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Textbook of Pharmacotherapeutics
DOTS
DOTS stands for ‘directly observed therapy, short course’. This is undertaken for
patients where the sputum test does not come negative even after two months of
therapy. The patient is asked to take the anti-TB medication under the observation of
a healthcare worker. The medication is administered to the patient under DOTS
therapy once every three days.
KEY POINTS
• Tuberculosis is caused by Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium
africanum. 99% of cases are caused by Mycobacterium tuberculosis.
• A large population, comprising around 1/3rd of the world population, is affected by tuberculosis.
• A lot of effort is required in the form of patient counselling to stop its spread in the population.
• The treatment regimen recommended is of six-month duration with combination therapy.
• There is an issue of noncompliance and non-adherence due to this long therapy schedule.
• The development of multidrug resistant and extensive drug resistant TB is leading to problems in
many parts of the world.
8.2 PNEUMONIA
Pneumonia is defined as an infection or inflammation of the lung parenchyma which
is caused by various microbial pathogens.
The word ‘pneumonia’ has Greek origin meaning ‘a condition about the lung’. This
disease has been causing morbidity and mortality in patients for a long time. It still
remains misdiagnosed, mistreated, and underestimated many times.
Classification
Pneumonia is classified as:
• Community-acquired pneumonia (CAP) and
• Healthcare-associated pneumonia (HCAP)
– Hospital-acquired pneumonia and
– Ventilator-associated pneumonia
Classification based on lung involvement:
• Bronchopneumonia where small areas of lung tissue are affected
• Lobar pneumonia where one or more lobes of lungs are affected
Risk factors associated with pneumonia are shown in Table 8.2.
Aetiology
Community-acquired Pneumonia
The most common causative agent of community-acquired pneumonia is Streptococcus
pneumoniae which is also called simply the ‘pneumococcus’. The other causative
organisms are listed as follows:
• Mycoplasma pneumoniae
• Haemophilus influenzae
Infectious Disorders
Table 8.2: Risk factors associated with pneumonia
Community-acquired Patient develops pneumonia Elderly people diabetes mellitus chronic
pneumonia without any contact with a disease of heart, lungs, kidneys and liver
medical facility alcoholism and smoking asplenia
Hospital-acquired Patient develops pneumonia Lung disorders, coma, antacid H
pneumonia greater than 48 hours after antagonist proton pump inhibitors, supine
hospital admission position, internal nutrition nasogastric
tube, tracheostomy, head trauma, age
above 60 years
Ventilator-acquired Patient develops pneumonia Same as hospital-acquired pneumonia
pneumonia greater than 48 hours after
endotracheal incubation
2
• Chlamydophila pneumoniae
• Legionella pneumophila
• Gram-negative bacilli
• Staphylococcus aureus
• Viruses
• Hospital-acquired pneumonia
99
The synonym of hospital-acquired pneumonia is nosocomial pneumonia. This is
defined as pneumonia that occurs 48 hours or more after admission of patient into the
hospital.
Hospital-acquired pneumonia is sub-classified into early or late onset. Early onset
hospital-acquired pneumonia usually refers to the pneumonia which develops within
four days of hospital admission. Late onset hospital-acquired pneumonia occurs after
five or more days after the patient is admitted into the hospital. The various pathogens
associated with nosocomial pneumonia are:
• Common pathogens
• Streptococcus pneumoniae early onset of pneumonia
• Haemophilus influenzae early onset
• Anaerobic bacteria early onset
• Staphylococcus aureus early and late onset
• Gram-negative bacilli late onset
• Legionella pneumophila late onset
• Uncommon pathogens
• Influenza A and B late onset
• Respiratory syncytial virus late onset
• Aspergillus late onset
• Pneumocystis carinii late onset
• Mycobacterium tuberculosis late onset
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Textbook of Pharmacotherapeutics
Pathogenesis
Microorganisms may enter the lower respiratory tract by three routes:
• Inhalation of aerosol particles
• Via bloodstream
• Through aspiration
Aspiration commonly occurs in unhealthy and sick individuals during sleep and
pathogens may enter the airways during aspiration. The development of the disease
depends on the condition of defence mechanism of lungs. In case the pulmonary
defence is impaired, it may lead to pneumonia or pneumonitis. Certain factors like
neuromuscular disease changes perception allowing larger number of pathogens to
enter the lungs which the defence mechanism may not be able to overcome. This leads
to development of pneumonia.
Ethanol and narcotics, bronchial obstruction by mucus, tumour, and extrinsic
compression effect the mucociliary function of the respiratory tract, which in turn
depresses the pulmonary defence mechanism.
Clinical Manifestations
The signs and symptoms of pneumonia vary depending on the progression and
severity of the infection.
The common signs and symptoms are fever or hypothermia, chills and/or sweats,
non-productive or productive cough which maybe mucoid, purulent or blood tinged,
and chest pain due to pleuritis. Other symptoms are headache, fatigue, diarrhoea,
vomiting, nausea, night sweats, and leucocytosis. Patients might show shortness of
breath while speaking, crackles or rales, and diminished sounds of breath on
auscultation of lungs of the pneumonia patient. In case of plural effusion, the breath
sounds may be less or even absent. The patient may show increased respiration rate
and pulmonary consolidation.
The oxygen saturation level should be measured in patients suffering from
pneumonia to determine the need for supplement.
The elderly patients may not show the typical symptoms of pneumonia like fever,
chills, cough, etc. thus making it difficult to diagnose.
The pathogens associated with healthcare associated pneumonia are MRSA,
Pseudomonas aeruginosa, Acinetobacter species, and MDR Enterobacteriaceae.
Non-pharmacological Management
The general approach to treatment is based on results of assessment of pneumonia
patient.
Oxygen or mechanical ventilation and fluid therapy should be provided as
necessary. The supportive therapy of the pneumonia patient includes humidified
oxygen for hypoxaemia, administration of bronchodilators in bronchospasm, and
physiotherapy of chest with drainage of secretions. If required, nutritional support
and control of fever is also done.
Prevention
Vaccines and certain medications help in preventing some cases of pneumonia.
Polyvalent polysaccharide vaccines are available for the leading causes of bacterial
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pneumonia, S. pneumoniae, and H. influenzae type B. Children should be vaccinated
against influenza and pertussis along with the vaccines of S. pneumoniae and
H. influenzae type B.
Mechanical ventilation of patients: The length of mechanical ventilation of
patients should be limited. In order to prevent aspiration, the head of the patients
including hospitalised patients should be raised by 45°. Pneumococcal vaccines are
recommended for high-risk patients. Single use vials should be utilised for nebulisers.
In case of multidose medication, proper instructions of manufacturer regarding
handling, storing, and dispensing have to be followed.
Pharmacological Management
Antibiotics
Adequate antibiotic concentration in respiratory secretions is necessary for treatment
of pulmonary infections. The drugs need to cross the blood bronchus barrier to show
their effect. The ability of drugs to penetrate the blood bronchus barrier depends on
physicochemical properties.
Bacterial pneumonia involves initial use of empirical broad-spectrum antibiotics
effective against probable pathogens. Treatment should be with the drugs after
culture test. Various factors like patient’s age, medication history, underlying
disease, organ function, and clinical status need to be evaluated to select the
appropriate and effective empirical antibiotic treatment and also to decide the
appropriate route of administration.
KEY POINTS
• Pneumonia is defined as an infection or inflammation of the lung parenchyma which is caused by
various microbial pathogens.
• Pneumonia is classified as community-acquired pneumonia (CAP) and healthcare associated
pneumonia (HCAP)
• The most common causative agent of community-acquired pneumonia is Streptococcus
pneumoniae.
• Microorganisms may enter the lower respiratory tract by inhalation of aerosol particles, via
bloodstream or through aspiration.
• Vaccines and certain medications help in preventing some cases of pneumonia.
• Adequate antibiotic concentration in respiratory secretions is necessary for treatment of pulmonary
infections.
8.3 URINARY TRACT INFECTION
Urinary tract infections (UTIs) refer to the presence of organisms along with
inflammation in the urinary tract.
Classification
Urinary tract infections can be classified anatomically as:
• Upper urinary tract infections (acute pyelonephritis prostatitis)
• Lower urinary tract infections (urethritis cystitis)
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Urinary tract infections are also classified as:
• Uncomplicated UTIs
• Complicated UTIs
Infections of the urethra and bladder are considered superficial infections whereas
prostatitis, pyelonephritis, and renal suppuration are considered tissue invasion.
Microbiologically, urinary tract infections exist when pathogenic microorganisms
are seen in the urine. A microbiological count of around one lakh bacteria per ml of
urine is termed as “significant bacteriuria.”
Aetiology
Urinary tract infections are caused by enteric bacteria due to the anatomic proximity
of GI. About 80% of urinary tract infections are caused by Escherichia coli. Uropathogenic
E. coli possess certain virulence factors, including presence of adhesins, which lead to
infection.
Staphylococcus saprophyticus causes acute symptomatic UTIs in young female patients.
Staphylococcus epidermidis is a causative organism for catheter-associated UTIs. Other
enteric bacteria which cause UTIs are Klebsiella species and Proteus mirabilis.
Complicated UTIs are caused by a broad spectrum of microbial species. Apart from
E. coli, other organisms are Candida species, Pseudomonas aeruginosa, enterococci,
Enterobacter species, and other Gram-negative aerobic bacilli.
Mycobacterium tuberculosis and Salmonella species may cause urinary tract infection
via the bloodstream.
Fungal UTIs are common among hospitalised patients.
Pathogenesis
The routes by which microorganisms enter the urinary tract are through:
• The ureter (ascending route)
• Blood-borne (descending route)
The conditions affecting pathogenesis are:
• Gender and sexual activity
• Pregnancy
• Obstruction in the urinary tract
• Neurogenic bladder dysfunction
• Vesicoureteral reflux
• Bacterial virulence factors
• Genetic factors
Clinical Manifestations
The various terms used for the clinical conditions are given in Table 8.3.
Usually, urinary tract infections are asymptomatic. The symptoms vary according
to age as well as according to the infection.
Non-pharmacological Treatment
There are a few recommendations for preventing UTIs. Statistical data is not available
for these, but they are unlikely to cause any harm.
Infectious Disorders
Table 8.3: Various terms used for the clinical conditions
Various terms
Significant bacteriuria Presence of at least one lakh bacteria per ml of urine
Asymptomatic bacteriuria Significant bacteriuria in absence of symptoms in the patient
Cystitis Lower urinary tract infection (bladder and urethra) with syndrome of
frequency dysuria and urgency
Urethral syndrome Infection by conventional pathogen with syndrome of frequency and
this urea and absence of significance bacteriuria
Acute pyelonephritis Kidney infection along with lower urinary tract involvement
Chronic pyelonephritis Frequent recurring infection of the kidneys
Relapse and reinfection Relapse is the infection caused by the same organism which caused
the original infection. Reinfection is caused by different organism and
therefore a new infection
Dysuria Pain or burning on urination
Frequency Frequent removal of small amounts of urine
Urgency Need to urinate immediately
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Cranberry juice is thought to be beneficial in preventing urinary tract infections. It
is thought that cranberry inhibits entry of bacteria to urinary tract cells. A daily intake
of 750 ml of cranberry juice may decrease the risk of symptomatic UTI by 40%.
In case of frequent re-infections in some patients, antimicrobial prophylaxis with
specific antibiotics is indicated in some cases. One dose of trimethoprim 100 mg or
nitrofurantoin 50 mg at night would be enough.
Some recommendations with limited evidence are helpful. These are:
• Regular bladder emptying
• Cleaning perineal area or anal area from front to back after toilet
• Treating constipation properly
• Avoiding washing hair in the bath and
• Avoiding bubble bath.
Pharmacological Management
Antimicrobials used for the treatment of cystitis need to achieve high concentrations
in urine after oral administration and act against the uropathogens.
The first-line treatment used is a combination of sulphamethoxazole with
trimethoprim, trimethoprim and fluoroquinolones.
Sulphamethoxazole-trimethoprim combination is recommended for a three-day
regimen. If administered alone, trimethoprim is administered in the dose of 100 mg
bid for 7 to 10 days. The other drugs used are ciprofloxacin, gatifloxacillin,
levofloxacin, norfloxacin, ofloxacillin, cephalexin, and nitrofurantoin.
Since there are frequent recurrent episodes of UTI that may be seen as a relapse or
re-infection, prophylaxis and suppressive therapy may be required.
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Textbook of Pharmacotherapeutics
KEY POINTS
• Urinary tract infection may involve bladder (cystitis), kidneys (pyelonephritis) or other structures
of the urinary system.
• The common causative agent is Escherichia coli.
• The common symptoms are dysuria, frequency and urgency in cystitis.
• Fever, chills, nausea, and leucocytosis may be seen in pyelonephritis.
• The drug of choice is sulphamethoxazole-trimethoprim combination recommended for three days.
• Prophylactic antibiotics may be useful in recurrent episodes of UTI.
8.4 HEPATITIS
Viruses responsible for hepatitis are hepatitis A, hepatitis B, hepatitis C, delta hepatitis
(or hepatitis D), and hepatitis E. Hepatitis A and E are transmitted through the faecal
oral route, whereas hepatitis B, C, and delta variants are transmitted parenterally.
Aetiopathogenesis
Hepatitis A
Hepatitis A virus, also known as HAV or infectious hepatitis, is usually self-limiting
and is an acute viral infection of the liver. This is a non-enveloped RNA virus and
affects people worldwide. The route of transmission is the faecal oral route. It is
associated with water and food epidemics.
Hepatitis B
Hepatitis B, also known as HBV, is highly infectious. This is a DNA virus which
replicates within the liver. The main routes of transmission are vertical transmissions,
i.e. mother to child and sexual transmission in the case of adults. HBV can be
transmitted via blood transfusion or blood product transfusion or via intravenous
drug use or needle sharing. Various factors like age, genetic factors of the host, and
virus characteristics determine the HBV infection.
Hepatitis C
Hepatitis C virus (HCV) is a single-stranded RNA virus which was earlier labelled as
‘non-A non-B hepatitis’. Over 170 million people are infected worldwide with HCV. The
hepatitis C virus replicates very fast inside the hepatocytes, thereby posing a challenge
to the immune system of the host. The diagnosis was difficult in the past because it
was not easily identified. Testing was implemented commonly only after the 1990s.
Transmission of HCV commonly occurs through intravenous drug use, sharing of
contaminated needles, and contaminated blood and blood products. A small risk is
associated with tattooing, electrolysis, ear piercing, acupuncture, sexual contact, and
transmission from mother to child.
Hepatitis D
The hepatitis D virus (HDV) or delta hepatitis agent is a defective single strand RNA
virus that can co-infect with other hepadnaviruses like HBV. This virus cannot
replicate on its own and requires the helper function of hepadnaviruses for its
replication and expression.
Infectious Disorders
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Hepatitis E (HEV)
Hepatitis E virus, (HEV), was earlier labelled as ‘endemic’ or ‘enterically transmitted
non-A non-B hepatitis’. It is primarily seen in India, other Asian countries, Africa, and
Latin America. It is an RNA virus that causes acute hepatitis and is transmitted
enterically.
Clinical Manifestations
The incubation period for hepatitis A is about four weeks, for hepatitis B and D it is
8–12 weeks, for hepatitis C it is about 7 weeks, and for hepatitis E it is about 5–6 weeks
after which acute viral hepatitis is seen.
The symptoms seen are anorexia, nausea, vomiting, fatigue, malaise, arthralgias,
myalgias, headache, photophobia, pharyngitis, cough, and jaundice. The cutaneous
signs of liver disease are hyperpigmentation, pruritus, or vascular spiders (small
vascular malformations in the skin).
Abdominal distension may be due to ascites in both acute and chronic liver diseases.
An enlarged liver and splenomegaly may also be seen. Ascites is the accumulation of
fluid within the abdominal cavity. Jaundice is considered synonymous with liver
disease and is detected in the sclera of the eyes.
Non-pharmacological Management
Liver Transplantation
Liver transplantation is recommended for acute liver failure, decompensated chronic
liver disease, inherited metabolic disorders, primary liver cancer, and end-stage
cirrhosis cases. Immunosuppressive agents have to be administered in order to
avoid organ rejection or transplant failure. Corticosteroids, tacrolimus, and
cyclosporin are used as immunosuppressants in the initial transplant period. Longterm immunosuppressants used are azathioprine, mycophenolate, sirolimus, and
everolimus. This therapy has to be monitored closely.
Pharmacological Management
Prophylaxis
Immunisation can help in the prevention of viral hepatitis. The approach to
prophylaxis is different for each type of viral hepatitis. Earlier, passive immunisation
was used, consisting of an antibody globulin preparation purified by cold ethanol
fractionation from the plasma of normal donors. Nowadays, vaccines are available for
active immunisation against hepatitis A and B.
Hepatitis A
Active immunisation with killed vaccines and passive immunisation with
immunoglobulins are available for hepatitis A. In the early stages, immunoglobulin
preparations are effective before exposure or during the incubation period.
Vaccination gives protection against hepatitis A for about 20 years. The
immunoglobulin A (0.02 ml/kg) should be administered as a single dose. A 0.06 ml/
kg dose has to be administered every five months for a longer duration. The common
side effects of the hepatitis A vaccine are headache, fatigue, anorexia, and soreness
at the injection site.
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Hepatitis B
The prevention of hepatitis B was based on passive immunoglobulin containing
preparations till 1982. The active immunisation with vaccine was introduced in the
year 1982. This was prepared from purified non-infectious 22 nm spherical forms
of HBsAG derived from the plasma of healthy carriers. A recombinant vaccine
derived from yeast was introduced in 1987. The recommendations are different for
pre-exposure and post-exposure prophylaxes. Three intramuscular injections of
vaccines are recommended at 0, 1, and 6 months for pre-exposure cases. The postexposure prophylaxis consists of a combination of immunoglobulin and the
hepatitis B vaccine for unvaccinated people. The hepatitis B vaccine is probably
effective for five years.
Chronic Hepatitis B
The first approved agent for the treatment of chronic hepatitis B was interferon.
Interferon alpha-2b (5 million IU is administered subcutaneously daily or 10 million
IU dose thrice weekly) for a duration ranging from 16 weeks to 12 months. The side
effects seen due to interferons are fever, fatigue, headache, myalgia, nausea, diarrhoea,
anorexia, anaemia, leukopenia, and thrombocytopenia.
Lamivudine helps in blocking hepatitis B viral replication. It is given at a dose of
100 mg orally daily for 52 weeks. The side effects are headache, malaise, fatigue,
nausea, vomiting, diarrhoea, neuropathy, cough, congestion, and musculoskeletal
pain. Neutropenia, anaemia, thrombocytopenia, and pancreatitis are also seen. A
major concern with lamivudine treatment is the development of hepatitis B viral
mutation and drug resistance.
Adefovir has antiviral activity against hepatitis B and is administered at 10 mg daily
for 48 weeks. The side effects are nausea, diarrhoea, vomiting, dyspepsia, headache,
weakness, pruritus, rashes, and nephrotoxicity.
Entecavir is given at a dose of 0.5 mg orally once a day.
Hepatitis C
Immunoglobulins are no longer recommended for prophylaxis of hepatitis C
because they are not effective in preventing it. A vaccine for hepatitis C was
developed but was not found effective due to the rapidly mutating virus. The
transmission of hepatitis C via transfusion has been controlled by following various
screening procedures. The sexual transmission of hepatitis C can be prevented by
using barrier precautions like condoms. A person infected with hepatitis C should
avoid sharing items such as toothbrushes, razors, and nail cutters with family
members.
Chronic hepatitis C infections are treated with peginterferon plus ribavirin.
Ribavirin shows haemolytic anaemia, insomnia, depression, irritability, allergy like
rashes and pruritis as the side effects. Ribavirin is embryotoxic and highly
teratogenic, so it should not be used in pregnant women or in men with pregnant
female partners.
Hepatitis D
This can be prevented by vaccinating people with the hepatitis B vaccine.
Infectious Disorders
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KEY POINTS
• Liver is an organ associated with maintaining homeostasis of the body.
• The inflammation of liver is as termed as hepatitis.
• Hepatitis maybe caused by various reasons like viruses, intake of drugs, and alcohol abuse.
• The various types of viral hepatitis are hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E.
• Hepatitis can be controlled prophylactically.
8.5 GONORRHOEA
Gonorrhoea, a sexually transmitted infection, is caused by Neisseria gonorrhoeae.
Neisseria gonorrhoeae is a non-motile, non-spore forming Gram-negative organism
growing as single coccus or as diplococcus.
The risk factors include persons belonging to low socioeconomic strata, residents
in urban areas, single marital status, non-whites and history of gonococcal
infections.
Pathophysiology
Gonorrhoea affects the epithelium and the mucous membrane of the lower genital
tract primarily. It may affect the other organs like eyes, oropharynx, and anus.
N. gonorrhoeae is exclusively a pathogen found in humans. The gonococci get attached
to the human cell membrane with the help of their surface membrane proteins, they
are then pinocytosed, the polymorphonuclear leucocytes invade the tissue and lead
to pus exudates.
The rate of transmission of gonorrhoea from male to female is higher than that of
females to males probably because the cervix is an easily accessible target.
Clinical Manifestations
Gonococcal Infections in Males
The incubation period is usually 2 to 7 days after exposure. The most common clinical
manifestation of gonorrhoea is acute urethritis. In males, the major symptoms seen are
urethral discharge and dysuria. Several cases are asymptomatic. A few untreated cases
may show complications like development of acute epididymitis, periurethral
abscess, acute prostatitis, seminal vesiculitis or urethral strictures.
Gonococcal Infections in Females
The cervix and urethra are affected usually within 10 days of infection. Cervicitis is
the most common sexually transmitted infection (STI) seen. Cervicitis may exist with
candidal or trichomonal vaginitis. There is increased vaginal discharge and dysuria
seen in most women. Untreated gonorrhoea patients may develop pelvic inflammatory
disease.
Pharyngeal Gonorrhoea
Pharyngeal gonorrhoea may develop after orogenital sexual activity with an infected
partner. This is usually asymptomatic or mildly symptomatic. Occasionally it may be
seen as symptomatic pharyngitis with cervical lymphadenitis.