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SUPPLEMENT TO Journal of the association of physicians of india • july 2013 • VOL. 61

Atypical Pneumonia
Introduction • Decreased CAP-related mortality (6.4% vs. 3.8%).

S treptococcus pneumoniae causes up to 70% of community- It was concluded that empiric therapy for all hospitalized
acquired pneumonia cases and atypical pathogens are patients with CAP with a regimen that covers atypical pathogens
responsible for 30–40% of cases. The other bacteria which is supported by signifcant global presence of atypical pathogens
cause community-acquired pneumonia besides Streptococcus and better outcomes.5
pneumoniae are Haemophilus infuenzae, Staphylococcus aureus and In an Indian study conducted by Udwadia et al, the most
Gram-negative bacilli. Legionella, Mycoplasma pneumoniae and common atypical organism causing CAP were Chlamydia
Chlamydia pneumoniae are the atypical agents which cause CAP.1,2 pneumoniae and Mycoplasma pneumoniae.6 Following organisms
were identifed.
Atypical pathogens : Literature Review Organisms % Organisms %
A population-based, CAP surveillance study involving non- No organisms 44 Moraxella 6
institutionalized adults hospitalized due to CAP reported that S. pneumoniae 22 M. pneumoniae 3
Mycoplasma pneumoniae was the dominant pathogen in one-third C. pneumoniae 14 Pseudomonas aeruginosa 2
of all CAP cases. Chlamydia pneumoniae was responsible in 8.9% H. infuenzae 9 S. aureus 1
of cases whereas Legionella caused up to 3% of cases. In this
Klebsiella pneumoniae 3 Salmonella typhi 1
study, Streptococcus pneumoniae was implicated in 12.6% of cases,
Legionella pneumoniae 2 Mycobacterium tuberculosis 7
which was much lesser than noted in the earlier CAP surveillance
studies. However, the authors hypothesized that low rates of S. Need for Covering Atypical Pathogens
pneumoniae most likely refect the insensitivity of sputum Gram’s
The need for antibiotic cover for atypical pathogens is
stain and culture when these tests were performed in the context
controversial. Although there are not many studies, which show
of routine care.3
the importance of antibiotic therapy for atypical pathogens,
A study by Zaki and Godal reported that Chlamydia the need-to-treat infection with Legionella has been well-
pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila, established. Placebo-controlled trials and randomized trials
Coxiella burnetii, adenovirus, and infuenza virus were the comparing azithromycin, tetracycline, and penicillin show that
pathogens responsible for CAP. Streptococcus pneumoniae (22%) L. pneumophila is shown to have better survival rate on antibiotic
followed by Haemophilus infuenzae (18%). Mycoplasma pneumoniae treatment. 7
(5%) and Legionella pneumophila (5%) were the most common
Furthermore, the Medicare database noted statistically
isolated bacteria. The most common positive serological reaction
signifcant survival advantage in hospitalized patients with CAP
was for Chlamydia pneumoniae (30%) and adenovirus (30%).4
with fuoroquinolone or a β-lactam plus a macrolide as compared
Arnold et al. conducted a study to correlate the incidence of to β-lactam alone.7
CAP due to atypical pathogens in different regions of the world
Despite improvements in microbiological detection, it must
with the proportion of patients treated with an atypical regimen
be emphasized here that the specifc pathogen cannot be isolated
in those same regions. Clinical outcomes of patients with CAP
in about 30% of cases of CAP.8
treated with and without atypical coverage were also evaluated
in the study.5 It would also be helpful to have brief look at the most common
atypical pathogens involved in causing CAP in order to arrive
The study divided the various regions in the world as follows:
at appropriate treatment regimens for the same.
• Region I: North America
Mycoplasma pneumoniae3
• Region II: Europe
Mycoplasma pneumoniae is the smallest of all free-living
• Region III: Latin America organisms. It does not have a peptidoglycan wall. However, it
• Region IV: Asia and Africa has a sterol plasmic membrane. This parasitic organism attaches
Outcome measures assessed included: to the respiratory epithelium, acquires essential exogenous
nutrients for growth and may become intracellular. It causes
• Time to reach clinical stability
injury to epithelial cells and their associated cilia by producing
• Length of hospital stay hydrogen peroxide and superoxide. This facilitates co-infection
• Mortality with other pathogens. Most of minor respiratory illnesses are
It was found that the incidence of CAP due to atypical caused by Mycoplasma pneumoniae.
pathogens in the regions I to IV were 22, 28, 21, and 20% A report by the Center for Disease Control and Prevention
respectively. The proportion of patients treated with atypical (CDC) of an outbreak in Colorado highlights the importance of
coverage were 91%, 74%, 53%, and 10% in regions I, II, III CAP caused by M. pneumoniae. The infection has an incubation
and IV, respectively. The study also showed that compared to period of 1-3 weeks, followed by gradual symptom onset.
those without atypical coverage, patients treated with atypical Patients may not seek medical attention until a few days or even
coverage had: a week has passed as the onset of illness is gradual.
• Decreased time to clinical stability (3.7 vs. 3.2 days) Symptoms such as headache, malaise, fever and cough may be
• Decreased length of stay (7.1 vs. 6.1 days) prominent at this stage of the illness where no identifable signs
are observed during physical examination. The chest radiograph
• Decreased total mortality (11.1% vs. 7%) may reveal an infltrate.
SUPPLEMENT TO Journal of the association of physicians of india • july 2013 • VOL. 61 29

The second week of the illness progression may show sputum been identifed to date. About 80–90% of infections are caused
production and localized crackles or wheezes. These symptoms by Legionella pneumophila. Serogroups 1, 4 and 6 are the most
may extend for over a month beyond the incubation period. common causative pathogens. Legionella micdadei is the frst
However, these general symptoms do not provide any clue to most common causative pathogen. The second most common
the likely diagnosis. Confrmation of M. pneumoniae infection can is Legionella pneumophila. Legionella bozemanii is more virulent or
be provided by culture or serology, but most clinical laboratories resistant than Legionella pneumophila.
do not culture for the organism, and serologic response can take Legionella pneumoniae is an intracellular organism. Infection
weeks to peak. Consequently, antimicrobial therapy for CAP in humans is caused by serotype 1. The mode of transmission
is initiated empirically before infection with M. pneumoniae is is environment-to-human and human-to-human transmission.
confrmed.
Moist soil, heating and cooling water system, respiratory
It was previously thought that M. pneumoniae pneumonia was therapy equipments and showers are the common sources of
only a mild illness primarily afficting older children and young infection. Overnight stay outside home, recurrent plumbing in
adults, but there is now mounting evidence that it is a frequent house, chronic renal failure, malignancy, diabetes mellitus, liver
cause of hospitalization among children as young as 2 years of failure and immunocompromised state are the risk factors for
age and can even necessitate ventilatory assistance. Legionella pneumoniae infection.3
Chlamydia pneumoniae3 The classic clinical manifestations of Legionnaires’ disease
Chlamydia pneumoniae has emerged as an important cause were confrmed by two comparative studies by Gupta et al.9 and
of pneumonia in both adults and children as young as 2 years Helms et al.10 The clinical manifestations include:
old. Over 50% of adults worldwide have antibodies against the • Temperature more than 39°C
pathogen, indicating prior infection. Unfortunately, immunity
• Diarrhea
is not long lived.
• Neurologic fndings especially confusion, hyponatremia and
Chlamydia pneumoniae, an intracellular bacterium damages
hepatic dysfunction (transaminase and bilirubin elevations).
host cells by releasing antigens onto epithelial cell surfaces. This
stimulates host immune (infammatory) responses and ciliostasis. • Hematuria
The incubation period of Chlamydia pneumoniae is about 2–4 A retrospective case-control study was conducted by Gupta et
weeks. The disease is usually mild but may be prolonged. The al. to evaluate sensitivity and specifcity of Winthrop-University
common symptoms are fever and cough. Crackles are usually Hospital (WUH) criteria to identify
revealed on chest examination. The only reservoir for Chlamydia Legionella pneumoniae vs. bacteremic pneumococcal
pneumoniae is human beings. The signs and symptoms are seen pneumonia at the time of hospitalization for community-
in prodromal phase. Sputum is scanty and pulmonary infltration acquired pneumonia involved about 37 patients with Legionella
is minimal. About 9% of mortality is seen with Chlamydia pneumoniae and 31 patients with bacteremic pneumococcal
pneumoniae infections. pneumoniae. A subgroup of patients were analyzed further.
Chlamydiaceae has two genera (Chlamydia and Chlamydophila) The study noted that
under the new taxonomic classifcation. Chlamydia genera include • The sensitivity and specifcity of WUH criteria was 78% and
C. trachomatis, C. muridarum, and C. suis. Chlamydophila includes 65%, respectively.
the newly renamed strains of C. abortus, C. felis, C. pecorum, C. • Positive and negative predictive values were 42% and 90%,
pneumoniae, C. caviae, and C. psittaci. Chlamydophila psittaci has respectively.
eight known serovars; six have been primarily isolated in birds
and two strains have been isolated in mammals. Identifcation of • In the subgroup analysis, sensitivity of 87% and specifcity
serovar may help to determine the source of infection. of 50% was noted; positive and negative predictive values
were 37% and 92%, respectively.
There are many specifc occupational and recreational
activities that could increase the risk of acquiring psittacosis. • Although the sensitivity was relatively high, 13–22% of
A few of the at-risk professions are laboratory workers, patients with Legionnaires disease were missed by the WUH
veterinarians, avian quarantine workers, zoo workers, farmers, score.
pregnant women, bird fanciers (pigeon fanciers too), bird The study concluded that given the high mortality rate, the
owners, pet shop employees, poultry slaughter and processing WUH score cannot be used to focus antibiotic therapy since
workers and wildlife rehabilitation workers. the specifcity was low (50 to 65%), the application of the WUH
The common modes of transmission of Chlamydia pneumoniae score also could lead to unnecessarily broad coverage. The WUH
infection to humans are inhalation (dried infective droppings, score might be used to screen patients for specialized Legionella
secretions or dust from feathers), mouth-to-beak, direct contact testing. If the WUH score were fulflled, the patient could receive
(handling plumage or of infected birds) and person-to-person anti-Legionella antibiotics as empiric therapy without Legionella
transmission. laboratory testing. But, if the criteria were not fulflled, Legionella
testing could be performed on these patients to cover the 13–22%
Legionnaires’ Disease3 of patients who do not have the classical syndrome.9,10
Legionellosis is an infectious disease caused by Legionella Viral Pneumonia11
pneumophila and presents in two distinct forms. One is pontaic
fever which is an acute, febrile and self-limited illness. The other Viral pneumonia occurs in young children and older adults
form is Legionnaires’ disease, which is a severe form of infection and is caused by adenovirus, infuenza, H1N1, parainfuenza and
and leads to pneumonia. respiratory syncytial virus (RSV).
Legionella pneumophila is an aquatic, aerobic, thin and • Infuenza A and B usually occur in the winter and spring.
Gram-negative bacillus. At least 46 species of Legionella have Respiratory symptoms, headache, fever, and muscle aches
are the main symptoms of this condition.
30 SUPPLEMENT TO Journal of the association of physicians of india • july 2013 • VOL. 61

• Respiratory syncytial virus (RSV) is most common in the Community-Acquired Pneumonia,

spring and infects children.
• Adenovirus and parainfuenza viral pneumonias are Tuberculosis and Fluoroquinolones
often accompanied by cold symptoms (runny nose and Mycobacterium tuberculosis and community-acquired
conjunctivitis). pneumonia
• Post-infuenza pneumonia is usually secondary bacterial Mycobacterium tuberculosis causes infection in about one-third
infection caused by Staphylococcus pneumoniae and of the world’s population and causes 1.6 million deaths
Staphylococcus aureus. worldwide.13 It is estimated that about 3.3–7% CAP cases are
Infectious causes of pneumonia in immuno­compromised due to M. tuberculosis.6
patients include measles, HSV, CMV, HHV-6 and Infuenza Fluoroquinolones are resistant to streptococci in about less
viruses. Viruses cause partial paralysis of ‘mucociliary escalator’. than 3% of cases. They have excellent activity against atypical
There is also an increased risk of secondary bacterial lower organisms and Mycobacterium tuberculosis. Fluoroquinolones
respiratory tract infection (LRTI). The known complication are used for the treatment of multidrug-resistant tuberculosis,
following infuenza infection is Staphylococcus aureus pneumonia. shortening the duration of AKT and as replacement drug.14
Impact of Empirical Therapy of CAP on Treatment of M.
Treatment of Atypical Pneumonia tuberculosis Infections
Therapy for pneumonia is empiric because specifc pathogens Initiation of empirical therapy of CAP is known to have two
usually are not identifed at the time the treatment is initiated. important concerns of on Mycobacterium tuberculosis.13 These are:
Several classes of antibiotics are effective against atypical 1. Delayed initiation of anti-TB treatment
pathogens. However, because C. pneumoniae and Legionella
spp. are intracellular organisms and M. pneumoniae lacks a cell 2. Resistance to fuoroquinolone
wall, p-lactams are not effective. The traditional choices for Dooley et al. conducted a retrospective cohort study to
the treatment of atypical pneumonia are erythromycin and evaluate the effect of empiric fuoroquinolone therapy on delays
tetracycline.1 in the treatment of tuberculosis. About 33 patients with culture-
In Legionell infection erythromycin is effective as confrmed tuberculosis were included in the study. Sixteen
demonstrated in some trials and in case of Mycoplasma patients received fuoroquinolones for presumed bacterial
pneumoniae, erythromycin and tetracycline are effective. They pneumonia and the rest did not receive fuoroquinolones.
also reduce symptom duration in Chlamydia pneumoniae infection. Median time between presentation to the hospital and
initiation of antituberculosis treatment in patients who received
Azithromycin and clarithromycin are very effective against fuoroquinolones and patients who did not receive was 21 days
Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella and 5 days, respectively.15
spp. and show better tolerability profle as compared to
erythromycin. Doxycycline is also effective and is associated with It was concluded that initial empiric therapy with a
fewer gastrointestinal side-effects. Fluoroquinolones are highly fuoroquinolone and delay in the initiation of appropriate
effective against Mycoplasma pneumoniae, Chlamydia pneumoniae antituberculosis treatment were associated. Empiric
and Legionella spp. The advantage of fuoroquinolones is once- fuoroquinolone therapy delays the diagnosis of tuberculosis by
daily dosing and excellent bioavailability (intravenous or oral).12 21 days, prolongs patient’s infectivity, morbidity and mortality,
and develops fuoroquinolone-resistant mycobacteria.15
The basic dosage of antibiotics prescribed is given follows:1212
Yoon et al. evaluated the effect of empiric fuoroquinolone
1. Macrolides therapy on delay in diagnosis in patients with pulmonary
• Azithromycin: 500–1000 mg daily tuberculosis initially misdiagnosed as bacterial pneumonia.14
• Clarithromycin: 250–500 mg BID Patients with pulmonary tuberculosis initially treated
• Erythromycin: 500 mg QID with fuoroquinolones for more than fve consecutive days
were enrolled in the study group. Patients with pulmonary
2. Doxycycline: 100 mg daily
tuberculosis initially treated with non-fuoroquinolones were
3. Fluoroquinolones enrolled in the control group.
• Levofoxacin: 500–750 mg daily The study found that both clinically and radiologically
• Moxifoxacin: 400 mg daily improvement in fuoroquinolone group (89%) was signifcant as
• Gemifoxacin: 320 mg daily compared to non-fuoroquinolone group (42%). Delay in initiation
of antituberculosis treatment was longer in fuoroquinolone
• Gatifoxacin: 400 mg daily group (43.1 days) as compared to non-fuoroquinolone group
The combination of rifampin plus a macrolide or a quinolone (18.7 days).
can be used for initial treatment in severely ill patients with These studies indicate that newer fuoroquinolones should
Legionnaires’ disease. Initial therapy should be given by the be restricted in tuberculosis endemicity because of its potential
intravenous route. Usually, a clinical response occurs within to mask active tuberculosis and emerging drug-resistant
3–5 days, after which oral therapy can be substituted. The tuberculosis.
total duration of therapy in the immunocompetent host is
10–14 days; a longer course (3 weeks) may be appropriate Ruiz-Serrano et al. compared the activities of the
for immunosuppressed patients and those with advanced fuoroquinolones, ciprofoxacin, ofoxacin, levofoxacin,
disease.12 grepafoxacin, trovfoxacin, and the novel compound gemifoxacin
(SB-265805) against 250 clinical isolates of Mycobacterium
tuberculosis with different levels of susceptibility to frst-line
antituberculosis drugs. Overall, levofoxacin (MIC 90, 1 μg
SUPPLEMENT TO Journal of the association of physicians of india • july 2013 • VOL. 61 31

mL) showed the greatest activity against the M. tuberculosis 3. Gleason P P. The Emerging Role of atypical pathogens in
strains tested, with 96.4% of the strains inhibited at 1 μg/mL. community-acquired pneumonia. Pharmacotherapy 2002;22:2S–11S.
Ciprofoxacin (MIC90, 1 μg/mL; 92.0%), grepafoxacin (MIC90, 4. Zaki MS, Goda T. Clinico-pathological study of atypical pathogens
1 μg/mL; 90.4%), and ofoxacin (MIC90, 2 μg/mL; 88.8%) also in community-acquired pneumonia: A prospective study. J Infect
showed good activity. Trovafoxacin (MIC90, 64 μg/mL; 0%) and Developing Countries 2009;3:199–205.
gemifoxacin (MIC90, 8 μg/mL; 6.4%) were inactive against most 5. Arnold FW, Summersgill JT, LaJoie AS, et al. A worldwide
of the strains tested.16 perspective of atypical pathogens in community-acquired
pneumonia. Am J Respir Crit Care Med 2007;175:1086–1093.
Prevention of Resistance
6. Udwadia ZF, Doshi AV, Joshi JM. Etiology of community acquird
The common approach for preventing the emergence of pneumonia in India. Eur Respir J 2003;22:5445.
resistance is to administer the drug at doses that produce blood 7. Bartlett JG. Is Activity against “Atypical” Pathogens Necessary in
concentrations that continuously exceed the resistance level of the Treatment Protocols for Community-acquired pneumonia?
all spontaneous mutants. This prevents the selective amplifcation Issues with Combination Therapy. Clin Inf Dis 2008;47:S232–236.
of any mutant population. The greater the activity of the agent, 8. Baudouin S V. The pulmonary physician in critical care 3: Critical
the less likely they will select for mutants that have reduced care management of community acquired pneumonia. Thorax
susceptibility. The duration of exposure of the M. tuberculosis 2002;57:267–71.
infecting organisms to the fuoroquinolone may also be a risk 9. Gupta KS, Imperiale FT, Sarosi AG. Evaluation of the Winthrop-
factor for the development of resistance.17 University Hospital Criteria to identify legionella pneumonia. Chest
2001;120:1064–1071.
Recommendations 10. Mulazimoglu L, Yu VL. Can Legionnaires disease be diagnosed by
• Atypical coverage is a must in moderate-to-severely ill clinical criteria? Chest 2001;120:1049–1053.
patients with pneumonia requiring hospitalization and 11. Eun-Hyung Lee F, Treanor J. Viral infections. In: Mason RJ,
intensive care unit care. Broaddus VC, Martin TR, et al. (eds). Mason: Murray and Nadel’s
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12. Lim WS, Baudouin SV, George RC, et al. BTS guidelines for the
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• Tuberculosis should always be considered while treating 13. Low DE. Fluoroquinolones for Treatment of Community-Acquired
CAP in India. Therefore fuoroquinolones Pneumonia and Tuberculosis: Putting the Risk of Resistance into
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be considered in the clinical setting. treatment of tuberculosis. Clin Inf Dis 2002;34:1607–1612.
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