protein
synthesis
 Ribosomes are the site of protein synthesis
 many classes of antibiotics inhibit protein
synthesis by binding to the ribosome
 binding may be reversible or irreversible
 Macrolides, ketolides, lincosamides,
streptogramins
Tetracyclines
Aminoglycosides

33. Inhibitors of protein synthesis
 Macrolides (erythromycin, clarithromycin, azithromycin)
- primarily gram positive, mycoplasma, chlamydia
- bacteriostatic, time dependent killing
 Lincosamides (clindamycin)
- gram positive, anaerobic activity
 Resistance (acquisition of a gene)
- M phenotype: macrolides only
efflux
- MLSB phenotype:
macrolides, lincosamides, streptogramins
target site modification
constitutive, inducible

34. Inhibitors of protein synthesis
 Aminoglycosides: gentamicin, tobramycin,
amikacin
- excellent gram negative, moderate gram positive
- bactericidal, concentration dependent
 Resistance
Primarily due to aminoglycoside modifying
enzymes

35. Inhibitors of nucleic acid synthesis
 Fluoroquinolones (ciprofloxacin, norfloxacin, levofloxacin, moxifloxacin)
- bactericidal, concentration dependent
- bind to 2 essential enzymes required for DNA replication
- DNA gyrase and topoisomerase IV
- gram pos and gram neg
- atypical bacteria, some have anaerobic activity
 Resistance
- altered permeability (porin channels)
- altered target site
- efflux

36. Inhibitors of metabolic pathways
 Trimethoprim/sulfamethoxazole (Septra,
TMP/SMX)
- good gram negative, some gram positive
 -block folic acid synthesis at two different
points
TMP and SMX act synergistically
 Resistance may arise if the organism can
“bypass” the pathway making it redundant

37. Mechanism of action of
TMP-SMX

38. 38
Antibiotic resistance
 Major health challenge
 Due to largely to inappropriate use of antibiotics
in hospitals and the community
 Treating patients with viral infections with antibiotics
(common cold, flu, viral pneumonia, viral
gastroenteritis)
 Using broad spectrum rather than narrow spectrum
antibiotics
 Using new, special antibiotics to treat infections when
an older antibiotic would be effective
 Use of antibiotics to improve growth &
production in animals

39. 39
We are running out of new
classes of antimicrobials
Antimicrobial class Year of launch
 Sulphonamides 1936
 Penicillins 1940
 Tetracyclines 1949
 Chloramphenicol 1949
 Aminoglycosides 1950
 Macrolides 1952
 Glycopeptides 1958
 Streptogramins 1962
 Quinolones 1962
 Oxazolidinones 2001
 Cyclic lipopeptides 2003
 Ketolides 2004
 Glycylcyclines 2005
1969 – US Surgeon General said “It is time to close the book on
infectious diseases.”

40. 40
The resistance
“crisis”
 No new classes of antibiotics in the pipeline
 Some have been retrieved from animal use:
 Streptogramins – SynercidR – to treat multi-drug
resistant Gram-positive infections
○ Concern that resistance already present because of animal use
 Already resistance emerging to newly released
antimicrobials
 Community acquired MRSA an emerging
problem
 Now facing untreatable Gram-positive & Gram-
negative infections

41. 41
MMWR Morb Mortal Wkly Rep 2002;51:565–567
Evolution of drug resistance in
S. aureus
S. aureus Penicillin-resistant
S. aureus
Penicillin Methicillin
1950s 1970s
Methicillin-resistant
S. aureus (MRSA)
Vancomycin-resistant
enterococci (VRE)
Vancomycin
Vancomycin-
intermediate
S. aureus (VISA)
Vancomycin
-resistant
S. aureus (VRSA)
1990s1997
2002

42. 42
Emergence of resistance in Gram-
negative bacteria
 1960s - E coli and its relatives started to emerge
as problems
 These rapidly developed resistance to ampicillin,
early cephalosporins, aminoglycosides
 Multi-drug resistant (MDR) G-ves major problem in
hospitals in 1970s and 1980s
 More antibiotics (aminoglycosides, extended
spectrum -lactamases, -lactam/ -lactamase-
inhibitor combinations, fluoroquinolones) –
situation improved
 2000 - extended spectrum -lactamase producing
Gram-negatives (ESBLs) – untreatable infections

43. 43
What enables a bacterium to
become resistant to an
antibiotic?
 Some organisms are naturally resistant to some classes of
antibiotics (natural or intrinsic resistance)
 Mutation continually occurring in bacterial genomes (all
genomes!)
 Mutation of key genes important to the action of an antimicrobial
can result in resistance in that organism to that antimicrobial
 This resistance may evolve before the organism has been
exposed to that antimicrobial
 So, resistance determinants that have always been present in
bacteria
 Antibiotic producing strains of bacteria (note that resistance
genes have been found in antibiotic preparations …)
 Soil and gut organisms
 Bacterial housekeeping proteins eg efflux pumps

44. 44
How does antibiotic resistance come
about?
 Use of antibiotics selects out the
(low) number of resistant strains –
they multiply – the sensitive strains
die out – the population of bacteria is
resistant …….
 So antibiotic resistant strains of
bacteria emerge under the selection
pressure from use of antibiotics

45. 45
Resistant Strains
Rare
Resistant Strains
Dominant
Antimicrobial
Exposure
Selection for antimicrobial-
resistant Strains
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

46. 46
Types of antibiotic resistance
 Natural resistance - particular microbes are inherently resistant to particular
agents – eg multi-drug efflux pumps in Pseudomonas aeruginosa, aminoglycoside
resistance in strict anaerobes; inability of penicillin G to penetrate Gram-negative
cell wall
 Acquired resistance involves bacteria becoming resistant to a drug that was
previously effective. eg multi-drug resistance in Mycobacterium tuberculosis,
fluoroquinolone resistance in Neisseria gonorrhoeae, methicillin resistance in
Staphylococcus aureus and penicillin resistance in Streptococcus pneumoniae
 Multiple resistance of particular concern
Acquired resistance occurs in response to exposure of bacteria to antibiotics
 Mutational change and resistance passed to progeny
 Horizontal transfer of resistance genes

47. 47
Antibiotic resistance
Examples of natural or intrinsic resistance
 1-Inaccessibility of the target (i.e.
impermeability resistance due to the absence
of an adequate transporter: aminoglycoside
resistance in strict anaerobes)
 2-Multidrug efflux systems: i.e. AcrE in E. coli,
MexB in P. aeruginosa
 3-Drug inactivation: i.e. AmpC
cephalosporinase in Klebsiella

48. 48
Antibiotic resistance
Examples of acquired resistance
 1-Target site modification (i.e. Streptomycin
resistance: mutations in rRNA genes (rpsL), ß-
lactam resistance: change in PBPs (penicillin
binding proteins))
 2-Reduced permeability or uptake
 3-Metabolic by-pass (i.e trimethoprim resistance:
overproduction of DHF (dihydrofolate) reductase
or thi- mutants in S. aureus)
 4-Derepression of multidrug efflux systems

49. 49
Antibiotic resistance
Examples of horizontal transfer of resistance genes
 1-Mobile genetic elements – transposons & plasmids)
 2-Drug inactivation (i.e. aminoglycoside-modifying
enzymes, ß-lactamases, chloramphenicol
acetyltransferase)
 3-Efflux system (i.e. tetracycline efflux)
 4-Target site modification (i.e. methylation in the 23S
component of the 50S ribosomal subunit: Erm
methylases)
 5-Metabolic by-pass (i.e trimethoprim resistance:
resistant DHF reductase)

50. 50
Five strategies of antimicrobial
resistance
1. Antibiotic modification - the bacteria avoids the
antibiotic's deleterious affects by inactivating the antibiotic.
eg : production of B lactamases
2. Prevention of antibiotic entry into the cell - Gram –ve
bacteria - porins are transmembrane proteins that allow
for the diffusion of antibiotics through their highly
impermeable outer membrane. Modification of the porins
can bring about antibiotic resistance,
eg : Pseudomonas aeruginosa resistance to imipenem.
3. Active efflux of antibiotic - Bacteria can actively pump
out the antibiotic from the cell.
eg : energy dependent efflux of tetracyclines widely seen
in Enterobacteriaceae.

51. 51
Five strategies of antimicrobial
resistance
4. Alteration of drug target - Bacteria can also evade
antibiotic action through the alteration of the compound's
target.
eg : Streptococcus pneumoniae modified penicillin-
binding protein (PBP) which renders them resistant to
penicillins.
5. Bypassing drug's action - bacteria can bypass the
deleterious effect of the drug while not stopping the
production of the original sensitive target.
eg : alternative PBP produced by MRSA in addition to the
normal PBP;
sulfonamide-resistant bacteria that have become able to
use environmental folic acid like mammalian cells, and in
this way bypass the sulfonamide inhibition of folic acid
synthesis.

52. 52
Resistant mechanisms against the
major classes of antibiotics
antibiotics Mechanism of action Major resistance
mechanisms
-lactams Inactivate PBPs
(peptidoglycan
synthesis)
•-lactamases
•Low affinity PBPs
•Decreased transport
Glycopeptides Bind to precursor of
peptidoglycan
•Modification of
precursor
Aminoglycosides Inhibit protein synthesis
(bind to 30S subunit)
•Modifying enzymes
(add adenyl or PO4)
Macrolides Inhibit protein synthesis
(bind to 50S subunit)
•Methylation of rRNA
•Efflux pumps
Quinolones Inhibit topoisomerases
(DNA synthesis)
•Altered target enzyme
•Efflux pumps

53. 53
Mosaic PBP Genes in penicillin-resistant
Strep pneumoniae
 Resistance is due to alterations in endogenous PBPs
 Resistant PBP genes exhibit 20-30% divergence from sensitive
isolates (Science 1994;264:388-393)
 DNA from related streptococci taken up and incorporated into S.
pneumoniae genes
Czechoslovakia (1987)
USA (1983)
South Africa (1978)
S SXN
= pen-sensitive S. pneumoniae = Streptococcus ?
PBP 2B
http://www.uhmc.sunysb.edu/microbiology/35
Target modification

54. 54
vanR vanYvanS vanH vanA vanX vanZ
Vancomycin resistance gene sequence
Detects
glycopeptide;
switches on other genes
Cleaves
D-Ala-D-Ala
Produces D-Lac *Cleaves
D-Ala and
D-Lac from
Produces
D-Ala-D-Lac
Exact role?
Teicoplanin
resistance?
Resistance to vancomycin
 Seven-step gene co-operation
 Involves activity of resolvase, transposase and ligase
enzymes
 Alters pentapeptide precursor end sequence from
D-alanyl-D-alanine to D-alanyl-D-x, where x is lactate, serine
or other amino acid
 Or produces (vanY) tetrapeptide* that cannot bind
vancomycin
Target modification

55. 55
Action of -lactamase
Enzyme modification of the antibiotic

56. 56
Examples of -lactamases
Group of
enzyme
Preferred substrate Inhibited
by
clavulanat
e
Representative
enzymes
1 cephalosporin - AmpC (G-ves)
2a penicillins + Penicillinases from
G+ves
2b Penicillins,
cephalosporins
+ TEM-1, TEM-2, SHV-
1 (G-ves)*
2be Penicillins,
cephalosporins,
monobactams
+ TEM-3 to TEM 26
2br penicillins +/- TEM-30 to TEM-36
2c Penicillins,
carbenicillin
+ PSE-1, PSE-3, PSE-
4
*Plasmid encoded (TEM, PSE, OXA, SHV)

57. 57
Enzyme modification of
antibiotics
Inactivation of aminoglycosides
Chemical inactivation
 1- performed by enzymes produced by the
bacteria
 2- three distinct classes based upon the
reactions that they catalyse:
(i) acetyltransferases which acetylate amino
groups on the aminoglycoside;
(ii) nucleotidyltransferases which transfer a
nucleotide moiety onto the drug, and
(iii) phosphotransferases which phosphorylate
one or more hydroxyl groups on the antibiotic.

58. 58
Multi-drug Efflux Pumps
Bacteria use ATP-powered membrane proteins to pump
foreign molecules out of the cell
- common in antibiotic-producing bacteria, to get substances out
of their cells without poisoning themselves
Powerful method of resistance, because many different drugs
will be equally affected by these efflux pumps
Examples: tetracyclines, macrolides, quinolones

59. 59
Many pathogens possess multiple
mechanisms of antibacterial resistance
+–Quinolones
–++Trimethoprim
–++Sulphonamide
++Macrolide
+–Chloramphenicol
+–Tetracycline
+++–Aminoglycoside
+Glycopeptide
++++-lactam
Modified target Altered uptake Drug inactivation

60. 60
Transfer of antibiotic
resistance (horizontal
transfer of DNA)
 Transformation
 Conjugation
 Transduction
 Of these conjugation is the most
important
 R plasmids
 Transposons & integrons

61. 61
Plasmid carrying transposons
&
antibiotic-resistance genes
•From S. N. Cohen and J. A Shapiro, “Transposable Genetic Elements.” Copyright © 1980 by Scientific American, Inc.

62. 62
Examples of transposons carrying
antibiotic resistance genes.
Ref : http://www.uhmc.sunysb.edu/microbiology/12
Tn5397
Ref : http://www.eastman.ucl.ac.uk/~microb/gene_transfer.html

63. 63
Class 1 integron

64. 64
Multi-resistance
 Multiresistance gene
cluster on the
chromosome of
Salmonella typhimurium
DT 104
Ref :
http://www.irishscientist.ie/2001

65. 65
Examples of major antibiotic resistance
problems
Hospital
 Methicillin resistant Staphylococcus aureus
(MRSA) – hospital and community acquired
 Vancomycin resistant enterococci (VRE)
 Multi-resistant Gram-negative bacteria (eg
Acinetobacter baumannii, many others
Community
 Community acquired MRSA
 Penicillin-resistant Streptococcus pneumoniae
 Multi-drug resistant Mycobacterium tuberculosis

66. Antibiotic resistance in food-
borne organisms
Salmonella, Shigella,
Campylobacter,
Enterococcus spp, multi-
drug resistant E coli (and
salmonella)

67. 67
Strategies to reduce antibiotic
resistance
1. Hospitals
 1-Improved infection control
 2-Implement and enforce hospital policies
for prescribing antibiotics
 Monitor antibiotic use
 3-Use narrow spectrum antibiotics where
possible
 4-Combined therapy where appropriate
 5-Monitoring and surveillance of antibiotic
resistance patterns
 6-Vaccines where available

68. 68
Strategies to reduce antibiotic
resistance
2. Community
 1-Education of doctors and patients
 eg : no antibiotics for simple viral infections
 2-Vaccines where possible – Haemophilus
influenzae type b (Hib), Streptococcus
pneumoniae (pneumococcus)
 3-Combined therapy for TB
 4-Research - eg : to understand the
epidemiology of community acquired MRSA

69. Strategies to reduce antibiotic
resistance
3. Food borne infections
 1-Reduce prevalence of salmonella, campylobacter on
farms
 2-Reduce contamination of carcasses with faecal
material (salmonella, campylobacter, enterococci)
 3-Reduce post-processing contamination (salmonella)
 4-Reduce contamination of fresh produce (salmonella)
 5-Improved hygiene in food handling and preparation in
home and in community (salmonella, shigella,
campylobacter)
 6-Reduce antibiotic use on farms

70. 70
Common misuses of
antibiotics
1. the patient does not have an infection
2. the infection does not respond to antibiotics - eg viral
infections
3. the latest "wonder drug" is used when an older product
would be effective
protecting the new product for situations where it is really
needed
4. the patient "prescribes" for him/herself - using antibiotics
left over from a previous illness
5. in countries with poor health care services antibiotics
are sold without prescription
6. use of antibiotics for non-therapeutic purposes – eg
growth promotion or improved production in livestock

71. Alternatives to antibiotics
 Probiotics, prebiotics & competitive exclusion
organisms
 Reduce pathogenic microorganisms in animal GIT
 Bacteriophages
 Potential to use to control campylobacter, salmonella
 Natural products – eg tea tree or eucalyptus oils
 Bacteriocins
 Vaccines

72. 72
Resistance to antiviral drugs
 This is often a big problem – especially with RNA
viruses
 Resistant mutants arise spontaneously (even in the
absence of drug) and are selected,
 eg acyclovir-resistant mutants are unable to phosphorylate the
drug (TK mutants) or,
 do not incorporate the phosphorylated drug into DNA (pol
mutants)
 To overcome resistance it is crucial to use drugs at
sufficient concentration to completely block replication
 The use of more than one drug, with more than one
target, reduces significantly the emergence of resistant
mutants

73. 73
Anti-protozoan resistance
Mechanisms
 alteration in cell permeability
 modifications of drug sensitive sites
 increased quantities of the target enzyme
Means of development in protozoa
 Physiological adaptations.
 Differential selection of resistant individuals from a
mixed population of susceptible and resistant
individuals.
 Spontaneous mutations followed by selection.
 Changes in gene expression (gene amplification).

74. 74
Some useful and interesting web
sites
Communicable Disease Centre USA
 http://www.cdc.gov/drugresistance/
World Health Organisation
 http://www.who.int/drugresistance/en/
Australia
 http://www.healthinsite.gov.au/topics/Ant
ibiotic_Resistance