PHARMACOTHERAPEUTICS III

PR3124

PNEUMONIA

COMMUNITY-ACQUIRED PNEUMONIA

Learning Objectives:

The student should be able to:

1. List the most common organisms causing CAP.

2. List the risk factors for the development of CAP.
3. Describe the usual clinical presentation of a patient with CAP.
4. Discuss the various tests used in the diagnosis of CAP.
5. Describe the risk stratification tools that can be used to guide site of care for patients with CAP (i.e.,
outpatient vs. general ward vs. ICU).
6. Recommend appropriate empiric antibiotic therapy for a patient with CAP; both for
outpatient treatment and hospitalized patients. Including drug, dose, route of
administration and duration of therapy.
7. List the parameters that can be used to monitor the drug therapy of a patient with CAP
(both efficacy and toxicity); including converting patients from intravenous to oral therapy.
8. Suggest appropriate steps to take in a patient who does not respond to initial antibiotic
therapy.

PNA is a lower RTI (LRTI)

I. Epidemiology

A. US data

1. Incidence varies by age

a. Highest at extremes of age (< 5 years and > 65 years of age)
b. Mortality is higher in elderly
c. Elderly are hospitalized more often

B. Singapore data

1. Most common cause of death from infectious disease

2. #2 in overall causes of death (2015)
3. #5 in causes of hospitalization (2014)

C. Increased mortality risk persists after discharge from hospital

D. Mortality rates have not changed in past several decades despite better overall care and new
antibiotics

II. Microbiology Half the time, we don't identify the organism that cause pneumonia.

A. Most common organisms (SG & Asia data)

1. Streptococcus pneumoniae (~ 65%)

2. Haemophilus influenzae (~ 10%)
3. Mycoplasma pneumoniae, Legionella sp. and Chlamydia pneumoniae (~ 20%) (atypical)
4. Mycobacterium tuberculosis --> Locally, we need to think about this if someone has PNA because TB
5. Viruses is more common here than in the US/Canada.
 B. Other organisms

1. Staphylococcus aureus
2. Gram negative bacilli – Burkholderia pseudomallei (meloidosis), Klebsiella
pneumoniae More common in SG than Europe
3. Anaerobic bacteria – Peptococcus, Peptostreptococcus
a. Cause aspiration pneumonia From gastric content; Use slightly different abx

III. Risk Factors for CAP

A. Host factors

1. Increasing age
2. Male sex

B. Modifiable risk factors

1. Smoking
2. Malnutrition
3. Low vitamin D level

C. Underlying lung disease

1. COPD, asthma
2. Preceding viral respiratory infection (secondary)

D. Chronic medical conditions

1. Stroke
2. Diabetes
3. Renal disease
4. Dysphagia --> Predispose to aspiration PNA

E. Immune suppression

1. TNFα inhibitors (drug)

2. HIV infection (disease)

F. Medications

1. PPI’s
2. Inhaled steroids

G. Socioeconomic factors

1. Low-income household
2. Crowded living conditions

IV. Clinical Presentation

A. Usual presentation Non-specific sx: HA, N/V

Sudden onset
1. Fever
2. Cough – productive
3. Shortness of breath
4. Tachypnea

B. Clinical signs and symptoms cannot reliably be used to predict the microbial etiology of
community-acquired pneumonia.

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 C. Physical examination findings - Lungs

1. Decreased breath sounds

2. Inspiratory crackles Collection of bac, wbc and pus in lungs --> Air bubbling through this
3. Dullness on percussion
Lungs should be hollow, but collection of pus makes it more solid --> Dull sound

D. Elderly and patients with co-existing illnesses may not present with usual signs and symptoms

1. May present with poor feeding, drowsiness, no fever Not talking as much; Confusion
2 infections we think about in elderly patients are UTI & RTI
V. Diagnosis B,C, D: Mainly for those who are hospitalized

A. Clinical presentation

B. Chest X-ray Clinical dx fail to identify

the specific bacteria 50%
1. Changes that may indicate pneumonia – consolidation, infiltrate of the time
2. Assess pre-existing lung disease
3. Baseline assessment – monitor response to therapy

C. White blood cell count (GP may do this test)

1. Aid in the diagnosis of infection, in general

D. Other

1. Electrolytes
2. Renal function Affects choice and dosing of abx
3. C-reactive protein (CRP) – Not specific for infection (any kind of inflammation)
4. Procalcitonin
- Released in response to bacterial toxins and inflammatory mediators
- Aids in differential diagnosis of viral vs. bacterial infection Does not increase in viral infection
- Non-ICU patients > 0.25mcg/L or ICU patients > 0.5mcg/L → can aid in decision
to start antibiotic therapy webcast

E. Microbiologic diagnosis

1. Aid selection of antibiotic therapy

a. Use drug active against organism

b. Narrow down spectrum of drug
c. Use lower cost drug

2. Identify unusual pathogens e.g. MTB & resistant-strains

3. Gram stain sputum

a. Sputum vs. saliva

per field i. < 10 epithelial cells
ii. > 25 neutrophils

b. Technique and operator dependent (skills)

4. Sputum culture

a. Takes at least 48 – 72 hours to get results Usually just start empiric therapy first

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 5. Blood culture

a. Bacteremia in ~ 11% of patients Need to be treated longer

b. Infection can spread from blood to lungs, or lungs to blood
c. Associated with higher mortality
d. Selected hospitalized patients
i. severe pneumonia
ii. immunocompromised

6. Urine culture Usually for hospitalised; Routinely done in elderly patients

7. Urine antigen tests

a. Legionella, Strep. pneumoniae --> Don't grow well in culture

b. Only indicates that there has been exposure to the organism and an
immunologic response Doesn't mean that it is causing the infection, just that the body has
mounted a response.
8. Polymerase chain reaction (PCR) assays (blood)
More used for research, not clinical
a. Selected organisms - Legionella, Mycoplasma, Strep. pneumoniae,
Chlamydia and Viruses --> Don't grow well in culture
b. Higher sensitivity and specificity compared to urine antigen tests

F. Guidelines on CAP are conflicting for recommendations on extent and importance of

diagnostic work-up

1. Performing diagnostic tests should never delay the start of antibiotic therapy

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VI. Treatment

A. Risk stratification for Inpatient vs. Outpatient treatment Most important to differentiate this
Physician judgement overwrites these tools.
1. Pneumonia severity index (Don't need to calculate)
(-) Complicated; Need a lot of data points; Not user friendly; GP don't have these data

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1-step strategy for stratifying patients with CAP into risk groups according to risk of mortality at 30days when the results of blood urea
are available.
2. CURB-65 severity score
MUST REMEMBER THIS

3. Social issues

a. Caregiver support at home Those who live alone may not be able to manage.
b. Likelihood of compliance with outpatient therapy and follow-up

B. Other factors to consider in choosing initial empiric antibiotic therapy

1. Adverse reactions or allergies to antibiotics (Require accurate allergy reports)

2. Co-existing illnesses
Avoid certain drugs / Decrease doses

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 C. Empirical antibiotics for the initial treatment of CAP (Based on Ministry of Health 2006
guidelines, TTSH 2010 guidelines, and NUH 2016 guidelines)
For adults
Clinical Setting Organisms Empiric Therapy Common Dosage Regimens

Outpatient Strep. pneumoniae Erythromycin 500mg po qds or 800mg bd (EES)

Atypical organisms OR
PSI = I or II Clarithromycin 500mg po bd
OR OR
CURB-65 = 0 - 1 Azithromycin 500mg po om
OR
Doxycycline 100mg po bd

OR
Macrolide OR Doxycycline
top + bottom PLUS
Amoxicillin/clavulanate 625mg po tds
OR
Ampicillin/sulbactam 750mg po bd
OR
Cefuroxime 250 – 500mg po bd
Inpatient Strep. pneumoniae Amoxicillin/clavulanate IV/po 1.2g IV q8h
(Non-ICU) Haemophilus influenzae OR
Atypical organisms Ampicillin/sulbactam IV/po 1.5g IV q6h
PSI = III or IV OR
OR Ceftriaxone 1g IV q12h or 2g IV q24h
CURB-65 = 2 PLUS (plus sth that covers the atypicals)
Clarithromycin po
OR
Azithromycin po

OR
When pt. is allergic to penicillin --> Levofloxacin alone; 2nd line 750mg IV/po q24h
Inpatient Strep. pneumoniae Penicillin TTSH 4MU IV q6h
(Severe pneumonia, Atypical organisms OR
ICU) Burkholderia pseudomallei Amoxicillin/clavulanate NUH 1.2g IV q6h
Klebsiella pneumoniae PLUS
PSI = V Azithromycin --> cover atypicals 500mg IV q24h
OR PLUS
CURB-65 ≥ 3 Ceftazidime -->cover gram-ve 2g IV q8h
3-drug therapy
OR
Levofloxacin 750mg IV q24h
PLUS
Ceftazidime

1. Treatment issues
2nd-line
a. Respiratory fluoroquinolones, anti-pneumococcal fluoroquinolones

i. Increased activity against Gram positive and atypical organisms (levo & moxi only)
ii. Approved as monotherapy for outpatients and hospitalized
patients
iii. Not recommended as first-line treatment (local practice) Not recommended for routine use
- Concerns about development of resistance with overuse
- Concerns about inappropriate use for other respiratory E.g. upper (URTI); viral URTI
infections
- Use has been associated with delays in diagnosis and
treatment of pulmonary TB

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 b. Need for empiric coverage of atypical organisms

i. Legionella sp., Mycoplasma pneumoniae, Chlamydophila

pneumoniae
ii. Conflicting recommendations from clinical trials and treatment
guidelines
iii. US guidelines (2007)
- empiric coverage for all patients
iv. Systematic review (2016)
- hospitalized, non-ICU patients
- β-lactam plus macrolide or fluoroquinolone monotherapy had better
outcomes compared to β-lactam alone
v. Local practice (include atypical coverage according to table above - but rarely for non-ICU)

c. Early initiation of antibiotics for hospitalized patients

i. Early initiation (within 8 hours) results in better outcomes upon patient arrival
ii. Start therapy in emergency department rather than wait until patient
is on ward

d. Duration of therapy

i. Traditionally = 7 – 14 days
ii. Rationale for shorter courses of therapy
- Decrease development of resistance
- Reduce costs
- Decrease adverse reactions
ii. New agents with long serum and tissue half-lives may be able to E.g. Azithromycin
give shorter course (3 – 5 days)

iii. IDSA/ATS guidelines (2007)

- Treat for minimum of 5 days
- Should be afebrile for 48-72 hours and clinically stable
before discontinuation of therapy
iv. Levofloxacin dosing
- Recent guidelines specify 750mg once daily x 5 days

e. Adjunctive corticosteroid therapy

i. Rationale
- Inflammatory response in lungs
ii. Only studied in patients who were hospitalized due to CAP
iii. Outcomes
- May decrease need for mechanical ventilation, length of stay and Not in guidelines yet
time to clinical stability
- Some evidence to show decreased mortality

D. Monitoring response to therapy

1. Goals of therapy

a. Cure of infection
b. Eradication of organism

2. Time course of response

a. Should start to see improvement in signs and symptoms in 48 – 72

hours
b. Elderly and patients with co-existing illnesses may be slower to
respond

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 c. Should not change antibiotics within first 72 hours
- Unless patient is deteriorating or culture results available

3. Monitoring parameters Procalcitonin more used to see if we should stop abx

a. Efficacy WBC count, T, HR, SOB, Cough, C-reactive protein (trend)

i. Chest X-ray If pt responds clinically, we won't repeat chest X-ray after initial one for dx.
- Changes are slow to resolve – 4-6 weeks or longer
- Repeat if patient deteriorates

b. Toxicity Depends on abx used

E. Conversion from IV to oral therapy

1. Benefits
- Allows discharge from hospital; Shorten hospital stay
- Cheaper drug

2. Criteria for switching Usually met within 3 days

a. Vital signs stable for 24 hours (Afebrile)

b. Able to take oral diet and oral medications
c. Others
- WBC count decreasing
- Improvement in signs and symptoms

3. Can be discharged the same day as convert to oral --> Don't need to monitor change; No change in
outcome

F. Patients who do not respond to initial therapy

1. Incorrect diagnosis (e.g., heart failure, pulmonary embolus)

2. Correct diagnosis

a. Drug-related issues
i. Compliance
ii. Drug interactions E.g. FQ x cations decrease abs
iii. Wrong dose
iv. Wrong drug

b. Pathogen-related issues

i. Unusual pathogen
ii. Resistant organism

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 HOSPITAL-ACQUIRED PNEUMONIA

Learning Objectives:

The student should be able to:

1. State the definition of hospital-acquire pneumonia (HAP).

2. Describe the risk factors for HAP, including patient-related factors, infection-related
factors, and intervention-related factors.
3. List the most common organisms that cause HAP. Compare this to the most common
causes of community-acquired pneumonia (CAP).
4. Recommend appropriate empiric antibiotic therapy for a patient with HAP. Including drug,
dose, route of administration and duration of therapy.

I. Definition

- Development of a pneumonia at least 48 hours after hospital admission

- Not incubating (present) at the time of admission

II. Epidemiology

A. Second most common hospital-acquired infection

B. Mortality  25%

C. Incidence higher in patients admitted to an intensive care unit (ICU) versus non-
ICU patients

D. Prolongs hospital stay 7 – 9 days

III. Risk Factors for HAP

A. Patient-related factors

1. Age > 70 years

2. Coma or impaired consciousness --> Increased risk of aspiration
3. Prolonged hospitalization
4. Malnutrition--> Impaired immune system
5. Cigarette smoking --> Impaired lung function
6. Co-existing illnesses
a. COPD
b. Diabetes mellitus
c. Renal failure
i. Associated with impaired lung function and defenses

B. Infection control-related factors

1. Transmission of bacteria from hands of healthcare workers to patients

2. Use of contaminated respiratory care equipment

C. Intervention-related factors

1. Drugs
a. Sedatives, narcotic analgesics --> Depress CNS --> Increased risk of aspiration
b. Antibiotics (for other infections) --> Eliminate normal flora & select for resistant
c. Steroids and immunosuppressive agents

2. Nasogastric tubes --> Impair function of esophagus --> Increased risk of aspiration
3. Intubation/mechanical ventilation (ventilator-associated pneumonia)
--> By-pass defence mechanisms--> Easier access for bacteria into lungs
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 IV. Microbiology

A. Wider list of potential organisms and higher chance of multidrug-resistant (MDR) organisms
compared to CAP

B. Gram positive organisms

1. Streptococcus pneumoniae
2. Methicillin-sensitive Staphylococcus aureus (MSSA)
3. Methicillin-resistant Staph aureus (MRSA)

C. Gram negative organisms

1. Escherichia coli
2. Haemophilus influenzae
3. Proteus species
4. Serratia marcescens
5. Enterobacter species
6. Klebsiella pneumoniae (including MDR and ESBL-producing)
7. Acinetobacter species (including MDR and ESBL-producing)
8. Pseudomonas aeruginosa (including MDR)

V. Treatment

A. Up to 50% of cases do not identify an organism

B. Cannot wait to start antibiotics until culture results are available
1. Studies show that mortality can be reduced with early initiation of appropriate empiric
therapy

C. Initial empiric therapy for HAP (IDSA/ATS 2016 guidelines)

1. Not at high risk of mortality and no risk factors increasing likelihood of MRSA

Recommended Antibiotic Therapy Common Dosage Regimens Higher doses compared to

(Choose one of the following) (Adults with normal renal function) CAP
Covers MSSA Piperacillin/tazobactam 4.5g IV q6h
OR
Cefepime 1 - 2g IV q8h
OR
Levofloxacin 750mg IV q24h
OR
Imipenem 500mg IV q6h
OR
Meropenem 1g IV q8h

2. Not at high risk of mortality, but with risk factors increasing likelihood of MRSA

Recommended Antibiotic Therapy Common Dosage Regimens 2 abx for MRSA coverage
(Adults with normal renal function)
Any of the above (Table 1)
OR
DO NOT cover MSSA nor MRSA Ceftazidime 1 – 2g IV q8h
OR
Ciprofloxacin 400mg IV q8-12h
OR
Aztreonam 1 – 2g IV q8h

PLUS
Vancomycin 15 – 20mg/kg IV q8-12h
(target trough = 15 – 20mg/L)
Cover MRSA OR
Linezolid 600mg IV q12h

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 3. High risk of mortality or receipt of IV antibiotics in prior 90 days

Recommended Antibiotic Therapy Common Dosage Regimens

(Choose two of the following, (Adults with normal renal function)
Avoid two beta-lactams)

3-drug therapy Piperacillin/tazobactam

OR
Cefepime
OR
Ceftazidime
OR
Imipenem
OR
Meropenem

PLUS
Ciprofloxacin
OR
Levofloxacin
OR
Amikacin 7.5mg/kg IV q12h or 15mg/kg IV q24h
OR
Gentamicin 1-2mg/kg IV q8h or 5-7mg/kg IV q24h
OR
Aztreonam

PLUS
Vancomycin (SG)
OR
Linezolid (USA)

D. Indications for empiric MRSA coverage Rarely in general ward in SG

1. Prior IV antibiotic use within 90 days

2. Hospitalization in a unit where > 20% of Staph aureus isolates are methicillin-resistant
3. Where the prevalence of MRSA is not known

E. Risk factors for mortality

1. Need for ventilatory support due to the pneumonia

2. Septic shock

F. Duration of therapy

a. Historically = 14-21 days

b. Optimal duration not clearly established from clinical trials
c. More recent recommendations for shorter duration (i.e., 5 – 7 days)
- Patient is responding to therapy
- No multidrug-resistant organism isolated
d. IDSA/ATS guidelines (2016) = 7 days

G. Monotherapy vs. Combination therapy

a. Rationale for combination therapy

- Synergistic activity with different MOA
- Prevent development of resistance
- Broader spectrum of coverage

b. Disadvantages
- More expensive
- Increased risk of adverse effects

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c. Combination therapy recommended (IDSA/ATS 2016)
- High risk of mortality
- Receipt of IV antibiotics in prior 90 days
- Pseudomonas aeruginosa as causative organism
i. Patients in septic shock or at high risk for death

d. Monotherapy sufficient
- Gram positive organism as cause of pneumonia
- Mild to moderate infection
Usually monotherapy for general ward; Combination for ICU

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Reading List:

1. Pharmacotherapy. 9th edition, 2014. Chapter 85.

OR
2. Applied Therapeutics. 10th edition. 2012. Chapter 64.
3. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-
associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and
the American Thoracic Society. Clin Infect Dis 2016;63(5):e61-111.

Case Discussion:

You must be prepared to answer the accompanying questions during the instructor-led class discussion.

DL 75 yo Chinese Male Ht = 177cm, Wt = 67kg

CC: Cough and SOB x 7 days

HPI: Presents to the Emergency Department with cough for 7 days. Associated with increasing SOB,
increasing sputum production and decreased appetite. Saw a GP 4 days ago. Given Augmentin but no
improvement. No nausea, vomiting or diarrhea. No dysuria. Episode of fever 4 days ago (Tmax = 38.2),
but now resolved. No recent changes in medications. Claims compliance to all of his medications.

PMH: Hypertension x 15 years

Diabetes type 2 x 15 years

SH: Lives with son and daughter-in-law. Home alone during the day.

Medication History: Enalapril 5mg bd x 10 years

Nifedipine LA 30mg om HTN
Metformin 500mg tds
Glipizide 5mg bd DM

Allergies: NKDA

PE:

VS: T = 37.6, HR = 85, RR = 22, BP = 130/80

HEENT: No lymph nodes

CVS: S1S2, no murmurs
Lungs: Poor breath sounds, bilateral basal creps
Abd: Soft, nontender
CNS: GCS = 15
CN: intact
Power = 5/5

Labs:
CrCl = 76 --> Don't need renal adjustment
Na = 138, K = 4.2, Urea = 5.4, Cr = 70, Glc = 7.5
WBC = 15.2, Hgb = 12.5, Plt = 400

CXR: Infiltrate right lower lobe (RLL)

Impression: Partially treated community-acquired pneumonia

1. What signs, symptoms and lab tests are compatible with the diagnosis of an infection in general,
and specifically a pneumonia?
2. What are the desired therapeutic outcomes for DL?
3. Suggest two potential therapeutic options for the treatment of the pneumonia. Drug regimens
must include drug, dose, route, frequency and duration.
4. Which is the most logical choice? Cite the advantages and disadvantages of your two options.
5. Develop a monitoring plan for efficacy and toxicity of the option you choose for this patient.

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