INTRODUCTION

1.1 Background:

        Pneumonia is the inflammation and consolidation of lung tissue due to an infectious agent (Marrie TJ, 1994). Pneumonia has the highest mortality rate among infectious diseases and represents the fifth leading cause of death (Brandstetter, 1993). Pneumonia causes excess morbidity, hospitalization, and mortality, especially among the elderly, the fastest growing sector of the population.According to first- or second-listed diagnosis, approximately 1 million persons were discharged from short-stay hospitals after treatment for pneumoniain the United States in 1990, and elderly persons aged 65 years or more accounted for 52% of all pneumonia discharges (Fedson & Musher, 1994). Pneumonia has the highest mortality rate among infectious diseases and represents the fifth cause of death (Brandstltter, 1993). In addition fine (2000) reported that lower respiratory tract infections affect three million persons annually and is the leading cause of death of infection in the United States.

• Pneumonia represented one of the 10th leading causes of hospitalization and deaths in Malaysia through 1999-2006 (Ministry of Health, Malaysia, 1999, 2000, 2001, 2002b, 2003, 2004, 2005band 2006b)

Because of differences in pathogenesis and causative micro-organisms, pneumonia is often divided into: hospital acquired and community-acquired pneumonia.Community acquired pneumonia (CAP) is caused mainly by streptococcus pneumoniae. Its symptoms include coughing (with or without sputum production), change in colour of respiratory secretion, fever, and pleuritic chest pain (Fine, 2000). Nosocomial pneumonia or hospital acquired pneumonia is the second most common nosocomial infection in the United States and it causes the highest rates of morbidity and mortality. It is caused mainly by streptococcus pneumoniae and pseudomonas aeruginosa. The highest mortality rates occurred in patients with pseudomonas aeruginosa or acineobacter infection. It is characterized by fever and purulent respiratory secretion. Nosocomial pneumonia results in increase length of hospitalization and cost of treatment (Kashuba, 1999; Levison, 2003; Wilks et al., 2003). The clinical criteria for the diagnosis of pneumonia include chest pain, cough, or auscultatory findings such as rales or evidence of pulmonary consolidation, fever or leucocytosis. In addition, there must be radiographic evidence, such as the presence of new infiltrates on chest radiograph, and laboratory evidence that supports the diagnosis. Because of differences in pathogenesis and causative micro-organisms, pneumonia is often divided in hospital acquired and community-acquired pneumonia. Pneumonia developing outside the hospital is referred to as community-acquired pneumonia (CAP).

Pharmacoeconomic study

Pharmacoeconomics is defined as the description and analysis of costs of drug therapy or clinical service to health care systems and society (Bootman et al., 1996). It has risen up as the discipline with the increase interst in calculating the value and costs of medicines (Sanches, 1994). Cost is defined as the value of resources consumed by the program or drug therapy of interest while a consequence is defined as the effect, outputs, or outcomes of a program. When identifying the costs associated with a product or service, all possible costs that include or related to the study are calculated (Sanchez, 1994). With the increase in financial pressure to hospitals to minimize their medical care costs, pharmacoeconomics can define costs and benefits of both expensive drug therapies and pharmacy based clinical services (Destache, 1993; Touw, 2005).Furthermore pharmacoeconomics can assist practitioners in balancing cost and quality that may result in improving patient care and cost saving to the institution (Sanches, 1994). Bootman and Harison (1997) stated that pharmacoeconomics and outcome research are very important to determine the efficient way to present a quality care at realistic rate. They suggested that pharmacoeconomics should have a remarkable authority on the delivery and financing of health care throughout the world.

Different methods have been used to perform pharmacoeconomics analysis which includes:

Cost-benefit analysis:

Cost-benefit analysis two or more alternatives that do not have the same outcome measures. It measures all costs and benefits of a program in monetary terms (Bootman et al., 1996; Fleurence, 2003). Cost-benefit analysis could play a major role in identifying the specific costs and benefits associated with the pneumonia.

Cost-effective analysis

Cost-effective analysis compares alternatives that differ in safety, efficacy and outcome. Cost is measured in monetary terms, while outcome is measured in specific objectives or natural units. The outcome are expressed in terms of the cost per unit of success or effect (Bootman et al., 1996).

Cost-utility analysis

Cost-utility analysis compares treatment alternatives; benefits are measured in terms of quality of life, willingness to pay, and patient preference for one intervention over another, while cost is measured in monetary terms. It has some similarity to cost-effectivness with more concentration on patient view. As an example, looking for new druig therapy; benefits can built-in together with expected risks.

Cost-minimization analysis

Cost-minimization analysis is one of the simplest forms of pharmacoeconomics analysis. It is used when two or more alternatives are assumed to be equivalent in terms of outcomes but differ in the cost which is measured in monetary terms (Fleurence, 2003).

Cost of illness analysis

Cost of illness analysis is the determination of all costs of aparticular disease, which include both direct and indirect costs. Since both costs were calculated, an economic evaluation for the disease can be performed successfully. It has been used for evaluating many diseases (Bootman et al., 1996).

1.2 Study problems and rationale

  • The management of pneumonia is very straight forward. However this is not always true for the diagnosis and selection of therapy. As there are some issues related to pneumonia that need to be addressed :
  • The first issue pertains to the inappropriate diagnosis of the pneumonia. Some physicians do not properly identify the causative organism, I.e, whether, it is bacterial or viral.
  • Bartlet et al (1998) found that the viral infections have been associated with at least 10% to 15 % of CAP in hospitalized adults (Bartlet et al, 1998).
  • Secondly is the use of inappropriate medications. The prescription of inappropriate or un-indicated drug therapy such as the prescription of antibiotics for pneumonia caused by nonbacterial infection may increase the incidence of bacterial resistance (Steinman, 2003).
  • Thirdly the adherence to guidelines improves quality of care and reduces the length of hospital stay (Marrie TJ et al, 2000).
  • Fourthly the adherence to guidelines reduces the cost of treating pneumonia (Feagan BG, 2001).
  • Fifthly Teaching hospitals are widely perceived to provide good outcome, and that reputation is thought to justify these institutions' comparatively higher charges relative to non-teaching (general) hospitals. Despite their reputation for specialized care, teaching hospitals have traditionally relied on revenue from routine services, such as treatment of pneumonia, and the costs of specialized services and medical training. However, with managed care and competition creating pressures for cost containment, these higher costs have come into question:
  • Do a teaching hospital provide good outcome for management of pneumonia, or do a general hospital provide comparable outcome at lower costs?

1.3 Significance of the Study

This study has the following important issues:

To the researchers:

  •      Several studies have compare the management of pneumonia in a university hospital versus a general hospital, but most of these studies were conducted in the USA and other parts of the world. There are no published studies in Malaysia or Asia to our knowledge.
  • This study also provides the difference in the outcome, cost and cost-effectivness of treating pneumonia between a university hospital and a general hospital.

To the practitioners:

  •     This study will provide information about the adherence to guidelines will reduce the length of hospital stay, reduce the cost of treating pneumonia and improve outcomes of treating pneumonia.

To the patients:

  •      This study attempts to highlight the benefits associated with adherence to the guidelines.

To the policy makers:

  • This study will help policy makers to develop new strategies for management of pneumonia.
  • This study will help policy makers to develop new guideline for management of pneumonia according to the microorganisms and the population in Malaysia.
  • This study also provides the difference in the management of pneumonia between a university hospital and a general hospital.
  • This study will provide information about how we can reduce the length of hospital stay, reduce the cost of treating pneumonia and improve outcomes of treating pneumonia.
  • The results of this study will help in improving the management of pneumonia.
  • It is the time to know whether a university hospital (H-USM) provide good outcome for treating pneumonia or do a general hospital (Penang-GH) provide comparable outcome at lower costs.
  • By analyzing the cost and effectiveness of the regimens being used, the most effective therapy can be defined and the information can be offered to the policy makers to improve the deciosion making in treating pneumonia.

The study will be able to help on:

  • How we can make the drug therapy cost effective keeping effectiveness and outcome in our mind and try to suggest the best and most appropriate drug therapy which should be cost effective which help to decrease the financial burden on patients as well as Ministry Of health.
  • This study will help to suggest how we can reduce the cost of therapy of treating pneumonia.

The study will be able to provide data on:

  1. The incidence of pneumonia in (H-USM and Penang-GH).
  2. The most common organisms causing pneumonia in (H-USM and Penang-GH).
  3. The pattern of drugs used and management of pneumonia in in (H-USM and Penang-GH).
  4. The outcome of treating pneumonia in (H-USM and Penang-GH).
  5. The cost of treating pneumonia in (H-USM and Penang-GH).
  6. The cost-effectivness of treating pneumonia in (H-USM and Penang-GH).
  7. Whether a university hospital provide a good outcome for management of pneumonia, or a general hospital provide comparable quality at lower costs.

1.4 Hypothesis of the Study:

  • H0: There is no significant difference of the management of pneumonia between a universiry hospital (H-USM) and a general hospital (Penang-GH).
  • H1: There is a significant difference of the management of pneumonia between a universiry hospital (H-USM) and a general hospital (Penang-GH).

1.5 Aim of the study

The aim of this study is to compare the management of pneumonia in a university hospital (H-USM) versus a general hospital (Pinanag-GH).

1.6 Objectives

The objectives of this study are:

  • To compare the incidence of pneumonia at a university hospital (H-USM) versus a general hospital (Penang-GH).
  • To compare the most common organisms associated with pneumonia at a university hospital (H-USM) versus a general hospital (Penang-GH).
  • To compare the drug therapy for pneumonia at a university hospital (H-USM) versus a general hospital (Penang-GH).
  • To compare the outcome of treating pneumonia (mortality rate, length of hospitalization, pneumonia related symptoms at discharge and complications of pneumonia) at a university hospital (H-USM) versus a general hospital (Penang-GH).
  • To compare the cost of treating pneumonia at a university hospital (H-USM) versus a general hospital (Penang-GH).
  • To compare the cost-effectivness of treating pneumonia at a university hospital (H-USM) versus a general hospital (Penang-GH).

1.7 Research Questions

  • What are the difference between the organisms that is commonly associated with pneumonia at H-USM and Penang-GH?
  • What are the difference between the antibiotics that is commonly used for the treatment of pneumonia at H-USM and Penang-GH?
  • What are the difference between the outcome of treating pneumonia (mortality rate, length of hospitalization, pneumonia related symptoms at discharge and complications of pneumonia) at H-USM and Penang-GH?
  • What are the difference between the cost of treating pneumonia at H-USM and Penang-GH? And how can these costs be reduced?
  • What are the difference between the cost-effectivness of treating pneumonia at H-USM and Penang-GH?
  • Do a university hospital (H-USM) provide good outcome for treating pneumonia or do a general hospital (Penang-GH) provide comparable outcome at lower costs?

CHPTER 2

LITERATURE REVIEW

2.1 Community-acquired pneumonia

2.1.1 Introduction

     Community-acquired pneumonia (CAP) is defined as an acute infection of the pulmonary parenchyma that is associated with at least some symptoms of acute infection, a new infiltrate on chest x-ray or auscultatory findings such as altered breath sounds and/or localized rales in community-dwelling patients (Infectious Diseases Society of America 2000). It is a common condition that carries a high burden of mortality and morbidity, particularly in elderly populations. Although most patients recover without sequellae, CAP can take a very severe course, requiring admission to an intensive care unit (ICU) and even leading to death. According to US data, it is the most important cause of death from infectious causes and the sixth most important cause of death overall (Adams et al. 1996). Even though the mortality from pneumonia decreased rapidly in the 1940s after the introduction of antibiotic therapy, it has remained essentially unchanged since then or has even increased slightly (MMWR 1995). Furthermore, significant costs are associated with the diagnosis and management of CAP. Between 22% and 42% of adults with CAP are admitted to hospital, and of those, 5% to 10% need to be admitted to an ICU (British Thoracic Society 2001). In the US, it is estimated that the total cost of treating an episode of CAP in hospital is about USD $ 7500, which is approximately 20 times more than the cost of treating a patient on an outpatient basis (Lave et al. 1999). CAP also contributes significantly to antibiotic use, which is associated with well-known problems of resistance. In treating patients with CAP, the choice of antibiotic is a difficult one. Factors to be considered are the possible etiologic pathogen, the efficacy of the substance, potential side-effects, the treatment schedule and its effect on adherence to treatment as well as the particular regional resistance profile of the causative organism and the co-morbidities that might influence the range of potential pathogens (such as in cystic fibrosis) or the dosage (as in the case of renal insufficiency). It may be a primary disease occurring at random in healthy individuals or may be secondary to a predisposing factor such as chronic lung disease or diabetes mellitus. CAP represents a broad spectrum of severity, ranging from mild pneumonia that can be managed by general practitioners outside the hospital to severe pneumonia with septic shock needing treatment in intensive care unit. Depending on severity of illness, about 20% of patients with pneumonia need hospitalization and approximately 1% of all CAP patients require treatment in ICU. Elderly persons and those with underlying conditions, such as cerebro and cardiovascular diseases, chronic obstructive pulmonary disease (COPD) and alcoholism, are at increased risk for developing lower respiratory tract infections and complicated courses of infection.

2.1.2 Definition:

     Community-Acquired pneumonia (CAP) is defined as inflammation and consolidation of lung tissue induced by infectious microbes such as bacteria, viruses, or parasites. When the onset of symptoms and signs of this disease is before or within 48 hours after admission, it is considered as CAP (Bartlett JG et al., 1995).

2.1.3 Epidemiology & Incidence:

    In the industrialized world, the annual incidence of CAP in community dwelling adults is estimated at 5 to 11 cases per 1000 adult population (British Thoracic Society 2001). The incidence is known to vary markedly with age, being higher in the very young and the elderly. In one Finnish study, the annual incidence for people aged 16-59 years was 6 cases per 1000 population, for those 60 years and older it was 20 per 1000, and for people aged 75 and over, 34 per 1000 (Jokinen et al. 1993). Annual incidences of 30-50 per 1000 population have been reported for infants below 1 year of age (Marrie 2001). Seasonal variations in incidence are also significant, with a peak in the winter months (Marrie 2001). The annual incidence of CAP requiring hospitalisation has been estimated at 1 to 4 patients per 1000 population (Marrie 1990, Fine et al. 1996). The proportion of patients requiring hospitalisation varies from country to country and across studies and has been estimated as ranging anywhere between 15% and 56% (Foy et al. 1973, Minogue et al. 1998). Of those, 5% to 10% required admission to an intensive care unit (ICU) (British Thoracic Society Research Committee and Public Health Laboratory Service 1992, Torres et al. 1991). Conversely, about 8% to 10% of admissions to a medical ICU are due to severe CAP (Woodhead et al. 1985). Community acquired pneumonia (CAP) is a leading infectious disease cause of death throughout the world (WHO Statistical Information System (WHOSIS). WHO Mortality Database. Released: January 2005; Health, United States, 2005; Annual Report, Hong Kong, 2003/2004).

     Adult community-acquired pneumonia is a serious, life-threatening illness that affects more than 3 million people each year and accounts for more than half a million annual hospital admissions in the United States alone (Lynch JP, 1992).

     Each year, more than 900 000 cases of pneumonia occur in the United States, accounting for nearly 3% of all hospital admissions,(National Hospital Discharge Survey, 1988) and about 50 000 people die as a result of community-acquired pneumonia (Farr BM et al 203).

     Bartlet et al (1998) found that viral infections have been associated with at least 10% to 15 % of CAP in hospitalized adults.

        Adult community-acquired pneumonia is a serious, life-threatening illness that affects more than 3 million people each year and accounts for more than half a million annual hospital admissions in the United States alone.

Each year, more than 900 000 cases of pneumonia occur in the United States, accounting for nearly 3% of all hospital admissions, and about 50 000 people die as a result of community-acquired pneumonia. In the USA, community acquired pneumonia is the fifth leading cause of death in people over the age of 65 years and an estimated 60 000 seniors die annually. Most of the excess deaths and hospitalizations due to lower respiratory infections occur in older adults, as reflected by the more than 44 000 hospitalizations for pneumonia and influenza in people aged 65 and older in 1997 in Canada. It is estimated that the age-specific incidence of pneumonia increases from 15.4 cases per 1000 in those aged 60-74 years to 34.2 for those 75 years and older. Residents of long-term care facilities, a distinct subpopulation of elderly people, are at particularly high risk for developing nursing-home acquired pneumonia. Health costs for this sector are growing at an accelerated rate as the age of death increases. Thirteen percent of the population is over the age of 65 in the United States and this is expected to increase to 20% by 2030. In Canada, the proportion of individuals over the age of 65 is expected to rise to 20% in the year 2021. Presently, while making up 12% of the Canadian population, older adults account for 31% of acute hospital days and half of all hospital stays. To meet their health-care needs and alleviate the burden onthe health-care system, we must improve our understanding of the management and prevention of pneumonia in this age group. Elderly people constitute an ever-increasing proportion of the population. CAP has traditionally been recognized as problems that particularly affect the older individuals. According to western studies, the overall rate of pneumonia requiring hospitalization increase with age, from 1 per 1,000 persons in the general population but increases to 12 per 1,000 persons for those over age 75 years3. As the population of those over age 65 years is predicted to rise from its current level of 11% to 25 % of the total population in the year 20504, respiratory tract infection will assume a greater degree of importance to the overall public health. In Hong Kong, pneumonia was the fourth leading death from a specific diagnosis in 2001. A total of 3026 people died of pneumonia in 2001 which 1526 cases were male. Out of the 3026 deaths, 2794 patients were 65 or older which accounted for more than 90% of the total death. Pneumonia in the elderly population is a major cause of morbidity and mortality and in some series represents the leading cause of death. The annual cost of treating patients age > 65 years with pneumonia to be $4.8 billion, compared with $3.6 billion for those < 65 years with pneumonia. The average hospital stay for an elderly person with pneumonia was 7.8 days, at cost of $7166, whereas for a younger patient the corresponding values were 5.8 days and at cost of $6042. Global mortality of the elderly patients hospitalized for CAP was 9.8% - 29%H'14. The cause of the death was attributed to acute respiratory failure (37%), septic shock and/or multiple organ failure (63%). Recovery is also prolonged in the elderly, especially the frail elderly who may require up to several months to return to their baseline state of mobility. Indeed, hospitalization often hastens functional decline in the elderly. 25-60% of elderly patients experience a loss of independent physical function during hospitalization. Twenty-one percent of those aged >85 years need help with bathing and 10% need help in using the toilet and transferring. The present of any or all of following identifies elderly persons at greatest risk for functional decline: pressure ulcer, cognitive impairment, functional impairment, and low level of social activity. The attack rate for pneumonia is highest among those in nursing homes. It is found that 33 of 1,000 nursing home residents per year required hospitalization for treatment of pneumonia, compared with 1.14 of 1,000 adults living in the community.

     Pneumonia is a major cause of morbidity and mortality worldwide. In the UK as a whole, pneumonia is responsible for over 10% of all deaths (66,581 deaths in 2001), the majority of which occur in the elderly.

     Community-acquired pneumonia (CAP) remains a common cause of morbidity. Because CAP also is a potentially fatal disease, even in previously healthy persons, early appropriate antibiotic treatment is vital. In Japan, pneumonia is the fourth leading cause of death, and from 57 to 70 persons per 100,000 populations died per year of this disease in the last decade.

     Community acquired pneumonia (CAP) is a leading infectious disease cause of death throughout the world, including Hong Kong,

     Pneumonia is the second most common infectious disease in Thailand. Whereas diarrhea is more common, pneumonia is associated with more fatalities.

     CAP remains the leading cause of death due to infectious diseases, with an annual incidence ranging 1.6-10.6 per 1,000 adult populations in Europe

     According to the Ministry of Health Malaysia (MOH), pneumonia is the 5th cause of death in Malaysia and the 4th cause of hospitalization.

     A prospective observational study by Jae et al (2007) of 955 cases of adult CAP in 14 hospitals in eight Asian countries found that the overall 30-day mortality rate was 7.3%.

     A prospective study by Liam CK et al (2001) of 127 cases of CAP in Malaysia found that the Mortality from CAP is more likely in patients with comorbidity and in those who are bacteraemic.

    A prospective study by LOH et al (2004) of 108 cases of adult CAP in urban-based university teaching hospital in Malaysia found that the mortality rate from CAP in hospital was 12%.

2.1.4 Syndromes of CAP

The presence of various signs and symptoms and physical findings varies according to the age of the patients, therapy with antibiotics before presentation, and the severity of illness. Patients with pneumonia usually present with cough (>90%), dyspnea (66%), sputum production (66%% pleuritic chest pain (50%), and chills is present in 40-70% and rigor in 15%. However, a variety of nonrespiratory symptoms can also predominate in pneumonia cases, including fatigue (91%), anorexia (71%), sweating (69%), and nausea (41%).

Metlay et al. (1997c) divided 1812 patients with CAP into four age groups: 18 through 44 years (43%), 45 through 64 years (25%), 65 through 74 years (17%), and 75 years or older (15%). For 17 of the 18 recorded symptoms there were significant decreases in reported prevalence with increasing age (p <.01). For example, the prevalence of cough was 90% in the youngest age group and 84% in the oldest. Other symptoms that differ in prevalence in the youngest and oldest age groups, respectively, include dyspnea (75% and 64%); sputum production (64% and 64%); pleuritic chest pain (60% and 31%); hemoptysis (19% and 12%); fatigue (83% and 84%); fever (85% and 53%); chills (85% and 52%); anorexia (77% and 64%); sweats (83% and 2945%); headache (72% and 36%); myalgia (67% and 25%); nausea (48% and 31%); sore throat (45% and 27%); inability to eat (31% and 14%); vomiting (29% and 21%); diarrhea (29% and 21%); and abdominal pain (27% and 18%). Fine et al 1998 found that Hypothermia and hyperthermia were present in only 1% and 1.3% of the patients, respectively. About 80% of the patients had an oral temperature reading of >37°C at presentation. Crackles were present on auscultation in 80% of patients, and rhonchi in 34% to 47% (more common in the nursing home patients). About 25% had the physical findings of dullness to percussion, bronchial breathing, whispered pectoriloquy, and aegophony. Alteration in mental status was common. Marrie and coworkers (1989) reported confusion in 48% of the patients with nursing home-acquired pneumonia and in 30% of the other patients with CAP. Fine and colleagues (1998) define altered mental status as stupor, coma, or confusion representing an acute change from the usual state prior to presentation with pneumonia. This was present in 17.3% of the hospitalized patients. The decrease in symptoms with increasing age, tachypnea increased with increasing age (Metlay et al., 1997c). Thirty-six percent of 780 patients with CAP in the 18-44 year age group had tachypnea on admission versus 65% of the 280 patients who were = 75 years old. There were minimal differences in the proportion of patients with tachycardia and hyperthermia in the different age groups Pneumonia in the elderly are quite different from that in a younger population. These differences are due to age-related alterations in immunology, different epidemiology and bacteriology. It is important to remember that pneumonia in the elderly may report fewer respiratory signs and symptoms. The clinical presentation may be more subtle than in younger population, with more gradual onset, less frequent complaints of chill and rigors, and less fever. The classical finding of cough, fever, and dyspnea may be absent in over half of elderly patients8. Instead they may be manifest as delirium, a decline in functional status, weakness, anorexia, abdominal pain, or decrease general condition. The incidence of fever may decline with age, and the degree of fever appears lower in old population10. Tachypnea which respiration rate greater than 24-30 breaths per minute is noted more frequently in up to 69% of patients. Although rales are common and are noted in 78% of patients, signs of true consolidation are found in only 29%. Bacteremia, metastatic foci of infection and death are more frequent in older populations. As many elderly present with non-specific clinical symptoms and nonspecific functional decline that makes an accurate diagnosis difficult and may lead a life-threatening delay of diagnosis and therapy. Metlay et al. compared the prevalence of symptoms and signs of pneumonia in a cohort of 1812 patients and found that patients aged 65-74 years and over 75 years had 2.9 and 3.3 fewer symptoms, respectively, than those aged 18 through 44 years. The reduced prevalence of symptoms was most pronounced for symptoms related to febrile response (chills and sweats) and pain (chest, headache, and myalgia). These findings are consistent with those of Marrie et al. demonstrating reduced prevalence of non-respiratory symptoms among elderly patients. In a retrospective chart review by Johnson et al., the presence of dementia seemed to account for non-specific symptoms. However the sample size of the study was small and precluded a multivariable analysis. Roghmann et al found a significant inverse correlation between age and initial temperature in 320 older patients hospitalized for pneumonia. Evidence therefore does exist for a less distinct presentation of nonrespiratory symptoms and signs of pneumonia in the elderly.

2.1.5 Radiographic findings in CAP

Radiographic changes usually cannot be used to distinguish bacterial from nonbacterial pneumonia, but they are often important for diagnosis of CAP, evaluating the severity of illness, determining the need for diagnostic studies, and selecting antibiotic agents. A chest radiograph usually shows lobar or segmental opacification in bacterial pneumonias and in the majority of atypical infections. Patchy peribronchial shadowing or more diffuse nodular or ground-glass opacification is seen less commonly, particularly in viral and atypical infections. The lower lobes are most commonly affected in all types of pneumonia. Small pleural effusions can be detected in about one-quarter of cases. Multilobar pneumonia is a feature of severe disease, and spread to other lobes despite appropriate antibiotics is seen in Legionella and M. pneumoniae infection. Hilar lymphadenopathy is unusual except in Mycoplasma pneumonia, particularly in children. Cavitation is uncommon but is a classic feature of S. aureus and S. pneumoniae infections. False negative results can be attributed to dehydration, evaluation during the first 24 hours, pneumonia due to Pneumocystis carinii, or pneumonia with profound neutropenia.

2.1.6 Etiology:

More than 100 microorganisms have been identified so far as potential causative agents of CAP (Marrie 2001). They can be classified according to their biological characteristics as either bacteria, mycoplasma and other intracellular organisms, viruses, fungi and parasites. The most common causative agent of CAP is the bacteriumStreptococcus pneumoniae, which is implicated in 20% to 75% of cases of CAP (Marrie 2001) and about 66% of bacteremic pneumonia (Infectious Diseases Society of America 2000). Another causative bacterium is Haemophilus influenzae. So called “atypical” organisms have also been implicated as causal agents. These include Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila (Marrie 2001). Influenza is the most common serious viral pathogen causing airway infections in adults (Infectious Diseases Society of America 2000). Although it does not itself cause pneumonia, it's most common serious complication is bacterial superinfection, usually due to Streptococcus pneumoniae. Affected patients are primarily older than 65 years and/or residents of chronic care facilities. Effective prevention is possible through yearly vaccination of populations at risk and should include vaccination of those who care for such patients (Potter et al. 1997).

The identification of the causal organism is a challenging task: since lung tissue cannot be routinely obtained, clinicians must rely on sputum samples - which can only be obtained successfully in about 33% of patients - or on blood cultures, that are positive in only 6% to 10% of patients with CAP (Canadian Community- Acquired Pneumonia Working Group 2000). Furthermore, it takes a minimum of 2 to 3 working days to obtain culture results, be it from sputum samples or blood. Consequently, it is often necessary to initiate therapy on empiric grounds alone. Furthermore, routine surveillance of samples sent to microbiology labs by primary care physicians does not provide an accurate picture of the actual situation in the community, as samples are often sent only when a first, empirical therapeutic attempt has failed. Although there are many microorganisms that can cause pneumonia, only a few cause most of the cases of pneumonia. They are S. pneumoniae, H. infuenzae, S. aureus, C. pneumoniae, Enterobacteriaceae, Legionella species, Influenza viruses, and respiratory syncytial virus. The rank order of causes of pneumonia changes according to the severity of illness, which is usually reflected in the chosen sit of care. The basic microbial patterns comprise (1) £ pneumoniae, (2) an atypical group, (3) nonpneumococcal- non-atypical group, and (4) the microbiologically negative group. The relative frequency of each group is affected by the severity of pneumonia, age, comorbidity, season, and individual risk factors. In many studies, patients with pneumonia due to S. pneumoniae often recognized as the most prevalent bacterial pathogen in CAP. Around 30-40% of cases of CAP are caused by S. pneumoniae, C. pneumoniae (21%), Gramnegative bacilli (5%). H. influenzae, usually a nontypable strain, is frequently the second most common agent, accounting for 7-11% of episodes. Other aerobic gram-negative bacilli, especially K. pneumoniae and S. aureus (19%), play important roles as well. Mortality is strongly associated with the etiology of the infection. Patients with P. aeruginosa, S. aureus, and enteric gram-negative rod pneumonias (eg, Klebsialla species and E. coli) have an extremely high risk of death.

Micro-organisms that can cause CAP in immunocompetent persons are numerous. Throughout the world, Streptococcus pneumonia is by far the most frequently isolated pathogen. Other frequently isolated bacteria are Haemophilus Influenzae and Staphylococcus aureus. Pseudomonas aeruginosa should be considered as a possible causative micro-organism in patients with structural damage of the respiratory tract, for example in patients with bronchiectasis or COPD. Atypical pathogens as Mycoplasma pneumonia, Chlamydia pneumoniae and Legionella pneumophila are also causes of community-acquired pneumonia, although their contribution to the etiology of CAP varies widely. Most frequent viral causes of community-acquired pneumonia include influenza virus, para-influenza virus and corona virus. However, even in study settings with extensive diagnostic testing, approximately 50% of episodes of CAP remain of unknown etiology. Some clinical features are associated with causative micro-organisms and may therefore, guide initial therapy, such as flucloxacillin treatment for CAP preceded by influenza because of a high risk of S. aureus infection, and cephalosporins with antipseudomonas activity in patients with bronchiectasis or other structural damage to the lungs, who are at risk for pseudomonas colonization. In general however, the microbial cause of CAP cannot be predicted upon clinical, radiological and laboratory features. Routine diagnostic procedures to identify these pathogens include Gram-staining of expectorated sputum, culturing of blood and sputum and serologic testing of acute and reconvalescent blood samples. Recently, diagnostic tests that can provide results within minutes to hours have become available. These include rapid urinary antigen testing for Legionella pneumophila sero group and S. pneumoniae and real-time PCR-tests of respiratory samples to detect respiratory viruses whether these diagnostic techniques enhance the etiologic yield in CAP, lead to cost-savings or more targeted antimicrobial treatments, however, is unknown. The course of pneumonia can be complicated by development of progressive pneumonia, despite appropriate antimicrobial treatment, development of pleural empyema, uncontrolled sepsis or death.

     These are some of the differences in the microbiology of CAP in Asia, as compared to what is reported in the West that must be taken into consideration when selecting tile appropriate initial empirical antibiotic therapy of CAP in Asia.

Specific etiology diagnoses are made less frequently in elderly patients, with approximately 20-40% of patients having an etiologic agent defined.The absence of productive cough and prior use of antibiotics help to explain this observation. In general, the cause of CAP in the elderly population follows the general trend of infection in younger population. The etiology has some difference as a function of deteriorating functional status, increased severity, and numbers of coexisting medical illness. S. pneumoniae remains the predominant organism, accounting for 20-60% of cases. H. influenzae is frequently the second most common agent, accounting for 7-11% of episodes. Other aerobic gram-negative bacilli, especially K. pneumoniae and S. aureus, play important roles as well, especially in elderly patients in nursing homes or extended care facilities. The role of ‘atypical' pathogens is controversial because the frequency of isolating these organisms is largely dependent on the diagnostic tests and criteria used, and it is uncertain whether these organisms infect along with a bacterial pathogen, or if they cause an initial infection that then predisposes to secondary bacterial infection. The term of ‘atypical' pathogen is misleading since these organisms do not cause a distinctive clinical syndrome. ‘Atypical' agent usually refers to the following group of organisms (M pneumoniae, C. pneumoniae and Legionella spp.). The diagnosis of infection of these atypical pathogens were generally based on serological testing, documenting fourfold rises in titres to Mpneumoniae, C pneumoniae, ox Legionella spp, and some of these diagnoses have been made with non-paired single high titre. The diagnosis would be more reliable if testing for surface antigens of these pathogens, or cultures of respiratory secretions were carried out. The role of agents causing atypical pneumonia in the elderly population remains unclear. Most series suggest that M. pneumoniae pneumonia is unusual, though it has been documented by others to be a significant cause of atypical pneumonia leading to hospitalization in the elderly patients. Chalamydial infection also occurs in the elderly population though the incidence varies. Viral agents also play an important role in causing pneumonia in the elderly population. In one series, both respiratory syncytial virus and influenza A caused infection 10-11% of the patient studies. Forty-eight percent of those infected with respiratory syncytial virus and 30% of those infected with influenza virus had pneumonia. As on younger populations, dyspnea, wheezing and sputum production are hallmarks of disease with those agents, with bronchospasm appearing more frequently with respiratory syncytial virus24'25. Coinfection with bacteria was noted in over 17% of cases, making interpretation of actual role of viruses in presenting symptoms of pneumonia somewhat unclear. Rhinovirus also appears to be an important cause of respiratory infection in elderly persons, with 24% of some population infected. Although about two thirds of those infected have lower respiratory tract symptoms, the role of rhinovirus as a cause of pneumonia is unclear. Jokinen et al. obtained paired serum samples from 88% of 345 episodes of community-acquired pneumonia in four municipalities in Finland where adults met clinical and radiological eligibility criteria. One hundred and forty (46%) of these cases were in persons aged 60 years or greater. Streptococcus pneumoniae was the etiologic agent in 48% of cases aged 60 and over, Chlamydia species were detected in 12%, Mycoplasma pneumoniae in 10%, Haemophilus influenzae in 4%, and respiratory viruses (parainfluenza, respiratory syncytial virus, adenovirus and influenza virus) in 10%. The study confirms the importance of S. pneumoniae in causing communityacquired pneumonia, whether in an unselected cohort of the elderly or in a compilation of data from serological studies in which pneumococcus accounted for 50% of cases. The recent estimates of the prevalence of so-called ‘atypical agents' in older people by Jokinen et al. fall within the range of previous prevalences of C. pneumoniae in the elderly (from 6% to 26%). They also complement Marrie's report, in which six (9%) of 64 patients with community-acquired pneumonia due to Mycoplasma pneumoniae were 65 years of age or older. Although atypicals occur in the elderly, they are relatively more important in younger populations. This was illustrated in a hospital-based study from Spain, in which Ruiz et al. found an increase in ‘atypical' pathogens in persons under the age of 60 years (odds ratio [OR] 2.3, 95%confidence interval [CI] 1.2- 4.5) but no discernable pattern in the elderly. Nevertheless, Legionella pneumophila must be considered as a potential cause of community-acquired pneumonia in the elderly, occurring in 8% of patients in this study. The role of gram negative bacterial pneumonia in elderly people living in the community is uncertain. However, evidence does exist that gram negatives play a more important role in older patients with comorbidities. Ruiz et al. demonstrated that patients aged 60 years and over who had a comorbid condition (cardiopulmonary, renal, hepatic, diabetes, central nervous system or neoplasia) had a greater likelihood of pneumonia due to a gram negative enteric bacillus (OR 4.4, 95%CI 1.2- 23.4, P 0.01) and Pseudomonas aeruginosa (OR 6.7, 95%CI 1.0-291, P 0.04). Additionally, gram negative pneumonia including P. aeruginosa along with pneumonia caused by S. pneumoniae appears to be associated with increased severity. Ruiz et al. reported that pneumonia requiring admission to the intensive care unit was independently associated with pneumococcus (OR 2.5, 95%CI 1.3-4.7), gram negative enteric bacilli and P. aeruginosa (OR 2.5, 95%CI 0.99-6.5). Along similar lines, Rello et al. found that of elderly patients admitted to the intensive care unit for community-acquired pneumonia, S. pneumoniae, Haemophilus influenzae Or other gram negative bacteria were the most common etiologic agents. El-solhet al., who assessed the etiology of severe pneumonia in elderly patients requiring mechanical ventilation, identified the following as the predominant pathogens: S. pneumoniae, gram-negative enteric bacteria, Legionella, Haemophilus influenzae And S. aureus.

     A prospective study by Liam CK et al (2001) of 127 cases of CAP in Malaysia found that the microbiology of CAP in patients requiring hospitalization in Malaysia appears to be different from that in Western countries.

     A prospective study by Chong-Kin Liam et al (2000) of 127 cases of adult CAP in Malaysia, found that the microbiology of CAP in patients requiring hospitalization in Malaysia appears to be different from that in Western countries. Gram-negative bacilli were more frequently isolated in older patients and in those with comorbidity. Mortality from CAP is more likely in patients with comorbidity and in those who are bacteraemic

2.1.7 Risk factors:

A variety of risk factors predisposing a patient to CAP have been identified. These include host factors, such as chronic obstructive pulmonary disease (COPD), alcoholism or immune suppression, environmental factors, such as exposure to certain animals, for example parrots (Chlamydia psittaci), parturient cats and sheep (Coxiella burnetii), and rabbits (Francisella tularensis), recent hotel stay (Legionella pneumophila), travel abroad or in endemic regions (Coccidioides immitis, Histoplasma capsulatum), and occupational factors, such as contact with body fluids containing infective agents (Mycoplasma tuberculosis) (Canadian Community-Acquired Pneumonia Working Group 2000). Smoking is also thought to be an important risk factor for acquiring CAP (Marrie 2001). As outlined above, a number of risk factors are related to particular causative organisms and enquiring about their presence may improve diagnostic accuracy with respect to the etiologic agent, however the British Thoracic Society (2001) cautions that due to the low frequency of some of these organisms in patients with CAP and the high frequency of the risk factors for exposure to these organisms in the population, routine questioning about such risk factors may be misleading. There are several risk factors, which enhanced the elderly to contract CAP. In one study, independently defined risk factors for CAP included alcoholism (Odd ratio, 9.0), asthma (OR, 4.2), immunosupression (OR, 3.1), and heart disease (OR, 1.9). Chronic obstructive pulmonary disease (COPD), dementia, seizures, congestive heart failure, cerebrovascular disease and malignancy are consistently reported in association with pneumonia requiring hospitalization1. More important is the cumulative effect of multiple medical illnesses, which continues to impair the host defense mechanism. With increasing age, it becomes more likely that more than one significant medical illness will be present. Recent studies have highlighted the association of the level of functional dependence, cognitive impairment, malnutrition, and hypoalbuminemia as specific risk factors for pneumonia in elderly; these factors may merely reflect the overall state of health and of host defenses. In addition, cigarette smoking is the strongest independent risk factor for invasive pneumococcal disease among immunocompetent adults. It is likely that this is also true for the elderly population. Recurrent aspiration, which has been identified as an independent risk factor for pneumonia in older individuals, integrates many of the above predispositions and serves as a potentially modifiable problem. There is a high incidence of silent aspiration in the elderly patient withCAP. Ageing itself results in reduced lung elasticity and respiratory muscle strength, with potential impact on secretion clearance after aspiration. It is also found that placement of a feeding tube in patients who had aspirated was associated with higher rate of pneumonia and death than for those who aspirated have no tube. There are several risk factors, which enhanced the elderly to contract CAP. In one study, independently defined risk factors for CAP included alcoholism (Odd ratio, 9.0), asthma (OR, 4.2), immunosupression (OR, 3.1), and heart disease (OR, 1.9). Chronic obstructive pulmonary disease (COPD), dementia, seizures, congestive heart failure, cerebrovascular disease and malignancy are consistently reported in association with pneumonia requiring hospitalization. More important is thecumulative effect of multiple medical illnesses, which continues to impair the host defense mechanism. With increasing age, it becomes more likely that more than one significant medical illness will be present. Recent studies have highlighted the association of the level of functional dependence, cognitive impairment, malnutrition, and hypoalbuminemia as specific risk factors for pneumonia in elderly; these factors may merely reflect the overall state of health and of host defenses. In addition, cigarette smoking is the strongest independent risk factor for invasive pneumococcal disease among immunocompetent adults. It is likely that this is also true for the elderly population. Recurrent aspiration, which has been identified as an independent risk factor for pneumonia in older individuals, integrates many of the above predispositions and serves as a potentially modifiable problem. There is a high incidence of silent aspiration in the elderly patient with CAP. Ageing itself results in reduced lung elasticity and respiratory muscle strength, with potential impact on secretion clearance after aspiration. It is also found that placement of a feeding tube in patients who had aspirated was associated with higher rate of pneumonia and death than for those who aspirated have no tube. Koivula et al. assessed risk factors for communityacquired pneumonia in a township in Finland, where 4175 individuals were aged 60 years or more. Independent risk factors for pneumonia included alcoholism (relative risk [RR] 9.0, 95%CI 5.1-16.2), bronchial asthma (RR 4.2, 95%CI 3.3-5.4), immunosuppression (RR 3.1, 95%CI 1.9-5.1), lung disease (RR 3.0, 95%CI 2.3-3.9), heart disease (RR 1.9, 95%CI 1.7-2.3), institutionalization (RR 1.8, 95%CI 1.4-2.4) and increasing age (70 years or more vs 60-69 years, RR 1.5, 95%CI 1.3-1.7). Two hundred and seventy-four episodes of pneumonia were documented over the three-year study period. Since this study included patients from primary care units and hospitals in the township, a carefullydefined population, the results are more likely to be representative of pneumonia occurring in the community than studies limited to an acute care setting. In another community-based study in which risk factors for community- acquired pneumonia diagnosed by general practitioners were assessed, Farr et al. found that increasing age (adjusted OR of 2.69 for a 30 years increment, 95%CI 1.66-4.35) and chronic obstructive pulmonary disease (adjusted OR 1.99, 95%CI 1.15-3.45) were risk factors. Derivation of the study sample plays an important role in determining risk factors for community- acquired pneumonia in the elderly. For example, Riquelme et al. found that that large-volume aspiration, and low serum albumin (< 30 mg/dL) were independent risk factors associated with communityacquired pneumonia in a hospital-based case-control study.

Environmental factors

There is a clear seasonal variation in the rate of pneumonia. The attack rates and mortality rate are high in the winter time. It is likely due to aninteraction between viruses such as influenza virus and S. Pneumoniae, and confinement indoors.

2.1.8 Diagnosis

The diagnosis of CAP remains a challenge for clinicians. There is no single finding that is pathognomonic of CAP, and even the gold-standard chest x-ray may fail to provide the necessary information to make the correct diagnosis. However, there is good evidence supporting the view that the diagnosis of CAP is inaccurate without a chest X-ray (British Thoracic Society 2001). It is important to differentiate between CAP and other lower respiratory tract infections, such as acute bronchitis, and to differentiate between these entities and other potential causes of similar symptom complexes, such as pulmonary neoplasia, congestive heart failure or pulmonary embolism, as the subsequent management of such patients differs greatly. Most cases of upper respiratory tract infections and acute bronchitis are caused by viruses, and therefore do not require antibiotic treatment (Infectious Diseases Society of America 2000). The use of antibiotics in such cases is inappropriate and should be avoided. Despite the importance accorded to history, physical examination, chest x rays and some laboratory investigations in the assessment of patients suspected of having CAP, only very few studies have attempted to assess the validity of such approaches (Canadian Community-Acquired Pneumonia Working Group 2000). Furthermore, none of these studies relied on autopsies as a diagnostic gold standard. Instead, they used chest x-rays or even clinical suspicion to decide whether pneumonia was present, thus making the validity of their conclusions highly questionable. Another factor that further complicates the diagnosis of CAP are inter observer variations in the identification of symptoms and signs in patients suspected of having CAP. The reliability of physical signs has been studied and found to be highly variable (Spiteri et al. 1988, Schilling et al. 1955). As for symptoms, inter-observer reliability has not been studied, but it is known from studies of other respiratory conditions that there is significant variation between observers (Cochrane et al. 1951, Fletcher 1964)., a urine test for rapid detection of Streptococcus pneumoniae has been approved by the American Food and Drug Administration (FDA) (Henney 1999). The test can be carried out in the physician's office or in the emergency room, requires only 5 ml of urine and results are available within 15 minutes. The test is reported to have a sensitivity of 86% to 90% and a specificity of 71% to 94%. It is intended as an adjunct to the usual clinical, laboratory and radiological investigations for suspected CAP. Whether it will become part of the diagnostic armamentarium in actual practice remains to be seen. Consequently, the diagnosis of CAP should be made based on a combination of physical, laboratory, microbiologic and radiographic findings, keeping in mind that none of them is perfectly reliable for diagnosis (Canadian Community-Acquired Pneumonia Working Group 2000).

2.1.9 Treatment:

Since the majority of cases CAP are caused by organisms amenable to treatment with an antibiotic drug, rapid initiation of antibiotic treatment is indicated in the vast majority of cases. Difficulties arise when a clinician is confronted with the need to choose an antibiotic drug for a particular patient.

2.1.9 (a) Antibiotic resistance

The problem of antibiotic resistance has received increasing attention in recent years. The problem is not confined to community-acquired pneumonia; however, since CAP can take a very severe course even leading to death, it is a condition for which the issue of antibiotic resistance takes on even greater importance. Traditionally, the preferred antimicrobial agent for the treatment of Streptococcus pneumoniae was penicillin G (Infectious Diseases Society of America 2000). However, widespread penicillin use for a variety of infectious conditions has lead to the emergence and rise of penicillin resistance. Recent studies estimate the proportion of penicillin resistant Streptococcus pneumoniae at around 25% (Marrie 2001). Similarly, the use of other antibiotics has led to the emergence of resistance against these agents in a variety of microorganisms. For example, it is estimated that approximately 30% of Haemophilus influenzae isolates are resistant to amoxicillin (Marrie 2001).

Furthermore, the phenomenon of antibiotic resistance is subject to wide regional and international variations, as access to and patterns of use of antibiotics vary widely. As is the case with the identification of pathogens, it is also difficult to estimate the exact prevalence of antibiotic resistance in a particular area by simple surveillance of specimen sent to microbiology laboratories because these come from preselected patients, some them having already failed a first empirical treatment and therefore being more likely to carry a resistant pathogen. For this reason, some practice guidelines emphasize the importance of obtaining baseline microbiologic specimen - the minimum being a Gram stain, with or without culture - before initiation of empiric therapy (Infectious Diseases Society of America, 2000). Guidelines for the management of community-acquired pneumonia in the elderly have not been assessed in randomized controlled trials. However, various aspects of management have been addressed in observational studies including antibiotic use and various processes of care. Gleason et al. assessed outcomes associated with the American Thoracic Society antimicrobial guidelines in a cohort of 864 outpatients, of whom 318 were older than 60 years. The study showed that outpatients older than 60 years who were treated according to the guidelines (i.e. second generation cephalosporin, sulfamethoxazole-trimethoprim or beta-lactam-betalactamase inhibitor) had higher antimicrobial costs and a non-significant trend towards higher mortality and hospitalization. The small number of event rates may have limited the ability of the study to detect true differences. It should be noted that the use of sulfamethoxazole- trimethoprim is not favored as an empiric regimen in recent guidelines. Gleason et al also assessed the effect of specific antimicrobial therapy for hospitalized elderly patients with pneumonia. Initial treatment with a second generation cephalosporin and a macrolide (hazard ratios 0.71, 95%CI 0.52-0.96), a non-pseudomonal third-generation cephalosporin and a macrolide (hazard ratios 0.74, 95%CI 0.60-0.92), or a fluoroquinolone alone (hazard ratio 0.64, 95%CI 0.43-0.94) was associated with lower 30-day mortality when compared with a non-pseudomonal cephalosporin alone. Since estimates of effect are generally increased in observational studies, a randomized controlled trial is needed to confirm these findings. Meehan et al. evaluated the relationship between processes of care and outcomes in 14 069 hospitalized patients aged 65 years and over. Lower 30-day mortality rates were associated with antibiotic administration within 8 h of admission (OR 0.85, 95%CI 0.75-0.96) and blood culture collection within 24 h of arrival (OR 0.90, 95%CI 0.81-1.00). Using a pneumonia-specific severity-of-illness score developed by Fine et al. Marrie et al. conducted a cluster randomized trial in which hospitals were randomized to either a clinical pathway or to usual care. The clinical pathway integrated criteria for site of care (based on the pneumonia severity of illness score) as well as hospital discharge criteria. Although the trial was not limited to the elderly, the mean age of patients was 64 years. Use of the pathway was associated with an 18% decrease in the admission of low risk patients

2.1.9 (b) Prognosis

The prognosis of CAP ranges from full recovery without sequellae to death on an intensive care unit within a few days of disease onset. Because of this broad and dramatic spectrum, prognostic factors for the identification of high-risk patients have been the subject of much research. The Pneumonia Patient Outcome Research Team (Pneumonia PORT) has developed a clinical prediction rule to identify patients at risk of short-term mortality from CAP that is intended as a tool to assist clinicians in making decisions about the initial location and intensity of treatment (Fine et al. 1997). This prediction rule has gained wide acceptance and has been included into recent clinical practice guidelines (Infectious Diseases Society of America 2000, Canadian Community-Acquired Pneumonia Working Group 2000). In ambulatory patients, the mortality rate from pneumonia is low, probably below 1% (British Thoracic Society 2001), but some estimates go as high as 5% (American Thoracic Society 2001). In hospitalized patients, it hovers around 12%, increasing to close to 40% (American Thoracic Society 2001) or even 50% (British Thoracic Society 2001) in patients requiring admission to an ICU. In the pneumonia-specific prognostic score by Fine Et al. age was demonstrated to play an important role in increased mortality. Conte et al. reported that age (OR 1.8, 95%CI 1.1-3.1), comorbid disease (OR 4.1, 95%CI 2.1-8.1), impaired motor response (OR 2.3, 95%CI 1.4-3.7), vital sign abnormality (OR 3.4, 95%CI 2.1-5.4) and elevated creatinine level (OR 2.5, 95%CI 1.5-4.2) were independent predictors of mortality. The authors derived a clinical prediction rule that they validated in a separate cohort. In contrast, Lim et al compared elderly patients with community acquired pneumonia who died in hospital with those who survived, and found that among people 75 years and older, advanced age alone was not an important predictor of death. In a long-term follow up study, Koivula et al. reported that the relative risk of mortality in elderly patients with community-acquired pneumonia was 1.5(95%CI 1.2-2.2). In a retrospective analysis of Medicare claims, Metersky et al. noted a decline in length of stay along with a decline in adjusted inhospital mortality rates for elderly patients between 1992 and 1997. However, risk of discharge to a nursing facility, adjusted risk of hospital readmission, and adjusted risk of death 30 days after discharge increased although the difference was not statistically significant (P =0.09). The effect of nutrition on outcome of elderly persons with pneumonia may be important. Lacroix et al. found that the risk of death was 2.6 times higher in men with the lowest quartile compared to men with the highest quartile of body mass index.

2.1.9 (c) Practice guidelines for the treatment of community-acquired Pneumonia

In recent years, there has been an explosion in the number of clinical practice guidelines being produced and published. The field of infectious diseases is no exception, and a few guidelines for the diagnosis and treatment of community-acquired pneumonia have been published over the past decade. Most recently, four major professional societies have updated the guidelines they had published in the early 1990s. These guidelines are based on a combination of literature review and expert opinions. As such, they represent an attempt at synthesizing the available evidence and aim at providing clinicians with diagnosis and treatment strategies that are based as much as possible on the current state of knowledge. In the following sections, these guidelines will be examined in further detail in an attempt to get an overall view of the current state of knowledge with respect to CAP. These guidelines were identified in the course of searching the literature for studies and reviews concerned with community-acquired pneumonia.

American Thoracic Society (2001)

In 2001, the American Thoracic Society published an update of its original 1993 statement on community-acquired pneumonia (American Thoracic Society 2001). These guidelines were developed by a committee composed of pulmonary, critical care, infectious disease and general internal medicine specialists. Ambulatory care physicians, general practitioners in particular, appear to have been left out. This raises concerns that the ambulatory care perspective may have been neglected. The guidelines development strategy is described in detail; however there is no detailed account of how the literature was searched. The American Thoracic Society claims that its guidelines are evidence-based and reports using a classification system based on the system used by the Canadian Infectious Diseases Society and Canadian Thoracic Society in their CAP guidelines update (Canadian Community-Acquired Pneumonia Working Group 2000), however, they do not state the level of evidence for each of their therapeutic recommendations, nor do they give any specific references supporting those recommendations. Finally, the committee reports that they focused on “studies that included an extensive diagnostic approach to define the etiologic pathogen” and that “most [studies] involved hospitalized patients&rldquo; (American Thoracic Society 2001, p. 1733). This raises concerns that the evidence-base on which the recommendations for outpatients were made may have been insufficient. The new statement includes a summary of the available literature as well as “evidence-based recommendations for patient management” (American Thoracic Society 2001, p. 1730). The guidelines recommend that all patients with suspected

CAP should have a chest radiograph to confirm the diagnosis, yet they recognize that this may not be feasible in some ambulatory settings. Sputum Gram stain and culture are recommended only if drug-resistant bacteria or an organism not covered by the usual empiric therapy are suspected. As for therapy and management, the Society advocates an empiric approach based on likely pathogens. Patients are to be classified into one of four groups depending on factors thought to influence the spectrum of potential pathogens, namely: 1) the place of therapy (outpatient, inpatient regular ward, inpatient ICU), 2) the presence of cardiopulmonary disease (COPD, heart failure), and 3) the presence of modifying factors, which include risk factors for drug-resistant Streptococcus pneumoniae (DRSP), enteric gram-negatives (nursing home residence) and Pseudomonas aeruginosa. Using these factors, the guidelines define four patient groups: 1) outpatients with no history of cardiopulmonary disease and no modifying factors, 2) outpatients with cardiopulmonary disease and/or other modifying factor, 3) inpatients not admitted to the ICU; this group is further subdivided into those with and without cardiopulmonary disease and/or other modifying factors, and 4) ICU-admitted patients, who are further subdivided into those with or without risk factors for Pseudomonas aeruginosa. For each group, the available evidence was reportedly combined to identify the most likely pathogens, and recommendations for empiric therapy were made on this basis. For group 1 (outpatients without additional risk factors), the recommended therapy is an advanced generation macrolide, such as azithromycin or clarithromycin, or doxycycline. The advanced generation macrolides were recommended on the grounds that erythromycin does not cover Haemophilus influenzae and is not tolerated as well. In group two (outpatients with cardiopulmonary disease and/or other modifying factors), a combination of a beta-lactam with either one of the abovementioned macrolides or doxycycline is recommended. The beta-lactams mentioned include cefpodoxine, high-dose amoxicillin and amoxi/clavulanate. The combination treatment is advocated because amoxicillin does not offer adequate coverage for H. influenzae. Furthermore, it is recommended that all patients, regardless of what group they belong to, should be treated for “atypical” organisms (Chlamydia pneu19 moniae, Mycoplasma pneumoniae, Legionella species). This is usually done by including a macrolide antibiotic in the recommended treatment plan.

British Thoracic Society (2001)

The British Thoracic Society also recently updated its 1993 guidelines for the treatment of CAP in adults admitted to hospital to include patients treated in an ambulatory setting (British Thoracic Society 2001). The British Thoracic Society guidelines committee was composed of 12 members, of which 6 were general practitioners, four of them with a special interest in respiratory medicine and an “active research interest” in respiratory infectious diseases. The other members of the committee were a clinical microbiologist, two infectious disease specialists, a registrar in respiratory medicine, a clinical epidemiologist and a medical librarian. The search and study selection strategy employed is described in details, and a level of evidence is explicitly given for every recommendation made by the committee. The guidelines do not advocate the routine use of chest radiographs or sputum culture for the majority of patients with CAP who are managed on an outpatient basis. The diagnosis of CAP is to be made on clinical grounds, and severity assessment is emphasized as the key to appropriate management, whether the patients are to be treated in the community or in hospital. The choice of antibiotic treatment for outpatients is empiric and the main target organism remains S. pneumoniae. The authors emphasize the fact that their literature search for the period 1981-99 yielded only 16 articles judged relevant to the antibiotic treatment of CAP and that few of these studies were conducted within a setting comparable to those of UK practices. Nonetheless, and despite explicitly acknowledging that the currently available evidence forms an “unsatisfactory basis” for making solid evidence-based recommendations, the British Thoracic Society continues to recommend amoxicillin as the preferred agent on the grounds of cost, current practice, “wide experience”, safety and drug tolerance, but recommends a higher dose (500 mg to 1000 mg po tid) than used commonly in practice. The fact that clinical treatment failures have rarely been documented when penicillin-resistant strains are treated with higher doses of amoxicillin and that penicillin resistant pneumococci are still relatively rare in the UK is given as the rationale for recommending higher doses of amoxicillin. Erythromycin (500 mg po qid) is recommended as the alternative treatment for patients who do not tolerate amoxicillin. Clarithromycin (500 mg po bid) is suggested as the alternative agent for the sub-group of these patients who do not tolerate erythromycin, usually due to gastrointestinal side-effects. Interestingly, the guidelines committee considered tetracyclines (doxycycline) as an agent of first choice because resistance rates for pneumococci are lower that for penicillins or erythromycin and it is also active against “atypical” agents, however they refrained from making it a first choice recommendation in their guidelines due to a presumed reluctance of physicians to change their current practice that would “limit compliance with recommendations”. This is an interesting example of how perceived inertia on the part of practitioners (whether real or only imagined by the guidelines committee) can significantly influence the content of practice recommendations (Keeley 2002).

Canadian Infectious Diseases Society / Canadian Thoracic Society (2000)

In 2000, the Canadian Infectious Diseases Society and the Canadian Thoracic Society updated their 1993 guidelines for the treatment of CAP (Canadian Community- Acquired Pneumonia Working Group 2000). Members of the guidelines committee are listed at the end of the report, however there is no mention of the members' area of specialty, so it is unclear whether physicians primarily involved in the care of ambulatory patients were involved in the guidelines formulation process. The literature search strategy is described in reasonable detail and a hierarchical evaluation of the strength of evidence was carried out. Accordingly, a level of evidence is explicitly given for each recommendation made by the committee; unfortunately these are included only in the text of the guidelines and not in the tables where the recommendations are also summarized. The committee bases its recommendations on a classification of patients according to the place of treatment (outpatient, inpatient, nursing home). The guidelines also provide a scoring system that uses objective criteria to assist physicians in deciding whether a patient should be hospitalized or not. With respect to chest radiography, the committee points out that a number of infectious and non-infectious conditions may present a radiographic picture that is indistinguishable from that of pneumonia and that only one small study has assessed the ability of chest radiography to detect pulmonary infiltrates in patients suspected of having CAP (the gold standard used was high resolution CT scanning). They also point out that expert opinions are divided concerning the necessity of performing routine chest x-rays in patients suspect of having CAP. Nonetheless, the committee recommends that chest x-rays be performed routinely “under most circumstances” in such patients because the diagnosis of pneumonia is strengthened (although not confirmed) by the presence of an infiltrate. As for microbiological studies, no specific investigations are recommended for the majority of patients treated on an outpatient basis. For outpatients without modifying risk factors, the treatment of choice is a macrolide (erythromycin, azithromycin or clarithromycin), the second choice treatment being doxycycline. Outpatients with modifying factors are further subdivided into three groups: those with chronic obstructive pulmonary disease (COPD) who did not receive antibiotics or steroids within the past 3 months, COPD patients who did get antibiotics or steroids within the past three months, and patients in whom macroaspiration is suspected (alcoholics, patients with impaired consciousness, impaired gag reflex or other deglutitional dysfunction). In the first group (COPD, no antibiotics or steroids in past 3 months), the first choice is a so-called “newer” macrolide, namely azithromycin or clarithromycin, the second choice being doxycycline. In patients with COPD who received an antibiotic or steroids in the past three months, a “respiratory” quinolone (levofloxacin, gatifloxacin or moxifloxacin) is recommended, the second line choice being amoxicillinclavulanate plus a macrolide, or alternatively a second-generation cephalosporin plus a macrolide. In cases of suspected macroaspiration, the first choice recommendation is amoxicillin-clavulanate plus a macrolide, the second choice being levofloxacin plus either clindamycin or metronidazole.

Infectious Diseases Society of America (2000)

In 2000, the Infectious Diseases Society of America (IDSA) updated their 1998 guidelines for the treatment of CAP in adults (Infectious Diseases Society of America 2000). Members of the guidelines committee are listed as co-authors of the report together with their affiliated institution; however there is no mention of the members' area of specialty, so it is unclear whether primary care physicians were involved in the guidelines formulation process. The literature search strategy is not described, however, the committee used a grading system to assess the quality of the evidence provided by the research studies that they reviewed, as well as another grading system to classify the strength of the recommendations they made. The grades for quality of evidence and strength of recommendation are explicitly stated with each recommendation presented in the guidelines. The IDSA guidelines emphasize the clinical importance of the decision to hospitalize a patient or to treat on an outpatient basis. They recommend the use of the clinical prediction rule for short-term mortality developed and validated by the Pneumonia Patient Outcome Research Team (Pneumonia PORT) (Fine et al. 1997) as a basis for deciding whether or not to hospitalize a patient. The IDSA guidelines state that the diagnosis of CAP is based on a combination of clinical and laboratory data, adding that a chest x-ray is usually necessary to establish the diagnosis. The guidelines recommend that posteroanterior and lateral chest radiography be part of the routine workup of patient in whom CAP is considered a likely diagnosis and they discourage the initiation of empiric therapy without radiographic confirmation, although they acknowledge that obtaining chest x-rays “may not always be practical” (Infectious Diseases Society of America 2000, p. 370). For outpatients, sputum collection for Gram stain and culture are deemed optional, however the IDSA panel makes a strong case in favour of establishing an etiologic diagnosis for all patients. For outpatients, the guidelines state that it is desirable to perform at least a Gram stain, with or without culture. Treatment recommendations emphasize a pathogen-directed antimicrobial therapy and prompt antimicrobial treatment. Treatment recommendations are made based on suspected pathogens. Recommendations for empiric antibiotic selection in the absence of an etiologic diagnosis, i.e. when Gram stain and culture are not diagnostic, are also made. Drugs of first choice are recommended in “no particular order” and include doxycycline, a macrolide (erythromycin, clarithromycin or azithromycin) or a fluoroquinolone (levofloxacin, moxifloxacin or gatifloxacin). For older patients or patients with co-morbidities, a fluoroquinolone is to be preferred. When S. pneumoniae or H. influenzae are the suspected etiologic agents, amoxicillin-clavulanate or some second-generation cephalosporins (cefuroxime, cefpodoxime and cefprozil) are considered appropriate alternatives.

2.1.10 Prevention

A systematic review that included one randomised trial and 20 cohort studies by Gross et al. showed that for frail older adults, influenza vaccine had an efficacy (1- odds ratio) of 53% (Cl, 35% to 66%) for preventing pneumonia, 50% (Cl, 28% to 65%) for preventing hospitalization and 68% (Cl, 56% to 76%) for preventing death. Based on this evidence, the influenza vaccine is considered an important means of preventing pneumonia in elderly people. In contrast to immunization against influenza, the efficacy of the pneumococcal vaccine in older adults has been more controversial. There have been four systematic reviews summarizing clinical trial data about the pneumococcal vaccine. Included in these reviews are seven randomized trials that assessed the pneumococcal vaccine in persons aged 55 and older. In the latest meta-analysis, Cornu et al. found a significant reduction in definite pneumococcal pneumonia (OR 0.29, 95%CI 0.20-0.42), mortality due to pneumonia (OR 0.68, 95%CI 0.51-0.92) and presumptive pneumococcal pneumonia (OR 0.60, 95%CI 0.37-0.96). There was no significant effect on all-cause pneumonia (OR 0.78, 95%CI 0.58-1.07) nor on all-cause mortality (OR 1.01, 95%CI 0.91-1.12). In an analysis of clinical trials of elderly persons, no significant effect of pneumococcal vaccination was noted for definite pneumococcal pneumonia (OR 0.58, 95%CI 0.18-1.0), mortality due to pneumonia (OR 0.69, 95%CI 0.28-1.27), all-cause pneumonia (OR 1.10, 95%CI 0.92-1.32), presumptive pneumococcal pneumonia (OR 1.16, 95%CI 0.74-1.80) or all-cause mortality (OR 1.09, 95%CI 0.98-1.21). These findings differ from the results of numerous observational studies in which the vaccine has been shown to be effective. It is important to note that although the clinical trial data do not show a significant effect in the elderly, the confidence intervals do not rule out clinically important effects.

2.1.11 Outcomes

The mortality rate for CAP requiring hospitalization ranged from 2% to 40% in the 14 studies reviewed by Marrie et al. (1989). The 40% mortality rate was reported for patients with nursing home-acquired pneumonia. The 2% rate was reported in a study of 100 patients with pneumonia, but the mortality rate was given for 188 patients (Fekety et al., 1971). The mortality rate in published studies is a function of the patient population, which, in turn, depends on the inclusion and exclusion criteria used in the study. In the study by Marrie et al. (1989) the mortality rate was 21.1%, whereas in Fine's 1998 study it was 8%. It is noteworthy that there was no difference in site-specific mortality in the Fine study; in Halifax, the mortality rate was similar to the rates reported in Boston and Pittsburgh. However, all patients admitted with CAP were included in Marrie's study whereas in Fine's study, only 2287 of the 12,502 patients with an admission diagnosis of pneumonia were enrolled in the study. A pneumonia-specific severity of illness score would allow for comparison among cohorts of patients with CAP. Fine et al. (1997) described such a scoring system; this system stratified patients into one of five risk classes, Class I being the lowest risk group and class V being the highest risk group. Classes I, II, and III had a mortality rate of 1.2% ranging from 0.5% for class I patients to 1.2% for class III patients. In contrast the mortality rate for class IV patients was 9% and for class V patients it was 27.1%. The mortality rate in Lave's study of 36,222 patients was 11.6% (Lave et al., 1996).

2.1.12Complications

The major complications occurring in patients with CAP who require admission to hospitals are respiratory failure, congestive heart failure, shock, anemia, Clostridium difficile-associated diarrhea and colitis, pneumothorax, nosocomial pneumonia, renal insufficiency, rash, and stroke or transient ischemia attack (Fine et al., 1998). Thirty-one percent of patients who were admitted with pneumonia had no complications (Fine et al., 1998).

2.1.13 Resolution of Symptoms

Metlay et al. (1997a) studied 576 adults with CAP. They noted the presence and severity of cough, fatigue, dyspnea, sputum, and chest pain at presentation and again at 7, 30, and 90 days after presentation. Ninety days after presentation, 57% of the patients reported fatigue, 32% cough, 28% sputum production, and 8% pleuritic chest pain. The percentage of patients who had those symptoms prior to onset of pneumonia were 29%, 16%, 10%, and 3%, respectively. It is evident that symptom resolution occurs only slowly in patients with CAP.

2.1.14 Cost of Treating Community-Acquired Pneumonia

Niederman et al. (1998) conducted a retrospective analysis based on national incidence data and paid claims data for patients treated for CAP to assess the frequency of services rendered and the recruiting costs. They found that the total cost of treating CAP in the United States was $8.4 billion; $4.8 billion was spent treating patients aged =65 years or older. Room and board represented the largest percentage of hospital charges 26.3%; pharmacy accounted for 19.9%; laboratory services 13.2%; respiratory services 10.6%, and medical/ surgical supplies 9%. The average CAP outpatient costs per visit, including diagnostics and radiology, were $74, $76, and $159 for physicians' offices, emergency departments, and outpatient departments, respectively. They also found that 71.9% of patients 64 years or younger with CAP were seen in physicians' offices, and 23.5% in emergency rooms. The corresponding percentages for those 65 years or older were 53.8% and 41.8%.

2.2 Nosocomial pneumonia

2.2.1 Introduction

Nosocomial pneumonia (NP) is defined as infection of lung parenchyma of the lower respiratory tract that was neither present nor developing at the time of hospital admission (Bergogne-Berezin et al., 1995 ; Craven, D et al., 1995 ; Craven, D et al., 1998 ; Garner, J et al., 1998). The term VAP “Ventilator-associated pneumonia” has been introduced to represent the subgroup of patients who develop NP during MV (Coalson, J. 1995) and specifically refers to NP developing in mechanically ventilated patients following 48-hours of intubation (Bauer, T et al., 2000 ; Chastre, J et al., 2002 ; Kollef, M. 1999b) Nosocomial pneumonia (NP) is defined as infection of lung parenchyma of the lower respiratory tract that was neither present nor developing at the time of hospital admission. The term VAP has been introduced to represent the subgroup of patients who develop NP during MV and specifically refers to NP developing in mechanically ventilated patients following 48-hours of intubation. Further differentiation of NP and VAP are described in the literature; the use of the terms ‘early onset' and ‘late onset' are common, although definitions have not been standardized. Early onset is described as NP or VAP that appears within the first three to four days of MV. Whilst late onset refers to VAP developing after three to five days of MV. Early onset VAP is most often reported to be due to antibiotic sensitive pathogens such as Haemophilus influenzae, Staphylococcus aureus and Streptococcus pneumoniae, and is associated with a better prognosis than late onset VAP which is frequently attributable to antibiotic resistant pathogens such as Pseudomonas aeruginosa, Acintobacters and Enterobacters.

2.2.2 Definition:

     Nosocomial pneumonia (NP) is defined as infection of lung parenchyma of the lower respiratory tract that was neither present nor developing at the time of hospital admission. The term VAP has been introduced to represent the subgroup of patients who develop NP during MV and specifically refers to NP developing in mechanically ventilated patients following 48-hours of intubation. Nosocomial pneumonia (NP) is defined as infection of lung parenchyma of the lower respiratory tract that was neither present nor developing at the time of hospital admission (Bergogne-Berezin et al., 1995 ; Craven, D et al., 1995 ; Craven, D et al., 1998 ; Garner, J et al., 1998). The term VAP “Ventilator-associated pneumonia” has been introduced to represent the subgroup of patients who develop NP during MV (Coalson, J. 1995) and specifically refers to NP developing in mechanically ventilated patients following 48-hours of intubation (Bauer, T et al., 2000 ; Chastre, J et al., 2002 ; Kollef, M. 1999b)

2.2.3 Epidemiology & Incidence:

     Nosocomial or hospital acquired pneumonia is the second most common nosocomial infection in the United States and it causes the highest rates of morbidity and mortality, NP results in increase length of hospitalization and cost of treatment (Levison, 2003; Wilks et al., 2003).

Nosocomial pneumonia is the second most common hospital acquired infection (Bergogne-Berezin, E. 1995 ; Celis, R et al 1988) and the most common infection in the ICU (George, D. 1995 ; Vincent, J et al., 1995 ; Vincent, J.-L. 2004).

     Nosocomial pneumonia and Ventilated-associated pneumonia is associated with increases in duration of MV, prolonged length of ICU and hospital stay, increased hospital mortality rates (Fagon, J et al 1996).

     The mortality rate of VAP ranging from 25 to 33 per cent (Chastre, J et al 1995).

Mortality rates for nosocomial infections in total are approximately one to four per cent but this can range from 20 to 50 per cent for VAP and even as high as 76 per cent in some specific settings or with high risk pathogens (Chastre, J. & Fagon, J. 2002).

     Mortality rates are reported as rising from 8.5 per cent for non-VAP patients to as high as 55.0 per cent in those with VAP (Kollef, M. 1993).

     Nosocomial pneumonia is the second most common hospital acquired infection and the most common infection in the ICU.The rate of NP is higher for patients in ICU than for non- ICU patients. With as much as a 20-fold increase in patients who are mechanically ventilated compared to those who are not. Nosocomial pneumonia is said to account for 18 per cent of all nosocomial infections and VAP accounts for up to 90 per cent of infections in patients requiring MV. The largest reported ICU prevalence study revealed that on the day of the study, 45 per cent of patients in ICU in Europe had infections, with almost half caused by VAP. In the USA, the National Nosocomial Infection Surveillance data showed that 27 per cent of all nosocomial infections in medical ICUs were due to pneumonia, with 86 per cent of NP associated with MV. Similarly, in combined medical-surgical ICUs, 31 per cent of infections were NP, with 83 per cent of NP associated with MV. Rates of VAP are generally higher in surgical compared to medical ICUs. The Canadian critical care trials group reported that 18 per cent of patients developed VAP on average nine days after ICU admission.

Significance

     Nosocomial pneumonia and Ventilated-associated pneumonia is associated with increases in duration of MV, prolonged length of ICU and hospital stay, increased hospital mortality rates and may substantially increase the cost of hospitalisation two to three-fold. Morbidity

   Ventilator-associated pneumonia is the most common nosocomial infection in ICU and is coupled with high morbidity and mortality. Ventilator- associated pneumonia is associated with prolonged MV, with reported mean MV duration increases of 5.0 to in excess of 22.0 days when VAP develops in the ICU population. Ewig et al (1999) found no differences in a general ICU population with early onset VAP in the duration of MV, but increased MV duration from 5.5 days to 10.1 days in those with late onset VAP. When reporting the influence of VAP on duration of MV in neurosurgical/neurological ICUs, Dietrich et al (2002) found no greater duration of MV to that observed in the general ICU population who developed VAP. In addition to increased duration of MV, many authors have reported that VAP significantly increases length of stay in ICU. In the general ICU population, increased mean length of ICU stay attributable to VAP of between 4.0 and 21.0 days is reported. Other authors report overall length of hospital stay increasing up to 34.0 days for those with VAP and from a mean of 3.5 to 10.3 days with early onset VAP or a mean of 21.0 days with late onset VAP. However, Ewig et al (1999) reported no significant difference in length of ICU stay with early onset VAP, but found late onset VAP increased ICU stay from a mean of 8.0 to 14.0 days.

Mortality

     Nosocomial pneumonia independently contributes to patient mortality in ICU, with the mortality attributable to VAP ranging from 25 to 33 per cent. In other words, one quarter to one third of patients in ICU who develop VAP and die would not have died otherwise. A risk ratio for death associated with VAP of 2.1 and 2.0 has been reported, which rises to 2.6 when attributable to multi-resistant micro-organisms. Mortality rates for nosocomial infections in total are approximately one to four per cent but this can range from 20 to 50 per cent for VAP and even as high as 76 per cent in some specific settings or with high risk pathogens. Mortality rates are reported as rising from 8.5 per cent for non-VAP patients to as high as 55.0 per cent in those with VAP. (Celis et al. 1988) found no differences in mortality between patients with or without VAP regardless of whether it was early or late onset.

A point prevalence study by Hughes AJ et al (2005) of 583 cases of nosocomial infections in a university medical center in Malaysia found that the prevalence of nosocomial pneumonia was 21.4%.

     A retrospective study by Rozaidi et al (2001) of nosocomial pneumonia in hospital university kebangsaan in Malaysia found that the mortality rate of nosocomial pneumonia remains one of the major causes of ICU mortality.

2.2.4 Pathogenesis

     (Rumbak 2002) found that, under normal circumstances the lower respiratory tract is kept relatively sterile by a number of protective mechanisms. Inhaled air is filtered by the nasopharyngeal mucosa, the integrity of the epiglottic barrier prevents significant aspiration, and the pulmonary defences attempt to destroy any organisms that are aspirated. There are only four routes through which bacteria can reach the lower respiratory tract to cause the development of VAP: inhalation, aspiration, hematogenous spread, and contiguous spread. Pneumonia develops when virulent organisms reach the lower airways and overwhelm the lung defenses of the host. A local inflammatory response occurs, with the accumulation of neutrophils and other effector cells in the peripheral bronchi and alveolar spaces; this may be manifested clinically by purulent sputum, lung infiltrates, fever, and leukocytosis. Colonisation of the upper airway and stomach plays a major role in the development of VAP and precedes invasive infection. Most VAPs result when micro-organisms are aspirated into the lung from a previously colonised oropharynx. Endotracheal intubation is the most important risk factor in the pathogenesis of VAP because it impairs local host defence mechanisms, creates binding sites for bacteria, and allows for the formation of biofilms that may serve as reservoirs of bacteria. The endotracheal tube (ETT) can contribute to VAP pathogenesis by allowing direct entry of bacteria into the lungs, by elimination or suppression of the cough reflex, and by providing a surface for the formation of a bacterial biofilm along the inside of the ETT. Intubation also facilitates the entry of bacteria into the lungs by pooling and leaking of contaminated secretions around the ETT cuff. Organisms that reach the inside of the ETT can proliferate easily because this site is not protected by host defences, and antibiotics do not penetrate this region. The source of the bacteria that colonise the upper airway is most likely the patient ' s own intestinal flora, but also other patients, health care staff, or other environmental sources can transmit flora to patients.

2.2.5 Etiology

The organisms most commonly associated with nosocomial pneumonia are S. aureus and enteric (e.g., Klebsiella or E. coli) and nonenteric (e.g., Pseudomonas) gram-negative bacilli, organisms that colonize the pharynx of the hospitalized, critically ill patient. The diagnosis of nosocomial pneumonia usually is established by the presence of a new infiltrate on chest radiograph, fever, worsening respiratory status, and the appearance of thick, neutrophil-laden respiratory secretions. In actuality, the diagnosis often is difficult to make in the intensively ill patient with underlying lung pathology that itself can be associated with an abnormal changing radiograph, as occurs with congestive heart failure or chronic lung disease. Broad-spectrum antibiotics frequently are started empirically even in equivocal circumstances, with bronchoscopy reserved for poorly responsive patients.

2.2.6 Risk factors

Risk factors for the development of VAP are varied and dependent on factors such as prior antimicrobial therapy, duration of hospital stay and the population of the ICU. Risk factors can be globally divided into four categories: host factors and underlying disease, factors that enhance colonisation of the oropharynx and stomach (such as antibiotics and hospitalisation in ICU), factors that increase the risk of aspiration of nosocomial pathogens into the lower respiratory tract, and devices or equipment that interrupt natural host defences; or more simply into two categories: intrinsic and extrinsic risk factors.

2.2.7 Diagnosis

     Essentially VAP can be diagnosed in three ways: using clinical criteria, non-invasive methods, and invasive techniques. Diagnosis of VAP remains a controversial issue, with variation in approaches potentially associated with misclassification bias, and use of different diagnostic strategies resulting in different infection rates. No difference exists between the sampling techniques in terms of reliability or in obtaining clinically significant pathogens, and to date no study has demonstrated the superiority of a specific diagnostic method in terms of a lower incidence of complications, better patient outcomes, or reduced hospital costs. Individual local settings act as systematic confounders to the incidence and diagnosis of VAP. Because of local bacteriological epidemiology, divergent susceptibility patterns of pathogens in the ICU, different antibiotic regimens, and variations in microbial and/or histological work-up, each ICU setting should establish its own preferred diagnostic techniques.

2.2.8 Prevention

    Prevention and management of VAP are integrally entwined; many preventative strategies also form part of the management to restrict the impact of VAP and are of critical importance for risk reduction, improvement in patient outcome, and reduction in hospital costs. To date, few interventions have been shown to be beneficial in the prevention of VAP. Prophylactic strategies should include an effective infection control programme, semi- upright positioning of the patient, judicious use of enteral feeding, reduction of the inappropriate use of antibiotics, and removal of unnecessary invasive devices. Foremost in the literature on VAP prevention are effective infection control practices and procedures. These infection control practices can be grouped into three categories: methods to eliminate endogenous pathogens and reduce oropharyngeal and intestinal colonisation, methods to prevent cross contamination and other environmental sources of contamination (e.g. cleaning of respiratory equipment, appropriate hand washing and isolation procedures), and antibiotic prophylaxis in post-operative high risk patients. The use of a multidisciplinary team approach focussing on educational measures has been shown to be effective in reducing or limiting further rises in VAP rates.

Mehta and Niederman (2003) found that a 10 point strategy for VAP prevention was proposed, Strategies for prevention of VAP 1. Proper patient position in semi-erect; avoid supine position 2. Using an ETT that allows for subglottic drainage 3. Maintaining adequate ETT cuff pressures to prevent aspiration of pooled secretions 4. Monitoring for excess gastric residuals that lead to aspiration 5. Small bowel feeding whenever possible (to avoid aspiration, bacterial translocation) 6. Careful handlin of ventilator circuits to avoid washing condensate back to patient 7. Using non-invasive positive pressure ventilation rather than intubation whenever possible 8. Potential antibiotic interventions, such as use of 24 hours of antibiotic therapy for patients with witnessed aspiration; antibiotic rotation 9. Possible role of selective digestive decontamination; oropharyngeal decontamination 10. Placing ETT and feeding tubes through the mouth, avoiding the nasal route

VAP = ventilator-associated pneumonia;

ETT = endotracheal tube.

2.2.9 Management

     Antimicrobial therapy is the mainstay of the management of VAP and is the focus of much debate in the literature, with relatively little attention given to other, non-pharmacological components of management. It is important to cover the factors contributing to the selection of antibiotic treatment, such as the identification of pathological organisms, their antibiotic susceptibility, the clinical setting (e.g. duration of hospitalisation and MV, prior antibiotic use), or pharmacokinetic considerations. Similarly, considerations for prophylaxis, type, rotation and duration of antibiotic therapy will not be addressed. Despite many advances in antimicrobial therapy, the management of patients with VAP remains difficult and complex. Because of the difficulty encountered in the diagnosis of VAP, therapy is often empirical, although this may result in costly over- treatment that can be dangerous and ineffective, leading to adverse outcomes in terms of morbidity. Rapid identification of infected patients and appropriate selection of antimicrobial agents represent important clinical goals, as early targeted antimicrobial treatment of patients with VAP significantly improves outcome. Worsening acute respiratory failure, septic shock, inappropriate antibiotic therapy all independently worsens the prognosis associated with VAP. Management of VAP generally involves supportive care (such as MV, nutritional support, inotropic support), targeted antibiotics, and treatment of the underlying disease. Inappropriate therapy is related to fatality, with relative odds ratio of 5.8. Significant debate continues surrounding the use of antibiotic therapy and in particular the relative merits of empiric antibiotic treatment versus single agent antibiotic therapy versus combination antibiotic therapy in the management of VAP. It is suggested that local epidemiological data combined with a patient-based approach will allow more accurate decision making regarding therapy. The distinction between a colonising and an infecting organism remains a difficult problem, although progress has been made in the diagnostic procedures and identification of pathogens, allowing appropriate antibiotic therapy based on documented microbiologic data. The major differences in the bacteriology between CAP and HAP//HCAP/VAP is a shift to Gram-negative pathogens, MDR pathogens, and MRSA in HAP/HCAP/VAP. Gram-negative bacilli commonly colonize oropharyngeal secretions of patients with moderate to severe acute and chronic illnesses without exposure to broad-spectrum antibiotics. Patients admitted to the hospital with acute illnesses are rapidly colonized with Gram-negative organisms. Approximately 20% are colonized on the first hospital day, and this number increases with the duration of hospitalization and severity of illness. Approximately 35% to 45% of hospitalized patients and up to 100% of critically ill patients will be colonized within 3 to 5 days of admission.

2.2.10 Outcomes

Kollef et al. reported that mortality rates associated with HCAP (19.8%) and HAP (18.8%) were comparable (p >0.05); and both were significantly higher than that for CAP (10 %, all p <0.0001) and lower than that for VAP (29.3 %, all p <0.0001). Mean length of stay varied significantly with pneumonia category (in order of ascending values: CAP, HCAP, HAP and VAP; all p <0.0001). In addition, the length of hospital stay increased progressively for CAP, HCAP, HAP and VAP patients, and, in parallel with this, hospital costs increased for each of the four groups in the same order (p <0.0001). If HCAP patients were included in the CAP category according to the traditional classification schemes, these would have accounted for 31% of hospitalised CAP patients. Multivariate analysis of the factors associated with pneumonia mortality indicated that S. aureus was the only pathogen that correlated with increased mortality. S. aureus not only increased mortality, but was also associated with increased length of hospital stay, and treatment costs observed in patients with HCAP, HAP and VAP. The clinical outcomes in patients with HCAP and HAP were comparable in terms of overall mortality. However, the mean length of hospital stay and treatment costs for HCAP patients was significantly lower in these groups of patients than in those with HAP.

2.2.11 Cost

Rello and colleagues examined costs related to HAP through a review of a large administrative database in the US. They included subjects with both HAP and VAP and observed that neither affected mortality. Compared to non-infected controls, however, HAP led to nearly $40 000 in extra hospital charges ($104 983 vs $63 689, p<0.001). Among 842 cases, the duration of both MV and ICU stay were doubled compared to the control population. One strength of this analysis is that it represented a multicentre experience and hence reflected a range of patient types. However, it is unclear if diagnoses based on administrative discharge diagnosis coding are adequate for identifying subjects actually suffering from HAP and VAP. If one conservatively corrects the charges to cost via a cost-to-charge ratio of 0.3, these findings suggest that HAP and VAP cost more than $10 000 per event.. Hugonnet and colleagues reviewed outcomes and cost related to VAP in a Swiss ICU. Using a case-control methodology, they matched for duration of MV, ICU admitting diagnosis, total number of discharge diagnoses and age. Unique to this study was the fact that more than 70% of cases had microbiological confirmation of the diagnosis of pneumonia. On average, subjects with VAP required an additional five days of MV and one week of ICU care. Median costs, which were calculated through a means validated for use in Swiss hospitals, were $24 727 in those with VAP vs $17 438 in persons lacking VAP (p<0.001).

3.1 Introduction

A retrospective observational study was carried out using medical records in H-USM and Penang General Hospital in Mlalaysia from 1st. January 2007 to 31st. December 2008. The study was carried out among adult patients (aged 18 years old and older) diagnosed of suffering from pneumonia in H-USM, Kelantan and in the Penang General Hospital, Malaysia. The Penang General Hospital is located about 450 kilometers north-west of Kuala Lumpur, Malaysia. The population of Penang state is roughly about 1,313,400. Chinese from 45%, Malays, 41%, Indians, 10 % and other nationalities, 4 % of the over all total Kelantan has a population of about 1.4 million comprising Malays, Chinese, Indians, Siamese and other races. Malays make up about 94 % of the population.

3.2 Literature search:

     An extensive literature search was done utilizing different books, pharmaceutical and medical journals, web sites like WHO, Science direct, Proquest, Pubmed, Medscape, and Springer link. Articles and abstracts were obtained which were related to the main purpose of this study.

3.3 Study Approval

  • The approval to conduct the study was obtained from the Clinical Research Committee, H-USM and Penang General Hospital.

3.4 Study Design

  • The study was a retrospective study of all adult patients admitted to the H-USM and the Penang General Hospital, Malaysia and diagnosis of pneumonia from 1st. January 2007 to 31st. December 2008.

3.5 Pilot study:

     A pilot test was conducted on 104 patients to determine the reliability and validity of research tool (data collection form). After feedback and review were obtained, slight modifications and finalization of data collection form were made like adding or omitting variables at the beginning and after the completion of pilot test

3.6 Study location

  • The H-USM, Kelantan, Malaysia.
  • The Penang General Hospital, Pulau Pinang, Malaysia.

3.7 Subjects

  • Adult patient's with a confirmed diagnosis of pneumonia from 1st. January 2007 to 31st. December, 2008.

3.8 Sample size

     The estimation of the suitable sample size for this study is necessary to obtain an adequate number of patients that will answer the study questions.

3.9 Selection Criteria

Inclusion criteria

  • Confirmed diagnosis of pneumonia.
  • Age group: adult's = 18 years old.

Exclusion criteria

  • Immunocompromised patients, including those with active malignancy and under treatment, on chemotherapy and those on long term immunosuppressant (cyclosporin, azathioprine, and prednisolone).
  • Those with the human immunodeficiency virus (HIV) infection.
  • Age group: < 18 years old.
  • Incomplete data or record.

3.10 Data Collection

        A data compilation framework was developed to facilitate data collection. This framework encompassed the following aspects

Demographic data

Demographic data including name, date of admission, date of discharge, age, gender and registration number.

Past History

Medical history, medication history and family history.

Clinical Data

        Consisting of diagnosis, signs and symptoms of pneumonia.

Culture /Sensitivity

        The source of culture (blood, sputum and others), organisms and sensitivity patterns.

Other Investigations

        X-Rays, scans, laboratory tests, lung sounds and others.

Antibiotics

        Types of antibiotics prescribed for the patient's management. such as penicillin, cephalosporin, macrolides and others.

Supportive and Symptomatic

        Drugs prescribed including antipyretics (paracetamol) and others.

Monitoring

        Vital signs such as blood pressure, temperature, pulse rate, respiratory rate, the relevant laboratories result and other related monitoring parameters.

Cost

Costs on patient therapy including drugs cost, doctors cost, pharmacists cost, nurses cost, ward per day cost, investigations cost, and others related costs.

Others

     Additional information about diagnosis, drug prescription and management.

Patient Selection

        All patients admitted to the H-USM and Penang-GH from 1st. January 2007 to 31st December 2008 with a confirmed diagnosis of pneumonia will be included in the study.

3.11. Sources of Data

        The main source of data was the Record Office, the Pharmacy Department, the Finance Department, the Laboratory Department, the X-ray Department and other relevant departments. Data pertaining personnel costs was obtained from the Hospital Financial Department, drugs costs from the Pharmacy Department, laboratory costs from the respective laboratories, X-ray costs from the Radiology Department, and the daily Hospital charge from the Revenue Department.

3.12. Data Analysis

  • The analysis of the data was carried out using SPSS 15.0 or latest version.
  • All data was tabulated and presented graphically.