Monday, July 28, 2014

CONTROL OF MICROBIAL INFECTIONS

ANTIVIRAL DRUG RESISTANCE:
When an antibacterial or antiviral agent acts at a single target site then resistance can develop through 
mutations at that site. The high mutation rates in RNA viruses will mean that such problems will occur 
more readily than with DNA-based bacteria and this is witnessed in HIV therapies. Again, as with 
antibiotic policies, certain manoeuvres can be employed to minimise resistance developing. These 
include the use of combinations of antiviral compounds, switching between two unrelated agents 
(although sequential use of antivirals has been criticised for simply promoting resistance rather than 
preventing it) and the use of high concentrations to prevent any viral replication (‘knock out’). This, 
theoretically, prevents any viable mutants being released. 
Resistance to antiviral agents will result from mutations in the viral genome. The modified proteins may 
act on cell events that occur upstream of the active compound (e.g. mutations in viral thymidine kinase 
will reduce its affinity of binding to the nucleoside) or mutations may occur in the target protein itself (e.
g. retroviral reverse transcriptase). Whilst mutation is a frequent event in RNA viruses, and resistance 
develops frequently during the course of an infection, the spontaneous mutation events in a DNA virus 
like Herpes simplex will be of much lower frequency. Note that latent Herpes simplex virus does not 
express TK or DNA polymerase, hence the virus remains unaffected by the drug. 
The laboratory testing for resistance to antiviral agents has a number of problems. Direct testing of the 
inhibitory concentrations of antiviral agent (phenotypic testing) gives a concentration that is active, at 
least under laboratory conditions. Phenotypic testing requires that the organism has been cultured and 
this is not possible for those viruses that have not yet been successfully cultured in vitro. Molecular 
mechanisms avoid this problem. Genotype testing can, in theory, be carried out on clinical samples as 
well as cultured virus. Polymerase chain detection for resistant gene sequences are increasingly available 
and are less technically demanding than phenotypic tests. The interpretation of both types of testing is 
somewhat arbitrary and, like antibiotic susceptibility testing in bacteria, will only indicate possible outcomes or provide frames of reference.

SURVEILLANCE:
In the latter half of the 1980s, the incidence of tuberculosis had increased to ‘epidemic’ proportions in a 
developed city, New York, in the most prosperous country in the world. How could such a well recognised infectious disease against which an effective vaccine and a range of antibiotics are available 
spread unnoticed in such a city? The reasons illustrate how good public health infrastructure can be 
undermined if unsupported. Famously associated with poverty, tuberculosis had steadily increased in a 
place where HIV was endemic amongst people living in overcrowded, poor housing. The treatment of 
tuberculosis uses three antibiotics over 6 months and patients with pulmonary disease who are the infectious sources quickly become non-infectious following antibiotic treatment. If patients fail to complete the treatment, they will relapse into infectious cases and 
antibiotic resistance may result. Of the measures taken, DOT (direct observation of therapy) was 
crucial to the management of the epidemic. DOT targets the source by effecting a reduction of the 
proportion of infectious cases. One of the reasons for the return of tuberculosis was the reduced funding 
to public health departments responsible for monitoring (surveillance) and treating the disease. Partly 
this was a consequence of years of success in reducing the incidence of tuberculosis such that 
complacency had set in. Not surprisingly the cost of bringing the epidemic under control was more than 
the savings made in the first place. 
The value of quarantine measures to screen imported animals for infectious diseases needs 
consideration. The ancient practice of retaining ships in port for 40 days (‘quarantina’) 
applied to all trade, not just to animals, and was driven mostly by a need to prevent the spread 
of plague. With the spatial isolation of an island, quarantine can prevent the introduction of a 
disease. With increasing international travel by air, the principle has been undermined. The 
building of a tunnel under the English channel to connect the United Kingdom with the rest of 
Europe means the isolation is breached again. 



FUTURE EPIDEMICS
Epidemics have been a regular feature of human existence throughout history, so it is easy to state with 
confidence that they will continue to be so. The reasons for such a gloomy outlook are not difficult to find.  As populations have increased in size, particularly in cities, so has the incidence of 
infectious disease. The proportion of people infected by certain infectious diseases (tuberculosis is again 
an example) may fall, but the absolute numbers of people infected will still increase. The present 
population forecasts indicate increasing numbers of large (greater than 10 million people) cities, mostly 
in ports and concentrated in developing countries. Other than providing a critical population threshold to 
sustain diseases like measles, sexually transmitted diseases and the common cold, large cities need 
global commerce to support them, as well as attracting migration, which both increase the inward and 
outward flux of people, goods and microbes. The public health infrastructure needs to be appropriately 
sized and funded to prevent the resurgence of old infections that, although once under control, will 
readily return without continued control. The expansion of the areas of known infectious disease is a 
result of expanding urban slums into the country such that the associated risks of deforestation and 
monoculture of crops all result in disturbing zoonotic cycles. It is also depressing to note the regular 
appearance of epidemics that accompany war, a habit that, far from diminishing, seems to be on the 
increase and risks employing biological weapons. Although poverty is famously linked with poor health, 
notably tuberculosis, wealthy nations are not excluded from risk as advances in medicine keep more people alive with increasing opportunities for infections. 

                               EXAMPLES OF CHANGING PATTERNS IN INFECTIOUS DISEASE 
•  Previously unrecognised diseases: Lyme disease (Borrelia burgdoferi), Helicobacter 
pylori gastritis
•  Increasing zone of disease: increasing malaria and Dengue due to the spread of 
mosquito vectors into new areas. 
•  Resurgence of ‘old’ infections: epidemic wave of diphtheria in Europe affecting the 
old communist bloc. 
•  Apparent synergy in tuberculosis with HIV in AIDS patients. 
•  Increasing incidence of drug-resistant tuberculosis. 
•  Food-borne infections increasing with globalisation of food products.

International surveillance will become increasingly important as the world shrinks through globalisation 
in order that infectious diseases can be tracked. The bioterrorist threat, exemplified by the crippling cost  of sending a few samples of anthrax spores through the post, is a further call to adequate microbiological infrastructure and expertise. The factors that are important in protecting the public from biological weapons are similar to those that are considered in all microbiology laboratories. The need for microbiologists is obvious but should that idea need reinforcement then it is worth noting 
that the cost of eradication of poliomyelitis in the USA has paid for itself every 26 days since 1977. The 
financial losses to a country incurred through infectious disease every year may yet make governments 
take notice. 
Having described the human activities that promote infectious disease, what are the features of the 
organisms that will continue to create problems? RNA viruses are the organisms with the highest 
mutation rates. It can be expected that such organisms will continue to cause epidemics, just as HIV has 
been the most frightening of recent times because of the genetic variation that occurs through inaccurate 
transcription and genetic reassortment. HIV has demonstrated the potential impact that an RNA virus 
can have if it is able to cross the species barrier (from apes to humans). The risk of mutational events 
resulting in greater virulence in bacteria and fungi is less than for RNA viruses, but the increasing 
recognition that toxins and pathogenicity islands are coded for on mobile genetic elements means that 
bacteria will continue to present threats. The increase in antibiotic resistance genes through horizontal 
gene transfer over the last 50 years reminds us that we have not yet overcome the existing microbial 
threats.   HAZARD GROUPS
In order to protect the staff in microbiology laboratories as well as the public and the environment, 
micro-organisms have been categorised into four Hazard Groups. The groups, in increasing order of 
hazard, are as follows: 
Group 1:  Unlikely to cause human disease. 
Group 2:  Can cause disease and may be a hazard to employees. 
Unlikely to spread to the community. 
Effective prophylaxis or treatment available. 
Group 3:  Can cause human disease. 
Risk of spread to the community. 
Effective prophylaxis or treatment available. 
Group 4:  Can cause severe human disease. 
Likely risk of spread into the community. 
No effective prophylaxis and treatment. 
The micro-organisms considered the most effective biological weapons are chosen because 
they: 
•  are easily disseminated into the public or are highly infectious (readily transmitted 
from person to person). 
•  cause high mortality. 
•  require special action for public health control
The organisms mostly fall into Hazard Group 4. Viruses such as Variola major virus 
(smallpox) and Ebola and Marburg viruses are not easily treated with antiviral agents but 
there are effective vaccines available (although not routinely used). Bacillus anthracis and Yersinia pestis(the aetiological agent of plague) can be treated with antibiotics.





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Friday, July 18, 2014

CONTROL OF MICROBIAL INFECTIONS

ANTIBIOTIC RESISTANCE(BACTERIA):
The most pressing problem facing medicine is the growing number of micro-organisms that are now 
resistant to a wide range of antibiotics. The term antibiotic resistance describes the condition where 
bacteria have developed or acquired means to overcome the inhibitory effect of one or more antibiotics. A chilling example is multidrug-resistant Mycobacterium tuberculosis. Without the development of new antibiotics, thoracotomy (removal of the affected lobes of the lung) appears to be
the only treatment option. The mechanisms by which bacteria develops resistance to antibiotics are either due to mutation or acquisition of resistance genes from other organisms.  
MUTATION
Clinically, mutation leading to resistance has not been a major problem compared with the acquisition of 
resistance genes. In general, the effect of mutation will be to modify the target protein such that the 
binding affinity of the antibiotic is reduced. The protein will tolerate a certain loss of efficiency due to 
mutations, but constraints will limit the number and frequency of viable mutations in the active site. The 
affinity of binding will fall, but not such that the protein function is lost completely. If the binding site 
for the antibiotic is distinct from the active site of the protein, then there will be more scope for mutation 
to occur without significant loss of function. For example, the binding of an antibiotic on a ribosome 
might sterically hinder the correct binding of the tRNA and lead to misreading. If the antibiotic 
competed with the tRNA for the same binding site, then mutation of the tRNA binding site will limit the 
extent of mutation. Mutational events reduce the potency of the antibiotic for the target site and this is observed by small increases in the concentration of antibiotic needed to inhibit the growth of the organism (minimum inhibitory concentration, MIC); for example, the MIC of Staphylococcus aureus to penicillin may increase from 0.01 µg/ml to 0.05 µg/mL. By comparison, acquisition of 
resistance genes usually results in large increases in the MIC (e.g. from 1 µg/ml to >64 µg/mL). 
An example of mutational resistance of clinical importance is the resistance of Mycobacterium 
tuberculosis to the aminoglycoside streptomycin. During the treatment of patients with tuberculosis, the 
proportion of bacteria that are resistant to the effects of streptomycin increases steadily with time due to 
mutations in the ribosomal binding site for streptomycin. The frequency of mutation of Mycobacterium 
tuberculosis is approximately 1 in 10^7 , meaning that one in every 10 million cells undergoes a 
mutational event that affects streptomycin activity. The mutation rate is fixed and therefore occurs 
irrespective of the presence of streptomycin. Thus, in patients taking streptomycin, the selective pressure 
results in the resistant mutants continuing to grow (unlike the susceptible cells), displacing the falling 
numbers of streptomycin susceptible cells until eventually all the bacteria will be resistant to 
streptomycin. If the antibiotic is withdrawn then the selective pressure vanishes and the susceptible cells 
will regain dominance because of the cost of streptomycin resistance in terms of reduced efficiency of 
ribosomal function. The key feature here is the constant rate of mutation; all that changes is the selective 
pressure on the organism by exposing the organisms to streptomycin. 
Mutational resistance that causes problems for the treatment of a bacterial infection is largely restricted 
to Mycobacterium tuberculosis.Why? 
The organism has a long generation time (2–4 hours) compared with ‘fast’ growing organisms such as 
Esch. coli with a generation time of 20–30 minutes and Escherichia coli has multiple copies of the 
rRNA gene whereas Mycobacterium tuberculosis has only one. Any mutation in one of the appropriate 
genes in Escherichia coli will be recessive to the unaffected gene copies whereas mutations in the single 
copy of the gene in Mycobacterium tuberculosis will be expressed.

ACQUISITION OF RESISTANCE GENES (HORIZONTAL GENE TRANSFER):
Resistance genes are thought to exist in populations of bacteria that will be exposed to antibiotics in their 
natural environment. Bacteria in the soil will encounter antibiotics produced by fungi and Streptomyces 
spp. The strong selection pressures exerted by antibiotic use in agriculture (animal feeds, crop spraying, 
etc.), hospitals and the home (in countries where antibiotics can be bought freely at the pharmacy 
without prescription) has resulted in bacterial pathogens acquiring resistance genes from other 
organisms. The horizontal gene exchange of transmissible plasmids containing resistance genes means 
that effective antibiotic resistance is acquired in one step rather than waiting for mutational events to 
develop. The resistance genes have become widespread throughout different pathogens across the globe. 
Their mobility is conferred by becoming incorporated in transposons that, in turn, accumulate as gene 
cassettes in mobile plasmids called multidrug resistance plasmids(often abbreviated to R plasmids). They resemble the pattern observed with pathogenicity islands, clusters of genes all coding for related functions. 
Mutational events may be the only option for organisms that do not readily exchange genes horizontally. 
Again, Mycobacterium tuberculosis is a good example. The cell wall structure of Mycobacterium 
tuberculosis has the extra mycolic acid/arabinogalactan layers that may prevent transformation, 
conjugation and transduction.
RESISTANCE TO ANTIBIOTICS: CELLULAR MECHANISMS:
Enzymatic inactivation of the antibiotic:
A good example is the production of β-lactamase, an enzyme that hydrolyses the β-lactam nucleus of β-lactam antibiotics (penicillins). These enzymes may be found on the chromosome or on resistance 
plasmids and are expressed constitutively or as an inducible enzyme, only when β-lactams are present. 
The strategy adopted is exemplified in the Gram positive organism Staphylococcus aureus which 
produces inducible β-lactamase to be released extracellularly. In contrast the Gram negative Escherichia 
coli constitutively produces much smaller amounts of β-lactamase but sites it in the periplasmic space. 
In this way Escherichia coli chooses to only degrade β-lactam antibiotic that permeates through the 
porins in the outer membrane. Inactivating enzymes are also found that attack aminoglycosides and 

chloramphenicol. 
Active efflux of antibiotic:
The bacterium expends energy to actively extrude antibiotic from within the bacterial cell. The efflux 
pumps responsible may be able to pump more than one type of antibiotic (multidrug resistance efflux 

pumps). 
Reduced uptake:
An alternative to removing antibiotic once it has reached the cytosol is to mutate the mechanisms that 
are responsible for the uptake of the antibiotic in the first place. Such a strategy relies on active, i.e. 

energy expending, mechanisms of uptake. Passive diffusion will not apply.
Modification of drug target:
Mutations will result in alterations of the binding sites in antibiotic target proteins. Penicillin binding 
proteins, for example, can reduce their binding affinity for -lactam antibiotics. Alterations in the amino 
acid sequences of the ribosomal proteins can also result in reduced binding of the antibiotics that act on 

protein synthesis. 
Overproduction of target:
With antibiotics such as the sulphonamides and trimethoprim, competitive inhibitors of enzymes 
involved in the biosynthesis of folic acid, it is logical to see how bacteria have developed resistance to 

these drugs by simply overproducing enzymes. In the case of trimethoprim, the organism produces excess dihydrofolate reductase in order to overcome the competition from the drug. 
Some of these mechanisms are produced by mutation, others are simply acquired through horizontal 
gene transfer. The origins of the resistance mechanisms lie in other organisms, presumably those that 
produce antibiotics themselves. When an organism is under prolonged pressure through exposure to 
antibiotics, in time, the appropriate resistance mechanism will eventually make itself available. 
It is important to realise that bacteria can be ‘resistant’ to the inhibitory effects of antibiotics through 
mechanisms that are neither mutational events nor resulting from acquisition of exogenous resistance 
genes. 
•  Antibiotics have a particular spectrum of activity. Those organisms that are unaffected by a 
particular antibiotic may lack the target site or the mechanisms by which the antibiotic enters the 
bacterium.  
•  Even though several antibiotics are bactericidal (e.g. β-lactams), they can only exert this effect on 
actively growing bacteria; the organisms in stationary phase are not killed. This is a general 
phenomenon and applies not just to antibiotics but to disinfectants and other antibacterial 
conditions (starvation, drought). Endospores represent the extreme example of this strategy: 
completely inert structures that dominate in unfavourable conditions that are effectively unaffected 
by antibiotics. 
•  Dense collections of bacteria as biofilms offer protection partially through physical restriction and 

binding of the antibiotic so as to reduce the active concentration that can penetrate the biofilm.

Cited By Anil Bhujel 
Bsc Microbiology, TU.
Microbiology Student At Pokhara Bigyan Tatha Prabidhi Campus, Nayabazzar-9, Pokhara.

SOME SUGGESTED REFERENCES:
en.wikipedia.org/wiki/Antibiotic_resistance
www.sciencedaily.com/articles/a/antibiotic_resistance.htm
textbookofbacteriology.net/resantimicrobial.html
www.who.int/mediacentre/factsheets/fs194/en/
www.rxlist.com/antibiotic_resistance-page3/drugs-condition.htm
textbookofbacteriology.net/resantimicrobial_3.html
www.ncbi.nlm.nih.gov/pubmed/21822035
www.life.umd.edu/classroom/.../MechanismsofAntibioticResistance.htm
www.sciencedirect.com/science/article/pii/S009286740700311X



























Wednesday, July 16, 2014

CONTROL OF MICROBIAL INFECTIONS

CONTROL OF ZOONOSES:
Zoonotic sources of infections will be impossible to eradicate without killing all the animal reservoirs. 
Alternative strategies are the only hope and, with over 200 organisms that can cause zoonoses in 
humans, control rather than eradication is of great importance. The transmission of many zoonoses from 
animals to humans occurs via insect vectors, for example louse-borne infections by Rickettsia 
spp. (typhus), tick borne infections by Borrelia spp. (e.g. Lyme’s disease), yellow fever virus is 
transmitted by mosquitoes of the genus Aedes, and plague (Yersinia pestis) transmitted by fleas. Perhaps 
the most famous zoonosis, rabies is caught directly from the bite of infected animals, typically dogs. 
With deforestation and increased expansion of cities (the slum regions, that is!) humans are encountering 
arthropod vector-borne diseases more frequently. The displaced vectors are driven from forests into new 
geographical locations and the micro-organisms spread into new vectors. 
Less shocking than exotic infections such as Ebola virus outbreaks, food acts as the source and vehicle 
for transmission of infections such as salmonellosis and campylobacteriosis and thus may be zoonoses. Food products are regulated at several levels but simple hygienic precautions will prevent many infections. Correct storage temperatures will prevent multiplication of microbes and adequate cooking 
temperatures will kill organisms. Pasteurisation of milk is an outstanding example of the efficacy of disinfection eliminating a disease; sterilisation of milk at extreme temperature levels is not necessary to kill 
Mycobacterium bovis. The control of food-borne disease will depend on removal of the pathogens in the 
original foodstuff (e.g. salmonellae in chickens and their feed) as well as maintaining correct handling 
and cooking methods. Each of the various steps in the food chain (source, manufacture, distribution and 
destination) should offer control points at which microbial contamination can be checked. 
CONTROL OF VECTORS
The control of vector-borne disease has significantly greater problems than in directly acquired zoonoses 
such as food poisoning. With the increases in the distribution and number of cases of Dengue fever, an 
arthropod-borne illness caused by a flavivirus, we have problems similar to those in controlling malaria, 
notably controlling the mosquitoes that carry the virus. The mosquitoes that carry dengue virus, Aedes 
spp., have spread back into the central Americas having once been eradicated. This means that Dengue 
is now the most common arbovirus infection in humans responsible for millions of cases annually. It is 
clear that eradication is likely to be impossible for any zoonosis because it will be unlikely that the 
reservoir(s) or vectors can be eradicated, especially if the organism is able to reside in a variety of host 
and vector species. With dengue virus, the virus is maintained in monkeys and transferred by the 
mosquito within forests (hence termed sylvatic cycle). Disturbingly, the virus has widened its vector 
range by using the Aedes species that prefer urban environments (Aedes aegypti) such that dengue is 
maintained within human populations (the urban cycle). Note then that urban dengue is not a zoonosis). 
You should note that with malaria in humans, the species responsible (protozoa of the genus 
Plasmodium) are restricted to, and transmitted only between, humans. Malaria is therefore not a 
zoonosis. Theoretically at least it is possible to eradicate malaria if you eradicate the vector. With 
zoonoses, eradication of the natural host is likely to be impossible. Under such circumstances one can 
only hope for controlling the infection rather than eradicating the infection. The term ‘eradication’ is not 
used to describe the treatment of an individual patient with antimicrobial drugs, but should be reserved 
when discussing the elimination of a disease from a geographical zone (or, famously, smallpox from the 
world!). 
To stand any chance of controlling vector-borne infections, an understanding of the biology of the vector 
itself is essential. As microbiologists, one may slip into thinking that expertise in the virus or bacterium 
is sufficient, but the behaviour of the vector is critical in devising strategies of control. For example, the 
sixty species of Anopheles mosquito that can transmit malaria to humans differ in their biting times and 
preference for breeding sites. The key features include knowledge of their breeding sites, biting  behaviour, resting sites and host preferences (animal or human). Female mosquitoes are blood sucking because of the nutritional demands of producing eggs. Males can live off nectar. Wholescale spraying with insecticides such as DDT has been effective in the past, but the problem of the 
mosquito developing resistance to the insecticide has been steadily increasing. At first sight DDT 
appears to be attractive: stable (it remains active on the walls of sprayed rooms for days) and selectively 
toxic; weight for weight the toxicity is greatest against insects than against higher animals. 
Unfortunately, DDT has a half life of greater then 100 years and accumulates to toxic levels in the food 
chain. The environmental side effects of DDT have led to the more controlled use of DDT and other less 
potent chemical insecticides exemplified best in the development of impregnated bed nets. Of the 
various biological controls tested the use of a larvacidal toxin has had the most success. Bacillus thuringiensis produces a pore-forming toxin that kills insect larvae and, being a member of the genus Bacillus, produces endospores which makes it feasible to spray large areas with a suspension of the organism in a suitably robust form. Prompt diagnosis and treatment of individual cases of vector-borne diseases will also serve to reduce the opportunities for transmission from infected hosts. 
The control of vectors is a national effort with the assistance of the World Health Organisation to coordinate such programmes. The financial resources and political commitment need to be maintained if 
any prolonged effects are to be realised. The return of mosquitoes to areas that have been previously 
cleared has been witnessed in many areas of the globe. Most vector control programmes aim to reduce 
the population size of the vector. Eradication being that much more difficult to sustain, it will usually 
stand better chances of success on islands rather than mainland areas.
IMMUNO- AND CHEMOPROPHYLAXIS:
Immunoprophylaxisis the administration of immune serum to people who are considered at acute risk 
of developing diseases against which there is a protective anti-serum, for example, tetanus, botulism and 
diphtheria. Such protection is effective but of limited scope in that it protects the few people at risk for a 
limited period of time but has no effect on the control of the disease in the community. There is little, if 
any, distinction between the terms ‘immunoprophylaxis’ and ‘passive vaccination’. 
Chemoprophylaxisis the use of antibiotics in two circumstances: 
1 . to protect contacts of patients with infectious diseases from developing clinical disease, and 
2 . to provide temporary protection during the course of a medical intervention or surgical operation. 
Again, chemo-prophylaxis provides cover for the immediate contacts and cannot be employed to provide 
prolonged, widespread protection for communities. Antibiotics have not eliminated infectious disease or 
infections from the world, nor in fact have they significantly reduced their incidence. It may be argued 
that the prophylactic use of antibiotics has prevented infections in specific circumstances such as 
outbreaks of meningococcal meningitis in schools. In these circumstances close contacts (e.g. school 
children in the same school) are given antibiotics to prevent the disease developing. Immunization will 
be inappropriate (assuming there is a suitable vaccine) because the time needed to develop immunity (2–
4 weeks) will leave the contacts unprotected in the short term. Meningococcal meningitis can occur in clusters of people in a pattern consistent with a common source outbreak. As vaccines are not available for all the sero groups of Neisseria meningitidis(antibodies against the polysaccharide capsules are protective) antibiotics are given to prevent the disease developing. Another area where antibiotics have prevented infection is the prophylactic cover for surgical operations. For protection during surgery, the antibiotics need to be broad spectrum and given so that the peak levels are obtained during the operation. Whilst this has not abolished post-operative infections, the incidence of post-operative infections would undoubtedly be higher if such prophylaxis was omitted.

CITED BY KAMAL SINGH KHADKA
MSC MICROBIOLOGY, TU.
ASSISTANT PROFESSOR IN PU, PBPC, PNC.
POKHARA, NEPAL. 

SOME SUGGESTED REFERENCES:
www.who.int/zoonoses/control_neglected_zoonoses/en/
www.fao.org/docrep/006/y4962t/y4962t01.htm
www.cdc.gov/24-7/cdcfastfacts/zoonotic.html
www.oie.int/doc/ged/D8633.PDF
www.dshs.state.tx.us › Infectious Disease Control
en.wikipedia.org/wiki/Zoonosis
en.wikipedia.org/wiki/Vector_control
www.who.int/malaria/areas/vector_control/en/
www.cdc.gov/nceh/ehs/topics/vectorcontrol.htm




























Monday, July 14, 2014

CONTROL OF MICROBIAL INFECTIONS

VACCINATION(CONTD...)

HETEROLOGOUS VACCINE
The use of cow pox virus as a vaccine for smallpox by Edward Jenner is an example of a live, 
heterologous vaccine. The term ‘heterologous’ is used to describe how a micro-organism (cow pox 
caused by Vaccinia virus) that causes infections in other hosts (cows) is able to induce protective immunity to the human form of the disease (smallpox caused by Variola virus) if used as a vaccine.


LIVE, ATTENUATED VACCINE
The BCG is a live strain of Mycobacterium tuberculosis that has been cultivated on culture medium containing bile, thereby reducing the virulence of the organism compared with the wild type. The Sabin polio vaccine is another example of a live, attenuated vaccine. 

KILLED ORGANISMS
Influenza and rabies vaccines are killed organisms, achieved by treating the virus with β-propiolactone, 
a chemical not dissimilar to formaldehyde, which does not destroy the protective antigens on the virus. 
The difference between influenza and rabies vaccine is that rabies is a monotypic virus (has one 
antigenic type), unlike influenza virus which undergoes antigenic modulation and requires a new vaccine for each type. 

SUBUNIT VACCINES
Inactivated intact bacteria have been largely replaced (where possible) by the use of the appropriate 
component that provides protective immunity. This reduces the risk of any contamination of vaccine by 
organisms that are not killed. The protective antigens on an organism are likely to be exposed on the 
surface. Several vaccines use the appropriate structures in place of intact organisms, e.g. the 
polysaccharide capsules from Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae.

TOXOIDS
Toxoids are the secreted exotoxins from toxigenic pathogens such as Clostridium tetani(tetanus toxin) 
inactivated by formaldehyde. The formaldehyde treatment inactivates the toxin but does not destroy the 
antigenic determinants that evoke the immune response. In this case the antigens that protect against the 
disease are coded on the toxin rather than a surface structure of the organism. Such vaccines prevent clinical illness developing but not necessarily infection. 

PASSIVE VACCINES
Passive vaccines differ fundamentally from the other types of vaccine. Passive vaccines are simply 
injections of pre-formed immunoglobulin raised against the organism in question. Hepatitis A virus is 
usually acquired from infected seafood, particularly mussels and other filter feeders. The virus is passed 
into the sea water from faeces of infected patients but are concentrated in the mussels growing in the 
contaminated water. People travelling to areas of particular high risk of Hepatitis A infection are given 
anti-hepatitis A immunoglobulin as immunoprophylaxis. Such a procedure provides protection for the 
individual only, driven by the particular circumstances rather than national campaigns. The protection is 
finite, lasting only the duration of the immunoglobulin in the bloodstream (approximately 3 months). 
WHAT DO THESE VACCINES HOPE TO ACHIEVE?
With smallpox vaccine, global eradication was achieved following a WHO campaign that chased all 
cases of the disease across the world. Usually vaccination is used to limit the impact (morbidity and 
mortality) of an infectious disease rather than eliminate it. It is only realistic to attempt eradication of an 
infectious disease that has no inanimate or animal reservoir, i.e. a strict human pathogen. Even many 
strict human infectious diseases may be impossible to eradicate because of antigenic variation in the 
organism, or short-lived protection against the disease. For infectious diseases that cause childhood 
epidemics, such as measles, vaccination seeks to protect the community as well as the individual. 
Vaccination is also used for individuals at high risk of acquiring specific infections, usually related to 
their work. For example, vaccination against anthrax for people who work with animal skins/hides/carcasses or vaccination against hepatitis B virus for 
healthcare workers. Such specific vaccination has no expectation of reducing the incidence of the 
disease in the population at large, nor of providing herd immunity. Instead, these people are vaccinated 
because they are at greater risk of encountering the organism. 
Vaccination against certain infectious agents may be futile. It is suggested that chickenpox (Varicella
virus) is usually sufficiently mild when caught as a child and vaccination simply will be an unnecessary 
financial cost and the associated vaccine-related side effects will increase.
THE PROBLEMS OF VACCINATION
There is no such thing as a perfectly safe medical procedure. Ironically, vaccination suffers from poor 
public perception as a result of its effectiveness in eliminating the infectious disease. By eliminating 
whooping cough and all the associated crippling illness that Bordetella pertussis creates, the only events 
that attract attention are adverse reactions in a small proportion of children vaccinated. Vaccine-induced 
disease will always accumulate in absolute numbers against a background of falling or absent numbers 
of cases. If the vaccination uptake rate has not reached the threshold level for R= 1 then the organisms will still circulate (i.e. remain endemic) in the population. In these circumstances vaccination can be envisaged to 
increase the average age at which people become infected because it is taking longer for the organism to encounter the susceptible fraction of the population.With rubella virus (German measles) 
infections in older children may coincide with pregnancy. Pregnant women that contract rubella virus in 
the first three months of pregnancy are at risk of the virus also infecting the developing foetus. Such an 
infection causes permanent damage such as impaired vision, deafness, cardiac defects and other 
abnormalities (congenital rubella syndrome, CRS). Thus, vaccination rates below that required for 
eradication will inadvertently place women at increased risk of CRS. A less catastrophic consequence is 
seen with mumps virus infections in men. With an increased age at infection, the illness has more 
serious effects such as orchitis (inflammation of the testicles, with possible temporary sterility) and even 
meningitis. Maintaining the necessary high vaccination rates against infectious diseases such as measles requires continued public health momentum. Complacency will occur if the disease is not seen for several years and people will forget or relegate the childhood disease to history. Compulsory vaccination in order to 
attend school has been one approach to counter this problem. 
Vaccines need to cover the window of susceptibility in newborn children. The maternal antibodies 
provide immunity for the first 3 months but the levels of circulating immunoglobulins in the newborn 
child will disappear over time. The period that follows (3–12 months of age) is when the child is most 
vulnerable to acquiring highly infectious diseases such as measles and Haemophilus influenzae capsule 
type b. Unfortunately, vaccines tend to be less efficient in children of this age range (for a variety of 
reasons such as poor immunogenicity of the vaccine target and residual maternal antibodies). This leaves 
the child vulnerable. The concept of timing of vaccination obviously means that vaccines must be given
 before the average age of infection. 
Microbes that undergo antigenic variation will be under selective pressure such that the antigenic variant 
that is not in the vaccine will be selected for. The continual surveillance of influenza virus for new 
antigenic types is the only option for creating an appropriate vaccine until a generic cross-protecting 
antigen can be found. 
MICROBIAL CONTROL (OTHER THAN VACCINATION)
The old adage that prevention is better than cure is undeniable because it will be impossible to eliminate 
pathogenic micro-organisms from our environment (despite the apparent success in eliminating 
smallpox virus). Rather than attempt to kill organisms in their natural habitat, which will include soil 
and animal sources, the control of infectious diseases aims to reduce contact between the organism and 
potential hosts. Three targets can be proposed: 
•  reducing the source of the infection, 
•  reducing the opportunities for transmission, 
•  increasing the resistance of the host. 
The measures that a country takes (for it must be a national programme if there is to be any real chance 
of being effective) are usually the following: 
•  general public health: provision of clean drinking water and disposal of sewerage, 
•  control of animals that might cause zoonoses, 
•  vaccination, 
•  immuno- or chemo-prophylaxis, 
•  vector control. 
GENERAL PUBLIC HEALTH
In the nineteenth century, considerable improvements in public health resulted from the introduction of 
clean water supplies and public sanitation systems. These, and other improvements that followed (nutrition, housing, education, childcare improvements) drastically cut morbidity and mortality rates in city and rural populations across Europe. Even before the introduction of antibiotics, the infectious disease burden had started to fall in England, a testament to the importance of these measures. With increasing biomedical sophistication it is easy to lose sight of the value of the essential public health measures in favour of costly new innovations. Faeco-oral transmission of Vibrio cholerae is prevented when clean water supplies are maintained. Vaccination should not seek to replace or obviate the need for water supplies free of sewerage. The high childhood mortality rates in countries with inadequate water supplies are due to infectious diseases and illustrate the impact of failing in these basic needs. Although entirely preventable by public sanitation, high childhood mortality tends to lead to high population growth and poverty which compound the problems. A word of warning, however, about cleaning up water supplies: poliomyelitis.

Cited By Kamal Singh Khadka
Msc Microbiology, TU.
Assistant Professor In PU, PBPC, PNC, LA, NA.
Pokhara, Nepal.


SUGGESTED REFERENCES:
www.historyofvaccines.org/content/articles/different-types-vaccines
www.vaccines.gov/more_info/types/
www.niaid.nih.gov › ... › Vaccines › Understanding
en.wikipedia.org/wiki/Vaccine
www.webmd.com/vaccines/adult-vaccine-schedule
www.nature.com/news/2011/110525/full/473436a.html
www.drlwilson.com/articles/VACCINES.08.htm
www.publichealthreviews.eu/show/p/104































































Friday, July 11, 2014

CONTROL OF MICROBIAL INFECTIONS

THE VALIDITY OF Ro:
One of the values of Ro lies in what its composition tells us. The characteristics that comprise Ro
must be essential and important for the organism, therefore reduce any of these values and the efficiency of spread will be impaired. If any of the parameters are reduced to zero, in theory the epidemic will be halted. If   then the number of susceptibles (S), the efficiency of transmission (β) and infectious period (D) will all be suitable targets for control of the epidemic. The easiest target will often be to reduce the  number of susceptibles through vaccination. As a marker of the ability of an organism to spread, Ro gives an indication of the propensity of an organism to invade a population (cause an epidemic). Organisms of high Ro will spread very efficiently and infect the very young. Ro can be used to predict the levels of vaccination needed to eradicate infectious disease. The effective reproductive rate R must  be less than one for the disease to disappear. 
Earlier, we defined  , where xis the fraction of the population susceptible. If a completely susceptible 
population is represented as unity, then the actual fraction of the population immunised can be 
represented as (1^-P), hence:
                                        R= Ro(1^-P)
Substituting R with 1 yields:
                                          ( )
This can be rearranged to find the percentage (p) that need to be vaccinated as follows:
                                      1/ Ro = 1^-P
                                      1/ Ro + P = 1
                                      P= 1-  1/ Ro 
p will be the boundary condition, i.e. it sets the minimum proportion of the population that needs to be 
vaccinated in order for the effective reproduction rate to fall to one. It follows that vaccination rates 

must not be less than that set by 1-  1/ Ro.
To combat measles it is necessary to achieve very high vaccination rates (around 95 per cent uptake) in children as young as possible. It is clearly not that helpful to vaccinate children at an age that is older than the average age of infection.
What measures can be implemented to reduce βand D?For highly infectious diseases such as measles the idea of mass action as the basis for describing the random mixing of infectious and susceptible people appears to be a good model for describing what actually happens. Hence, Ro
proves useful in comparing the infectiousness of different organisms. With measles, diphtheria and rubella, each confer lifelong immunity. This characteristic helps in monitoring a population for immunity as the protective antibodies, all developed against a single dominant antigenic type, can readily be measured in the serum of people. The variation in antigenic types seen with influenza virus make predictions of the virus almost impossible, as well as the manufacture of correct vaccine that will be protective every year. Ro can be estimated from serological surveys of the population. The age at which antibodies appear can be used to calculate Ro (the younger the age at which the 
infection occurs equates to a higher Ro and vice versa). Again, such methods are problematic for 
influenza virus because different strains of influenza virus may circulate through the population 
periodically, making the serological testing complicated. Not all infectious diseases spread horizontally like measles. Hepatitis B virus is acquired parenterally or vertically. Such transmission is not random; the chances of all individuals in the population encountering each other are not equal, thus mass-action models do not apply. An additional difficulty is that the efficiency of transmitting the infection may also vary between different groups of people. Sexually transmitted diseases are an example of a non-homogenous mixing of the population (celibate people will not become infected) as well as examples of differences in the efficiency of transmission (transmission of HIV and Hepatitis B virus is less efficient in heterosexual partners than in homosexuals). 

VACCINATION:
What measures exist to prevent and reduce the incidence of infection? Arguably the provision of clean drinking water, nutrition, sanitation and general economic health have a profound effect, but to these vaccination must be added. Only vaccination has resulted in an infectious disease being eradicated from the human population, with the global vaccination against smallpox declared successful by the World Health Organisation in 1979. The mechanisms by which vaccination works in humans is essentially immunology and will not be covered here. The area of interest to us is what vaccination tells us about infectious diseases of humans. The success of vaccination depends foremost on our understanding the physiology and ecology of the organism in question. 
Whilst vaccination protects the individual, there are benefits to the whole community when vaccination uptake rates are high. The few remaining individuals that have not been vaccinated are protected by the herd immunity principle.
 As discussed previously, DT represents the minimal number of susceptibles that are needed for a particular organism. Herd immunity arises if the number of susceptibles fall below that value. Herd immunity in humans only applies to infectious diseases that are strict human pathogens. Any 
infection that is acquired from the environment or from animals will be unaffected by the reduction in 
susceptibles (DT ) because it has a natural reservoir distinct and separate from humans (i.e. the 
environment or animals). For example, the reservoir for tetanus bacilli is the soil and rabies virus is a 
zoonosis.  Neither are caught from other humans. Thus, vaccination of other people provides no 
protection to the individual who has caught tetanus from a rose bush thorn or rabies from an infected 
dog. Note how influenza virus epidemics cloud the distinction. Influenza originates from an avian 
reservoir (notably ducks) and once transferred to humans, spreads as epidemic influenza from person to person. 
Strictly, this qualifies influenza as a zoonosis. The vaccination coverage is selective, i.e. targeted 
to the most susceptible, such as elderly people with chest disease. In this circumstance vaccination rates are unlikely to ever impact on the DT , hence effective reproductive rate (R) is unaffected and herd immunity is unlikely to occur. Ideally, a vaccine should be stable enough to withstand being transported across the country without loss of potency. One of the reasons for the success of the smallpox vaccine was its stability at high temperatures whilst being delivered to the populations close to the Equator. Also, a vaccine should be totally safe and effective, cheap and easy to administer (preferably oral) and provide lifelong immunity. The reality is that some vaccines have many of these features but none possess them all. Despite this vaccines have reduced the incidence of infectious disease, reduced the incidence of lifelong sequelae and disability and reduced the mortality rate. 
DDD, the value of vaccines: 
•  Reduce Disease, 
•  Reduce Disability, 
•  Reduce Death. 

The types of vaccine that are produced commercially can be separated according to whether the vaccine uses intact organisms, either live or killed, or components/ products of organisms. What follows are selected examples and important features of the different types of vaccine currently used.


Cited By Kamal Singh Khadka
Msc Microbiology, TU.
Assistant Professor In PU, PBPC, PNC, LA, NA.
Pokhara, Nepal.


SOME SUGGESTED REFERENCES:
www.path.org/vaccineresources
en.wikipedia.org/wiki/Vaccination
www.vaccines.gov/
www.cdc.gov/flu/professionals/vaccination/
www.nlm.nih.gov/medlineplus/ency/article/002024.htm
www.vaccineinformation.org