Day 1 Pfizer CAP HAP - Solante Zotomayor

New Insights in the management
of CAP, HAP/VAP
in an era of drug resistance
- An update in the approach and
management of CAP, HAP/VAP
Objectives
Part 1: Dr. Ric Zotomayor
To present current approach in the management of
a. CAP
b. HAP/VAP
Part 2: Dr. Rontgene Solante

To discuss trends in the antibiotic management of
pneumonia
a. PK-PD optimization
b. role of β-lactam-β-lactamase inhibitors (PTZ) vs ESBL,
carbapenem sparing agents
c. innovator vs generic PTZ
• Associate Professor IV, UERMMMC College of
Medicine
• Life Fellow - PCP, PCCP
• Member, PCCP Executive Committee, 1999 to 2003
• Examiner, Philippine Specialty Board of Internal
Medicine: Member 2006-2008
• Examiner, Specialty Board of the PCCP:
Member 2008-2010
Chairman 2009-2010
• Assistant Director, Institute of Pulmonary Medicine, St.
Luke’s Medical Center, QC
• PCCP Councils:
Asthma Council
Former Co-Chairman, Lung Infection Council
Disclosure
Speaker and advisory board consultant member for :
Astra Zeneca Phils.- Asthma/COPD
Novartis Phils. - COPD
Pfizer Phils. - Anti-infectives/
Pneumonia vaccine
This presentation may include personal clinical experience/s and recommendations

which may not necessarily reflect the views of Pfizer.
Community Acquired Pneumonia
Ricardo C. Zotomayor, M.D.

Life Fellow – PCP/PCCP
Presentation of CAP vs PTB
Clinical features suggestive of PTB Adjusted OR 95% CI P-value
Age up to 40 years 1.47 0.34-6.45 0.611
Duration of symptoms of >2 weeks 25.10 4.63-136.05 <0.001
History of night sweats 5.43 1.10-26.79 0.038
History of weight loss 0.76 0.18-3.56 0.764
Upper lobe involvement 8.23 1.59-42.53 0.012
Cavitary infiltrates on chest radiograph 19.41 2.94-128.19 0.002
Total WCC of 12 x 109/L or less 6.28 1.21-32.52 0.029
Lymphopenia 4.73 1.08-20.85 0.040
Table adapted from Liam, CK, Pang, YK, Poosparajah, S. Respirology (2006) 11, 786–792.
Community Acquired Pneumonia
Issues:
1. Determine the site of care and appropriate

antibiotic regimen
2. Update on diagnosis of CAP including role of new

diagnostic tools
Determining the Appropriate Site of Care
CAP
Any of the ff:
1. RR > 30/min
2. PR > 125/min
3. Temp > 40oC or <36oC Any of the ff:
4. SBP<90mmHg or DBP 1. Severe sepsis
<60mmHg YES YES
and Septic shock
5. Altered mental status of HIGH RISK CAP
acute onset
2. Need for
6. Suspected aspiration mechanical
7. Unstable comorbid ventilation
conditions*
8. CXR: multilobar, pleural ICU Admission
effusion, abscess NO
NO Adapted from the Philippine
MODERATE RISK CAP Clinical Practice Guidelines
on the Diagnosis, Empiric
Management and Prevention
LOW RISK CAP of Community-acquired
Pneumonia in
Immunocompetent Adults
Ward Admission 2010 Update.
Outpatient
Microbial etiology of CAP by site of care
Outpatients Ward Patients Intensive care unit Patients
[1}
Spain Canada [2] Spain [1] United States [3] Spain [1] United States [3]
Total patients evaluated 514 507 2521 585 488 145
Patients in whom pathogens was identified 161 (31.3) 244 (48.1) 1042 (41) 120 (21) 260 (53) 57 (39)
Patients whom no pathogens was identified 353 (68.7) 263 (51.8) 1479 (59) 465 (79) 228 (47) 88 (61)
Pathogens ¶
Streptococcus pneumoniae 56 (10.9) 30 (5.9) 447 (17.7) 38 (6.5) 110 (22.5) 22 (15.2)
Other Streptococcus spp 0 5 (1.0) 0 0 0 0
Haemophilus influenzae 8 (1.6) 25 (4.9) 54 (2.1) 16 (2.7) 8 (1.6) 3 (2.1)
Haemophilus parainfluenzae 0 10 (2.0) 0 0 0 0
Moraxella catarrhallis 0 6 (1.2) 4 (0.2) 0 1 (0.2) 0
Legionella pneumophila 10 (1.9) ∆ 87 (3.5) ◊ 21 (4.3) ◊
Mycoplasma pneumoniae 27 (5.3) § 87 (17.2) § 32 (1.3) § ¥ 6 (1.2) § ¥
Chlamydia pneumoniae 10 (1.9) § 72 (14.2) § 32 (1.3) § ¥ 8 (1.6) § ¥
Coxiella burnetii 11 (2.1) § ∆ 17 (0.7) § ¥ 2 (0.4) § ¥
Staphylococcus aureus 1 (0.2) 6 (1.2) 18 (0.7) 25 (4.3) 6 (1.2) 12 (8.3)
MSSA 1 (0.2) NR 9 (0.4) 18 (3.1) 4 (0.8) 9 (6.2)
MRSA 0 NR 9 (0.4) 7 (1.2) 2 (0.4) 3 (2.1)
Gram-negative enteric bacilli 1 (0.2) 2 (0.4) 23 (0.9) 15 (2.6) 3 (0.6) 4 (2.8)
Pseudomonas aeruginosa 1 (0.2) 1 (0.2) 37 (1.5) 12 (2.1) 12 (2.5) 8 (5.5)

15 (2.9) § † 123 (4.9) § † 10 (2.5) § †
Respiratory viruses
Other pathogen 6 (1.2) 14 (2.8) 33 (1.3) 8 (1.4) 15 (3.1) 3 (2.1)
> 1 pathogen 15 (2.9) ** 135 (5.4) 6 (1.0) 58 (11.9) 7 (4.8)
Table adapted from Marrie, TJ and File, TM. Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults.
Accessed thru UpToDate.com https://www.uptodate.com/contents/epidemiology-pathogenesis-and-microbiology-of-community-acquired-
pneumonia-in-adults/print?source=see_link on 01 Mar 2018.
Other references in notes page.
Low Risk (Outpatient) CAP
Clinical Criteria Potential pathogens
Stable Vital signs • Streptococcus pneumoniae
• RR <30/minute • Haemophilus influenzae
• PR <125/min • Chlamydophila pneumoniae
• SBP >90 mm Hg • Mycoplasma pneumoniae
• DBP >60 mm Hg • Moraxella catarrhalis
• Temp >36oC or <40oC • Enteric Gram-negative bacilli
(among those with co-morbid
• No altered mental state of acute illness)
onset
• No suspected aspiration
• No or stable co-morbid
conditions
• Chest X-ray
• Localized infiltrates
• No evidence of pleural effusion
Philippine Clinical Practice Guidelines on the Diagnosis, Empiric Management and Prevention of
Community-acquired Pneumonia in Immunocompetent Adults 2016 Update.
Moderate risk CAP
Unstable Vital Signs: • Streptococcus pneumoniae
• RR >30/min • Haemophilus influenzae
• PR >125/min • Chlamydophila pneumonia
• Temp <36oC or >40oC
• Mycoplasma pneumoniae
• SBP <90 mmHg
• Moraxella catarrhalis
• DBP <60 mmHg
• Altered mental state of acute onset • Enteric Gram-negative bacilli
• Suspected aspiration • Legionella pneumophila
• Unstable / Decompensated comorbid • Anaerobes (among those with
condition risk of aspiration)
• Uncontrolled diabetes mellitus, active
malignancies, neurologic disease in
evolution,
• Congestive heart failure (CHF) Class II-IV
• Unstable coronary artery disease
• Renal failure on dialysis
• Uncompensated COPD
• Decompensated liver disease
High Risk / Severe CAP
Any of the clinical features of • Streptococcus pneumoniae
Moderate risk CAP PLUS any of • Haemophilus influenza
the following: • Chlamydophila pneumoniae
• Mycoplasma pneumoniae
• Severe Sepsis and Septic Shock • Moraxella catarrhalis
OR • Enteric Gram-negative bacilli
• Need for Mechanical • Legionella pneumophila
Ventilation • Anaerobes (among those with risk
of aspiration)
• Staphylococcus aureus
• Pseudomonas aeruginosa
Low Risk CAP – Empiric Treatment
Preferred regimen
Without co-morbid illness With stable co-morbid illness
(β-lactam/β-lactamase inhibitor
AMOXICILLIN 1 gm TID combination (BLIC) OR 2nd gen oral
cephalosporin +/- extended macrolides )
If with β-lactam allergy, may use
Co-amoxiclav 1 gm BID OR
Extended macrolides: Sultamicillin 750 mg BID OR
Cefuroxime axetil 500 mg BID
Azithromycin 500 mg OD +/-
OR Azithromycin 500 mg OD
Clarithromycin 500 mg BID OR
Clarithromycin 500 mg BID
• In 2010, amoxicillin sulbactam, 2nd generation cephalosporin cefaclor and 3rd generation
cephalosporins (cefdinir, cefixime and cefpodoxime) were included as options
Philippine Clinical Practice Guidelines on the Diagnosis, Empiric Management and Prevention of Community-acquired
Pneumonia in Immunocompetent Adults 2016 Update.
Moderate Risk CAP - Empiric treatment
Preferred Regimen
• IV non-anti-pseudomonal β-lactam (BLIC, cephalosporin) + extended
macrolides or respiratory fluoroquinolones (PO)
Ampicillin-Sulbactam 1.5 gm q6h IV OR

Cefuroxime 1.5 g q8h IV OR
Ceftriaxone 2 g IV OD
plus
Azithromycin 500 mg OD PO
OR
Clarithromycin 500 mg BID PO Atypical
OR organism
Levofloxacin 500 mg OD PO coverage
OR
Moxifloxacin 400 mg OD PO
• In 2010, amoxicillin-clavulanic acid, 2nd gen ceph (cefotiam,cefoxitin), 3rd gen
ceph (cefotaxime, ceftizoxime) and ertapenem were included
Philippine Clinical Practice Guidelines on the Diagnosis, Empiric Management and Prevention of Community-
acquired Pneumonia in Immunocompetent Adults 2016 Update.
Moderate Risk CAP - Empiric treatment
Preferred Regimen
• If aspiration pneumonia is suspected and a regimen containing ampicillin-
sulbactam and/or moxifloxacin is used, there is no need to add another
antibiotic for additional anaerobic coverage. If another combination is used
may add clindamycin to the regimen to cover microaerophilic streptococci.
Clindamycin 600 mg q8h IV

OR
Ampicillin-Sulbactam 3 g q6h IV
OR
Moxifloxacin 400 mg OD PO
High Risk / Severe CAP - Empiric treatment
Preferred regimen
No risk for P. aeruginosa
IV non-anti-pseudomonal β-lactam
+ IV extended macrolides or IV respiratory fluoroquinolones
Ceftriaxone 2 gm OD OR
Ertapenem 1 gm OD
+
Azithromycin dihydrate 500 mg OD IV OR
Levofloxacin 500 mg OD IV OR
Moxifloxacin 400 mg OD IV
• In 2010, 3rd gen ceph (cefotaxime, ceftizoxime) were included
• Levofloxacin preferred dose 500 mg (non-pseudomonal dose)
• Ertapenem is the preferred choice over ceftriaxone if ESBL Enterobacteriaceae is suspected
Risk factors for Pseudomonas or drug-
resistant Gram negative pathogens
• Previous antibiotic therapy
• Recent hospitalization
• Immunosuppression
• Pulmonary comorbidity
• Cystic fibrosis
• Bronchiectasis
• Repeated exacerbations of chronic obstructive pulmonary
disease that require frequent glucocorticoid and/or antibiotic
use
• Probable aspiration
• Multiple medical comorbidities (e.g., diabetes mellitus,
alcoholism)
File, TM, Niederman, MS. Infect Dis Clin N Am 18 (2004) 993–1016.
Arancibia, F, Torsten, TB, Ewig, S et al. Arch Intern Med. 2002;162(16):1849-1858.
Shindo, Y et al. Am J Respir Crit Care Med. 2013;188(8):985-99.
High Risk / Severe CAP – Empiric treatment
Preferred regimen (1)
Risk for P. aeruginosa
IV anti-pneumococcal anti-pseudomonal β-lactam (BLIC, cephalosporin or
carbapenem) + IV extended macrolides + aminoglycoside
Piperacillin-tazobactam 4.5 gm q6h OR

Cefepime 2 gm q8h-12h OR
Meropenem 1 gm q8h
+
Azithromycin dihydrate 500 mg OD IV
+
Gentamicin 3 mg/kg OD OR
Amikacin 15 mg/kg OD
• In 2010, cefoperazone-sulbactam, cefpirome and ticarcillin clavulanic acid and AMG
netilmycin and tobramycin were included
• Dosage modified for piperacillin-tazobactam and cefepime
Preferred regimen (2)
Risk for P. aeruginosa
IV antipneumococcal antipseudomonal β-lactam (BLIC, cephalosporin or
carbapenem)
+ IV ciprofloxacin/levofloxacin (high dose)
Piperacillin-tazobactam 4.5 gm q6h OR

Cefepime 2 gm q8-12h OR
Meropenem 1 gm q8h
+
Levofloxacin 750 mg OD IV OR
Ciprofloxacin 400 mg q8-12h IV
• 14-21 days for those with suspected or confirmed gram negative, S. aureus or P.
aeruginosa
Risk factors for MRSA CAP
• Gram-positive cocci in clusters seen on sputum Gram stain
• Known colonization with MRSA
• Risk factors for colonization with MRSA
• End-stage renal disease
• Contact sport participants
• Injection drug users, those living in crowded conditions
• Men who have sex with men, prisoners
• Recent influenza-like illness
• Antimicrobial therapy (particularly with a fluoroquinolone)
in the prior three months
• Necrotizing or cavitary pneumonia
• Presence of empyema
File, TM, Niederman, MS. Infect Dis Clin N Am 18 (2004) 993–1016.
Arancibia, F, Torsten, TB, Ewig, S et al. Arch Intern Med. 2002;162(16):1849-1858.
Shindo, Y et al. Am J Respir Crit Care Med. 2013;188(8):985.
Preferred regimen
If MRSA pneumonia is suspected, add:
Vancomycin 15 mg/kg q8-12h

OR
Linezolid 600 mg q12h IV
OR
Clindamycin 600 mg q8h IV
• 14-21 days for those with suspected or confirmed gram negative, S. aureus or P.
aeruginosa
Diagnostic Testing for Microbial Etiology
• Hospitalized patients should have
• Blood cultures
• Sputum Gram stain and culture
• Patients with severe CAP requiring intensive care unit (ICU) admission
should have
• Blood cultures
• Legionella and pneumococcus urinary antigen tests (UAT)
• Sputum culture (either expectorated or endotracheal aspirate)
• Newer tests include:
• Polymerase chain reaction (PCR) for detecting Chlamydia
pneumoniae and Mycoplasma pneumoniae as well as 14 respiratory
tract viruses.
• These tests are rapid (one to two hours), sensitive, and specific
Bartlett, JG. Diagnostic approach to community-acquired pneumonia in adults. Accessed thru UpToDate.com on 26
February 2018.
Blood Sputum Legionella Pneumococcal Multiplex
Indication Other
culture culture UAT UAT PCR¶
Intensive care unit admission X X X X X X ∆
Failure of outpatient antibiotic

X X X X
therapy
Cavitary infiltrates X X X◊
Leukopenia X X X
X
Active alcohol abuse X X X X
Chronic severe liver disease X X X
Severe obstructive/structural
X X
lung disease
Asplenia (anatomic or
X X X
functional)
Recent travel (within past 2 §
X X X
weeks)
Positive Legionella UAT result X¥ NA
Positive pneumococcal UAT

X X NA
result
Pleural effusion X X X X X‡
Adapted from Bartlett, JG. Diagnostic approach to community-acquired pneumonia in adults. Accessed thru
UpToDate.com on 26 February 2018.
Mandell, LA et al. Clinical Infectious Diseases 2007; 44:S27–72.
Diagnostic Testing for Community-Acquired Pneumonia
Identify cavitation
TEST SENSITIVITY SPECIFICITY and loculated pleural
Chest radiograph 65%-85% 85-95% fluid; Recommended
in the evaluation of
Computed tomography Gold standard Not infection specific non-responding
Blood cultures 10%-20% High when positive patients.
Sputum Gram stain 40%-100% depending 0%-100% depending on

on criteria criteria
Use if suspect drug-
Sputum culture resistant or unusual
Oximetry or arterial blood gas pathogen
Serologic testing for

Legionella Chlamydophila
pneumoniae, Mycobacterium
pneumoniae, viruses
Legionella urinary antigen
Pneumococcal urinary
antigen Guide duration of
Serum procalcitonin therapy and need
for ICU admission.
Adapted from Nair, GB and Niederman M. Textbook of Critical Care. 7th ed 2017; Chap 74, pp.464-76
Prevention of CAP
• Influenza vaccination is recommended for the

prevention of CAP. (Grade A)
• Pneumococcal vaccination is recommended for the
prevention of invasive pneumococcal disease in
adults. (Grade A)
• Smoking cessation is recommended for all persons
with CAP who smoke. (Grade A)
HAP/VAP
Ricardo C. Zotomayor, M.D.

Issues identified
1. How is initial empiric antibiotic therapy
determined in HAP?
2. What are the important factors that determine
the choice of initial empiric antibiotic?
3. What are the recommended antibiotic options?
Common HAP / VAP Pathogens
Most commonly associated with VAP Drug resistance profile *
• S. aureus: 20%–30% • 50% MRSA
• Pseudomonas aeruginosa: 10%–20% • 19-26% resistant to piperacillin-

tazobactam
• Enteric gram-negative bacilli (e.g. E.
coli, Klebsiella pneumoniae):
20%–40%
• Acinetobacter baumannii: 5%–10% • 56%–61% resistant to carbapenem
• Inappropriate antibiotic therapy for VAP was associated with a higher risk of death
(OR, 2.34; 95% CI, 1.51–3.63; P = 0.0001)
Sievert, DM et al. Infect Control Hosp Epidemiol 2013;34(1):1–14.

Jones, RN et al. Clin Infect Dis 2010;51(S1):S81–S87.
Kuti, EL et al. J Crit Care 2008; 23:91–100.
Risk factors for MDR HAP/VAP pathogens
Risk factors For MDR VAP
Prior intravenous antibiotics use within 90 d
Septic shock at time of VAP
ARDS preceding VAP
Five or more days of hospitalization prior to the occurrence of VAP
Acute renal replacement therapy prior to VAP onset
Risk factors for MDR HAP
Risk factors for MRSA VAP/HAP
Risk factors for MDR Pseudomonas VAP/HAP
Adapted from Kalil, AC et al. Clin Infect Dis 2016;63(5):e61–111.

Risk factors for MDR HAP/VAP pathogens
• Duration of mechanical ventilation ⩾7 days (OR 6.0)

• Prior antibiotic use (OR 13.5)
• Prior use of broad-spectrum drugs (OR 4.1)
• Local ICU ecology

• Initial HAP or VAP severity (e.g. septic shock)
Torres A, Niederman MS, Chastre J, et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of
hospital-acquired pneumonia and ventilator-associated pneumonia. Eur Respir J 2017; 50:1-26.
Prior antibiotic exposures reflected a statistically
significant, linear, positive relationship with
the percentage of MDR isolates
More than half of the MDR isolates were in patients who received ≥1 anti-pseudomonal antibiotic
in the preceding 90 days.
Adapted from Trinh, TD et al. Diagnostic Microbiology and Infectious Disease 89 (2017) 61–66 .
Key factors that recommend combination
antibiotic as initial empiric in HAP
1. Does the patient have either of the
following risk factors? One of the ff:
• Piperacillin-tazobactam 4.5 g q6h
• Need for ventilatory support or mechanical
ventilation • Cefepime 2 g q8h
• Septic shock • Ceftazidime 2 g q8h
• Imipenem 500 mg IV q6h
2. Has the patient received antibiotics • Meropenem 1 g q8h
within the past 90 days? • Aztreonam 2 g q8h
3. Is the patient at increased risk for Plus one of the ff:
gram negative infections? • Levofloxacin 750 mg IV q24h
• Structural lung disease • Ciprofloxacin 400 mg q8h
• Respiratory specimen Gram stain with • Amikacin 15-20 mg/kg daily
numerous and predominant gram • Gentamicin 5-7 mg/kg daily
negative bacilli
• Tobramycin 5-7 mg/kg daily
4. Does the patient have either the
following MRSA risk factors? Plus one of the ff:
• Treatment unit/ICU > 20% prevalence of • Vancomycin 15 mg/kg q8-12h,
Staphylococcus aureus are MRSA Consider LD 25-30 mg/kg x 1 for severe
• Treatment unit prevalence of MRSA is illness
unknown • Linezolid 600 mg q12h
Kalil, AC et al. Clin Infect Dis 2016;63(5):e61-111.

Key factors that recommend combination antibiotic
as initial empiric in VAP
1. Are any of the ff risk factors for MDR GN One of the following:
VAP present ?
• Piperacillin-tazobactam 4.5 g q6h
• IV antibiotic use within the previous 90 days • Cefepime 2 g q8h
• Septic shock at the time of VAP • Ceftazidime 2 g q8h
• ARDS preceding VAP • Imipenem 500 mg IV q6h
• Meropenem 1 g q8h
• >5 days of hospitalization prior to the • Aztreonam 2 g q8h
occurrence of VAP
• Acute renal replacement therapy prior to VAP Plus one of the following:
onset
• Levofloxacin 750 mg IV q24h
• Treatment in the ICU in which >10% of gram
negative isolate are resistant to an agent being • Ciprofloxacin 400 mg q8h
considered for monotherapy • Amikacin 15-20 mg/kg daily
• Treatment in an ICU in which local antimicrobial • Gentamicin 5-7 mg/kg daily
susceptibility is not known • Tobramycin 5-7 mg/kg daily
• Colistin 5 mg/kg IV x 1 (LD), then 2.5 mg IV
q12h
2. Does the patient have either the • Polymyxin B 2.5-3.0 mg/kg/d divided in 2 daily
following MRSA risk factors?
IV doses
• Treatment in a unit in which >10-20% of S.
aureus isolates are MRSA
Plus one of the following:
• Treatment in a unit where prevalence of MRSA is • Vancomycin 15 mg/kg q8-12h
unknown
• Linezolid 600 mg q12h
Kalil, AC et al. Clin Infect Dis 2016;63(5):e61-111.

Some antimicrobials have stronger effects for their risk
of selecting bacterial resistance and collateral damage
than others.
• The indiscriminate use of metronidazole (e.g. in abdominal
surgery) is linked to an increase of infections due to 3GC-resistant
Enterobacteriaceae.
• Carbapenem use increase infections due to carbapenem-resistant
P. aeruginosa/Acinetobacter spp. as well as selection of
Stenotrophomonas maltophilia.
• Ceftriaxone promotes the selection and spread of extended
spectrum β-lactamase (ESBL)-producing and/or ciprofloxacin
resistant Escherichia coli more than cefotaxime.
There is no unique strategy to avoid the promotion of resistance -
Important to avoid the routine use of
the same few antibiotics for all situations.
G. Levy Hara et al. International Journal of Antimicrobial Agents 48 (2016) 239–246.

High MDR pathogen risk
• Hospital settings with high rates of MDR pathogens (i.e. a

pathogen not susceptible to at least one agent from three or
more classes of antibiotics)
• Prevalence of resistant pathogens in local microbiological
data >25%
• Previous antibiotic use
• Recent prolonged hospital stay (>5days of hospitalization)
• Previous colonization with MDR pathogens
Empiric Antibiotic Treatment Algorithm for
Hospital-Acquired Pneumonia (HAP) and
Ventilator-Associated Pneumonia (VAP)
HAP/VAP: assess risk for MDR pathogens and mortality
Low MDR pathogen risk and High MDR pathogen risk and/or >15%
low mortality risk # mortality risk
No septic shock Septic shock
Antibiotic monotherapy: Single Gram-negative agent

ertapenem, ceftriaxone, (if active for >90% Gram- Dual Gram-pseudomonal
cefotaxime, moxifloxacin or negative bacteria in the coverage ± MRSA therapy
levofloxacin ICU) ± MRSA therapy
Adapted from Torres A, Niederman MS, Chastre J, et al. International ERS/ESICM/ESCMID/ALAT guidelines for the
management of hospital-acquired pneumonia and ventilator-associated pneumonia. Eur Respir J 2017; 50:1-26.
Empiric antibiotic treatment algorithm for
hospital-acquired pneumonia (HAP) and
ventilator-associated pneumonia (VAP)
High MDR pathogen risk and/or >15%
mortality risk
Single Gram-negative agent

(if active for > 90% Gram- Dual Gram-pseudomonal
negative bacteria in the ICU) coverage ±MRSA therapy
±MRSA therapy*
• Imipenem, meropenem
• Vancomycin
• Ceftazidime , cefepime
+/- • Linezolid
• Piperacillin-tazobactam
* MRSA rate >25% in ICU
• Levofloxacin
Empiric antibiotic treatment algorithm for
hospital-acquired pneumonia (HAP) and
ventilator-associated pneumonia (VAP)
High MDR pathogen risk and/or >15%
mortality risk
Single Gram-negative agent

(if active for > 90% Gram- Dual Gram-pseudomonal
negative bacteria in the ICU) coverage ±MRSA therapy
±MRSA therapy *
• Gentamicin, tobramycin,
• Imipenem, meropenem
+/- amikacin +/- • Vancomycin
• Ceftazidime , cefepime
• Ciprofloxacin, levofloxacin • Linezolid
• Piperacillin-tazobactam
• Colistin if A. baumanii is * MRSA rate >25% in ICU
• Aztreonam
suspected
Proposed Strategy for Managing Antimicrobial
Therapy in Patients with VAP
Due to emergence of
drug resistance,
Step 1: Start therapy using broad-spectrum
antibiotics empirical treatment
with broad-spectrum
Step 2: Stop therapy if the diagnosis of infection antibiotics is justified.
becomes unlikely
Step 3: Use narrower spectrum antibiotics once the
etiologic agent is identified
Step 4: Use pharmacokinetic-pharmacodynamic data
to optimize treatment
Step 5: Switch to monotherapy on days 3 to 5
Step 6: Shorten the duration of therapy
Chastre, J and Luyt, CE. Chap. 34. Ventilator associated pneumonia. Murray and Nadel’s Textbook of
Respiratory Medicine, 6th ed., pp. 583-92.
Ensuring that ICU
patients with true
antibiotics bacterial infection
receive immediate
Step 2: Stop therapy if the diagnosis of infection appropriate
becomes unlikely treatment may result
Step 3: Use narrower spectrum antibiotics once the in more patients
etiologic agent is identified receiving
antimicrobial therapy
to optimize treatment than necessary.

antibiotics Therapy can be
narrowed either
Step 2: Stop therapy if the diagnosis of infection
becomes unlikely
because an
anticipated organism
Step 3: Use narrower spectrum antibiotics once the was not recovered, or
because the organism
Step 4: Use pharmacokinetic-pharmacodynamic data isolated is sensitive to
to optimize treatment a more narrow-
Step 5: Switch to monotherapy on days 3 to 5 spectrum antibiotic.

antibiotics

becomes unlikely Clinical and
Step 3: Use narrower spectrum antibiotics once the bacteriologic
etiologic agent is identified outcomes can be
Step 4: Use pharmacokinetic-pharmacodynamic data improved by
to optimize treatment optimizing the
Step 5: Switch to monotherapy on days 3 to 5 therapeutic regimen
according to PK/PD
Step 6: Shorten the duration of therapy properties.

antibiotics

becomes unlikely
etiologic agent is identified No clinical benefits to
Step 4: Use pharmacokinetic-pharmacodynamic data using a regimen
to optimize treatment combining two
antibiotics for more
than days 3 to 5,
Step 6: Shorten the duration of therapy provided that initial
therapy was
appropriate.

antibiotics

becomes unlikely
to optimize treatment
Reducing duration of
therapy in patients
Step 6: Shorten the duration of therapy with VAP has led to
good outcomes with
less antibiotic use.
Patients in whom short duration of therapy may not
be possible and in whom duration of therapy should
be individualized
• Initially inappropriate antibiotic therapy
• Severely immunocompromised patients (such as
neutropenia or stem cell transplant)
• Highly antibiotic-resistant pathogens:
• Pseudomonas aeruginosa
• Carbapenem-resistant Acinetobacter spp.
• Carbapenem-resistant Enterobacteriaceae
• Second-line antibiotic therapy (e.g. colistin, tigecycline)
END of PART I
Rontgene M. Solante, MD
• Past President, Philippine Society for Microbiology and Infectious Diseases

(PSMID)
• PCP, Board of Regent 2017-up to present
• Global Steering Committee Member , MEDSCAPE for Pneumococcal Disease
Prevention and Education
• Chairman, Fellowship Program Adult Infectious Disease and Tropical
Medicine- San Lazaro Hospital
• Medical Specialist IV , National Reference Laboratory for HIV/AIDS San
Lazaro Hospital
• Assistant Professor , UERMMMC
• Fellow, PCP and PSMID
| 47
Disclosure / Conflict of Interest
• Speaker, KOL , advisory board

• Pfizer AI, Pfizer vaccines
• MSD AI, MSD vaccines
• Biomerrieux
• Cathay Drug
• Natrapharm
• Sanofi Pasteur
• Unilab Westmont
| 48
Part 3: Current trends in the
antibiotic management of
CAP and HAP/VAP
Rontgene M. Solante, M.D.
Antibiotic management in an era of drug resistance
• Correct and adequate antibiotic coverage is essential

• Inappropriateness of antimicrobial coverage associated with
poor outcome, high mortality
• Most challenging in the critically ill/high risk pneumonia

• High prevalence of antibiotic-resistant strains
• Impact of critical illness and therapy on pharmacokinetics
(PK) and pharmacodynamics (PD) of antibiotics
• Delayed identification of microorganisms
Vincent et al. Advances in antibiotic therapy in the critically ill. Critical Care (2016) 20:133.
Antibiotic management in hospitalized pneumonia
• Choice of Empiric treatment

• De-escalation
• Duration of therapy (when to stop?)
• Dosing issues
• Pharmacokinetics/pharmacodynamics
• Target site penetration
• Clearance
• Volume of distribution
• Dosing of β-lactams
• Dosing in obese patients
• Dosing during extracorporeal therapies or hemodialysis
Vincent et al. Advances in antibiotic therapy in the critically ill. Critical Care (2016) 20:133.
Optimizing Initial Dosing of Antibiotics in MODS
Therapeutic drug monitoring

(TDM)
Clinical scenarios likely to alter antibiotic PK in MODS.

Maintenance dosing should be guided by the level of organ function
and in the context of the main elimination pathways for the drug and, where possible, guided by TDM.
Chest 2011;139;1210-1220
DALI: Defining Antibiotic Levels in Intensive Care Unit Patients:
Are Current β-Lactam Antibiotic Doses Sufficient for Critically Ill
Patients?
Cefepime Doripenem Piperacillin Meropenem
(n=14) (n=13) Tazo (n=89)
(n=109)
Dosage per 24 h gm 6.0 (5–6 ) 1.75-3 12-16 3-4
50% f T>MIC 78.6% 100% 80.6% 95%

achieved
50% f T>4×MIC 50% 69.2% 48.9% 68.8%
achieved
100% f T>MIC 78.6% 76.9% 67% 69.7%
achieved
100% f T>4×MIC 71.4% 30.8% 30.3% 41.6%
achieved
Infected critically ill patients may have adverse outcomes as a result of inadequate
antibiotic exposure; a paradigm change to more personalized antibiotic dosing may be
necessary to improve outcomes for these most seriously ill patients
Clinical Infectious Diseases 2014;58(8):1072–83
Strategies for defining dosing of antibiotics for infections in the lung
Physiochemical and Pharmacodynamics Dosing Considerations and

ELF Penetration Characteristics Example Antibiotic Class
Characteristics
Loading and maintenance doses
Time-Dependent Frequency, consider CI or EI
(%ƒT>MIC) e.g., Beta-lactams
Hydrophilic
(low to moderate
penetration ratio [<1])
Concentration- Dose
Dependent or same frequency
(ƒCmax/MIC or ƒAUC/MIC) e.g., Aminoglycosides
Antibiotic
or same loading and maintenance
Time-Dependent doses
(%ƒT>MIC) or same frequency, consider CI
Lipophilic e.g., Oxazolidinones
(high penetration ratio
[>1])
Concentration- or same dose
Dependent Same frequency
ƒAUC/MIC or ƒCmax/MIC e.g., Fluoroquinolones
↑, increase; CI, continuous infusion; EI, extended infusion
Adapted from Rodvold, KA, William, WH and Boyd, SE. Current Opinion in Pharmacology 2017, 36:114–123.
Infection site, pharmacokinetic considerations and
adaptation of dosing regimen
Infection Site Pharmacokinetic Alteration Potential Change to Dosing Regimen
Blood Expand Vd, enhanced CL Provision of LD, increase frequency

Lung Impaired permeability * Increase dose *
Soft tissue Contigent on body composition Increase dose in obesity
Bone Impaired permeability Increase dose, duration of therapy
CNS Impaired permeability Maximal dose
CL=clearance, CNS= central nervous system; LD=loading dose; Vd =volume distribution.

* Of hydrophilic agents (β-lactams, vancomycin, aminoglycosides).
Adapted from Onufrak, NJ, Forrest, A, and Gonzalez, D. Clinical Therapeutics. 2016;38:1930-1947.
Pharmacodynamic and dosing characteristics of
commonly administered antibiotics
Antibiotic Pharmacodynamic Index PAE * Dosing Paradigm
Higher frequency; prolonged
β-lactams ƒT>MIC Minimal †
infusions
Vancomycin ƒAUC:MIC __ flexible
Fluoroquinolones ƒAUC:MIC, Cmax:MIC Prolonged flexible; high dose
Aminoglycosides Cmax:MIC, ƒAUC:MIC Prolonged High dose, low frequency‡

Cmax:MIC = ratio of maximum concentration to minimum inhibitory concentration (MIC); ƒAUC:MIC = ratio of free
drug area under the concentration-time curve to MIC; ƒΤ>MIC = percentage of time free drug remains above MIC;
PAE = post antibiotic effect.
* For Gram-negative pathogens only
† Exception: carbapenems (prolonged)
‡ Exceptional: enterococcal endocarditis (lower dose, higher frequency)
Post-antibiotic effect (PAE), which quantifies the persistence of bacterial suppression after short exposure
to the drug, thus adding to the overall duration of antimicrobial effect.
Adapted from Onufrak, NJ, Forrest, A, and Gonzalez, D. Clinical Therapeutics. 2016;38:1930-1947.
Mortality Among Patients Treated With Prolonged Versus
Short-term Infusion Of Antipseudomonal Antibiotics
0.48
(A) Random sequence generation (selection bias) High risk of bias

(B) Allocation concealment (selection bias) Low risk of bias
(C) Blinding of participants and personnel (performance bias) Unclear risk of bias
(D) Incomplete outcome data (attrition bias)
(E) Selective reporting (reporting bias)
Adapted from Vardakas, KZ et al. Lancet Infect Dis 2018; 18:108-20.
Mortality Among Patients Treated With Prolonged Versus Short-
term Infusion Of Anti-pseudomonal Antibiotics According To
Antibiotic Classes
0.83
Adapted from Vardakas, KZ et al. Lancet Infect Dis 2018; 18:108-20.

The β-Lactam-β-lactamase
inhibitor combinations
Class A SHV-1 β-lactamase
Figure adapted from Drawz, SM and Bonomo, RA. Clinical Microbiology Reviews Jan. 2010, p. 160–201.
-lactamase inhibitors Combination (BLiC)
in Clinical Practice (Updated 2017)
BLICs (innovator brand)
Amoxicillin + Clavulanic Acid
Ampicillin + Sulbactam/Sultamicillin
Piperacillin + Tazobactam
Novel BLiCs
Ceftolozane-tazobactam
Ceftazidime-avibactam
Meropenem-vaborbactam
Letourneau, AR and Calderwood, SB. Accessed thru https://www.uptodate.com/contents/combination-beta-lactamase-inhibitors-

carbapenems-and-monobactams?search=combination%20beta-
lactamase%20inhibitors&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 on 20 Feb 2018.
Susceptibility Profile against P. aeruginosa
Antipseudomonal activity of piperacillin/tazobactam: more than

a decade of experience from the SENTRY Antimicrobial
Surveillance Program (1997-2007)
This illustrates the changing patterns of resistance for piperacillin/tazobactam

over time (1997–1999 versus 2005–2007) shown by geographic region.
Jones, RN et al. Diagnostic Microbiology and Infectious Disease 65 (2009) 331–334.

Susceptibility rates of piperacillin/tazobactam and 9 other
agents tested against 25,460 P. aeruginosa isolates collected
in the SENTRY Program (1999–2007)
Antimicrobial agent % susceptible by region (no. tested)
EU (7695) NA (9047) LA (4277) APAC (4441)
Piperacillin/tazobactam 83.0* 88.7 74.8 82.9
Piperacillin 78.4 86.1 67.7 79.3
Ticarcillin/clavulanate 71.6 77.2 56.4 67.6
Ticarcillin 70.0 78.7 55.4 73.6
Cefepime 77.1 84.8 64.6 77.0
Ceftazidime 75.9 82.4 62.8 74.7
Imipenem 78.0 85.9 68.7 80.4
Meropenem 81.5 89.4 71.6 83.5
Ciprofloxacin 70.7 76.1 58.6 75.8
Tobramycin 77.0 92.0 63.8 82.2
* Underlined value indicate highest susceptibility (broadest spectrum) in the region.
Adapted from Jones, RN et al. Diagnostic Microbiology and Infectious Disease 65 (2009) 331–334.
Trends in piperacillin/tazobactam susceptibility
rates (1997–1999 versus 2005–2007) for P.
aeruginosa in 4 geographic regions (5 continents)
Time interval (no. tested) % susceptible by region

EU NA LA APAC*
1997-1999 (7007) 86.0 89.7 76.5 88.7
2005-2007 (6831) 83.7 (-2.3) 85.7 (-4.0) 79.4 (+2.9) 77.1 (-11.6)
All years (25 460) 83.0 88.7 74.8 82.9
* APAC includes Asia and Australia
Susceptibility declined 2.3% to 11.6% (greatest for APAC) in all

regions except Latin America, where the rate actually
increased by 2.9%.
Adapted from Jones, RN et al. Diagnostic Microbiology and Infectious Disease 65 (2009) 331–334.
Piperacillin-Tazobactam Susceptibility Profile
Microorganism % susceptible Source

Pseudomonas aeruginosa 86.8% 2016 ARSP Data1
80.3% (UTI) 83.4% (IAIs) 2013-2015 SMART2
Escherichia coli, urine isolate 92.6% (out-patient)
2016 ARSP Data1
87.5% (in-patient)
ESBL + 86% 2016 ARSP Data1
Klebsiella pneumoniae
ESBL - 91.6% (UTI), 95.2% (IAIs) 2013-2015 SMART2
ESBL + 53.9% (UTI); 53.7% (IAIs)
1. 2016 Antimicrobial Resistance Surveillance Program, DOH RITM.

2. Karlowsky, JA et al. Journal of Medical Microbiology 2017;66:61-69.
Percentage of urinary Escherichia coli, all ARSP sites,
January - December 2016
Outpatient Inpatient
Antimicrobial Oral Agents N %R 95%C.I. N %R 95%C.I.
Ampicillin 879 84.4 81.8-86.7 2446 86.1 84.7-87.4
Co-amoxiclav 880 28.8 25.9-31.9 2388 39.6 37.6-41.6
Cefuroxime 359 39.3 34.3-44.6 803 41.7 38.3-45.2
Ciprofloxacin 809 52.2 48.7-55.7 2310 45.5 43.5-47.6
Co-trimoxazole 762 63.5 60.0-66.9 2148 68.7 66.7-70.6
Nitrofurantoin 614 4.4 3.1-6.7 1297 4.1 3.2-5.5
Intravenous Agents
Piperacillin-tazobactam 888 7.4 5.8-9.4 2337 12.5 11.2-13.9
Ceftriaxone 778 38.7 35.3-42.2 1824 44.8 42.5-47.1
Ertapenem 421 2.9 1.6-5.1 982 5.1 3.8-6.7
Amikacin 742 1.5 0.8-2.7 2293 2.4 1.8-3.1
Adapted from 2016 Antimicrobial Resistance Surveillance Program, DOH RITM.

Resistance Rates of Pseudomonas aeruginosa, all
versus blood isolates, ARSP, 2016
Adapted from 2016 Antimicrobial Resistance Surveillance Program, DOH RITM.

• suggest that PTZ
may be safely used in
bacte remia from
some non-urinary
tract sources, at least
if the MIC is low
enough (<2 mg/liter)
• there was no mortality
among patients with
UTI treated with PTZ,
irrespective of the MIC.
• mortality was higher in
patients with
intermediate and high
MICs of PTZ against BSI
from other sources
Antimicrobial Agents and Chemotherapy p. 3402–3404 July 2013 Volume 57 Number 7
Clinical Infectious Diseases® 2017;65(10):1607–14
Estimated prevalence of carbapenem-resistant
Enterobacteriaceae in South and Southeast Asian countries.
Carbapenem Resistance in South and Southeast Asia

Clinical Microbiology Reviews January 2017 Volume 30 Issue 1
• This study compared the clinical efficacy of TZP against ertapenem for the
treatment of adult patients with APN caused by TZP-susceptible ESBL-Ec
and has shown encouraging results.
• The clinical efficacy of TZP was 79.4% (54/68) and the microbiological
eradication rate was 95.6% (65/68), indicating that TZP could be an
effective carbapenem-sparing therapeutic option for the treatment of
APN caused by ESBL-Ec.
Y.K. Yoon et al. / International Journal of Antimicrobial Agents 49 (2017) 410–415
• PTZ appear to be very reasonable options
• low- to moderate-severity infections
• infections resulting from urinary or biliary sources
• infections with piperacillin MICs <4 μg/mL.
• if PTZ is administered to patients with invasive ESBL

infections, we would recommend administering 4.5 g every
6 hours (or 4.5 g every 8 hours as extended infusion)

drugs in selected patients (mostly in urinary tract and abdominal infections) with confirmed or suspected ESBL to avoid the
Fist-line and second-line therapy for the treatment of
use of carbapenems (Fig. 1; ).
extended-spectrum-β-lactamase infections.
Table 2. Fist-line and second-line therapy for the treatment of extended-spectrum-β-lactamase infections. Therapy
'adjustment is recommended depending' on renal 'function'
ESBL
Enterobacteriaceae PTZ
MIC ≤16/4 mg/l
Primary BSI Pneumonia Abdominal infection Urinary tract infection
First-line therapy
Piperacillin–tazobactam 16/2 g every 24 h Piperacillin–tazobactam 16/2 g

As for BSIs As for BSIs
i.v. (a) every 24 h i.v. (a)
Meropenem 1 g q 6 h i.v. (b) or Meropenem 1 g q 6 h i.v. (b) or

ertapenem 500mg every 6 h i.v. (c) or ertapenem 500mg every 6 h i.v. (c)
impenem 0.5 g every 6 h i.v. (d) or or impenem 0.5 g every 6 h i.v. (d)
imipenem 1 g every 8 h i.v. (d) or imipenem 1 g every 8 h i.v. (d)
Tigecycline 50mg every 12 h i.v. (e)

Ceftolozane/tazobactam 1.5 g every 8 h Ceftolozane/tazobactam 1.5 g every
i.v. 8 h i.v.+metronidazole 500mg every
8 h i.v.
Ceftazidime–avibactam 2.5 g every

Ceftazidime–avibactam 2.5 g every 8 h
8 h i.v. +metronidazole 500 mg
i.v.
every 8 h i.v.
Second-line therapy
Carbapenems i.v.
Curr Opin Infect Dis. 2016;29(6):583-594.
Carbapenems i.v. +amikacin 15–20 +amikacin 15–20
mg/kg/day every 24 h i.v. or tigecycline 50 As for BSIs As for BSIs mg/kg/day every 24 h
'adjustment is recommended depending' on renal 'function'
Second-line therapy
ESBL Carbapenems i.v.
Fist-line and second-line therapy for the treatment of extended-spectrum-β-lactamase
Enterobacteriaceae
infections. PTZ 'adjustment is recommended depending' on renal 'function'
Therapy
MIC ≤16/4 12h
mg every mg/li.v. (e) i.v. or fosfomycin 4 g
every 6 h i.v.
Primary BSI Pneumonia Abdominal infection Urinary tract infection
Enterobacteriaceae PTZ MIC>16/4 mg/l and/or severe infection
First-line therapy
Meropenem 1 g q 6 h i.v. (b) or Meropenem 1 g q 6 h i.v. (b) or
Piperacillin–tazobactam 16/2 g every 24 h Piperacillin–tazobactam 16/2 g
ertapenem 500 mg every 6 h i.v. (c) or As for BSIs ertapenem 500 mg every 6 h i.v. (c) As for BSIs
i.v. (a) As for BSIs every 24 h i.v. (a) As for BSIs
impenem 0.5 g every 6 h i.v. (d) or or impenem 0.5 g every 6 h i.v. (d)
imipenem 1 1g gevery
Meropenem q 6 h8i.v.
h i.v.
(b)(d)
or or imipenem11ggqevery
Meropenem 8 h(b)i.v.or(d)
6 h i.v.
ertapenem 500mg every 6 h i.v. (c) or ertapenem 500mg every 6 h i.v. (c)
Ceftolozane/tazobactam 1.5 g every
Ceftolozane/tazobactam 1.5 g
impenem 0.5 g every 6 h i.v. (d) or every 8 h or impenem 0.5 g every 6 h i.v. (d)
8 h i.v.+ metronidazole 500 mg
i.v.
imipenem 1 g every 8 h i.v. (d) or imipenem 1 g every 8 h i.v. (d)
every 8 h i.v.
Tigecycline 50mg every 12 h i.v. (e)
Ceftazidime–avibactam 2.5
Ceftolozane/tazobactam 1.5 gg every
every 88 hh Ceftolozane/tazobactam 1.5 g every
i.v.
i.v. 8every
h i.v.+metronidazole 500mg every
8 h i.v.
8 h i.v.
(a) Piperacillin/tazobactam: loading dose (4.5 g in 1 h) followed by maintenance doses with continuous infusion (16/2 g
every 24 h).
Ceftazidime–avibactam 2.5 g every 8 h
i.v.
every 8 h i.v.
Second-line therapy
Carbapenems i.v.
Curr Opin Infect Dis. 2016;29(6):583-594.
mg every 12h i.v. (e) i.v. or fosfomycin 4 g
every 6 h i.v.
Enterobacteriaceae PTZ MIC>16/4 mg/l and/or severe infection

Does generic equivalence of innovator antibiotics
demonstrate therapeutic equivalence?
• Generic medicinal products are copies of patented drugs

marketed at low cost following patent expiration of the
brand leader product
• Generic products must comply with standards of quality,
efficacy, and reliability
• The therapeutic equivalence of generic medicinal products
approved for use in humans has been challenged in various
therapeutic areas
• Some vancomycin generic products were less bactericidal than the
innovator in vivo in a neutropenic mouse thigh infection model1,
and could induce more resistant subpopulations2
1. Vesga O et al. Antimicrob Agents Chemother 2010; 54:3271–3279.

2. Rodriguez CA et al. Antimicrob Agents Chemother 2012; 56:243–7.
Efficacy and Quality of Antibacterial Generic Products
Approved for Human Use : A Systematic Review
Reference Evaluated Generic Products Study Design Main Findings
Tschudin-Sutter et al, 2011 1 piperacillin-tazobactam generic product In vitro susceptibility No significant differences in mean
(Sandoz, Switzerland) tests and median MIC between the
generic product and the innovator
for all tested strains
Jones et al,2008 26 samples of piperacillin-tazobactam In vitro study Compared to the innovator, all but
generic products from Philippines (n=10 (incremental MIC 1 lot of generic product
lots), India (n=5), Greece (n=3), China antimicrobial assay) demonstrated significantly
(n=2), Spain (n=2), Taiwan (n=2), Portugal decreased activity, at -5 to -35%
(n=1), and Jordan (n=1) (average, -16%)
Moet et al, 2009 46 lots of piperacillin-tazobactam generic In vitro study (1) Compared to the innovator, the
products (29 manufacturers, 17 (incremental MIC range of activity of the generic
countries) antimicrobial assay) products was -42% to 10%
(average, -16%);
(2) The range of activity between
lots of the innovator was -19%
to 7% (average, -6%)
Silva et al, 2010 Multiple samples of piperacilllin- In vitro susceptibility Compared to the innovator, no
tazobactam, and meropenem generic testes significant differences with respect
products purchased in different to potency, MICs, critical
pharmacies in Colombia concentrations, or mutant selection
Note: Studies on other antibiotics were included in the review; only those involving piperacillin-tazobactam are illustrated. Overall conclusion of
the review indicated that the published data are limited and heterogenous, thus precluding any attempt to generalize the study results and that
additional evidence would be needed before considering a revision of the marketing authorization process for antibacterial generic products.
Tattevin, P et al. Clinical Infectious Diseases 2014;58(4):458–69.

In vitro potency evaluations of variations
piperacillin/tazobactam generic products compared with the
contemporary branded (Zosyn, Wyeth) Formulation
• Twenty-three generic intravenous piperacillin/tazobactam

products were compared for in vitro activity to the branded
formulation (Zosyn®, Wyeth, Philadelphia, PA) by disk diffusion
and incremental broth microdilution assay methods.
• All but 1 lot demonstrated significantly decreased activity (−5 to
−35%), necessitating further investigations regarding the
chemical purity, potency, and therapeutic equivalence of these
products worldwide.
• The average −16% activity across all generic lots was equivalent
to underdosing piperacillin/tazobactam by 2.6 g daily for serious
clinical infections (4.5 g q6h)
Jones, RN, Fritsche, TR, and Moet, GJ. Diagnostic Microbiology and Infectious Disease 61 (2008) 76-79.
Expanded studies of piperacillin/tazobactam
formulations: variations among branded products
lots and assessment of 46 generics lots
• Analyzing the potency of piperacillin/tazobactam generic
formulations by a precise multiorganism in vitro assay was
expanded to 46 lots (29 manufacturers, 17 countries).
• In the comparisons of 8 branded lots to the RLOT, the range of
Zosyn® potencies varied from +7% to −19% (average, −6%).
• These results showed that only 22% of generic lots had vial
strengths at least equal to the average of all branded lots tested.
• Not only were generic lots usually deficient in drug activity, but
also some manufacturers lot potencies could vary by 22% to 30%
Moet, GJ, Watters, AA, Sader, HS and Jones, RN. Diagnostic Microbiology and Infectious Disease 65
(2009) 319-322.
Summary and conclusion
• CAP and HAP/VAP are the 2 infections where diagnosis and

treatment entail knowledge of current updates and
antibiotic recommendation in order to prevent
inappropriate treatment.
• The knowledge of antibiotic PK-PD in respiratory infection
will allow us to optimize the regimen and lessen drug
resistance.
• Piperacillin-tazobactam remains an important treatment
option in serious infections and those critically ill especially
in an era where the pipeline of new antibiotics is still
limited.
Thank You
For Healthcare Professionals Only
Pfizer, Inc.
18/F-20/F 8 Rockwell Building,
Hidalgo Drive, Rockwell Center,
Makati City, Philippines
March 2018
PP-ZOS-PHL-0012

Day 1 Pfizer CAP HAP - Solante Zotomayor

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New Insights in the management

Part 2: Dr. Rontgene Solante

This presentation may include personal clinical experience/s and recommendations

Ricardo C. Zotomayor, M.D.

1. Determine the site of care and appropriate

2. Update on diagnosis of CAP including role of new

Haemophilus parainfluenzae 0 10 (2.0) 0 0 0 0

Moraxella catarrhallis 0 6 (1.2) 4 (0.2) 0 1 (0.2) 0

Legionella pneumophila 10 (1.9) ∆ 87 (3.5) ◊ 21 (4.3) ◊

Mycoplasma pneumoniae 27 (5.3) § 87 (17.2) § 32 (1.3) § ¥ 6 (1.2) § ¥

Chlamydia pneumoniae 10 (1.9) § 72 (14.2) § 32 (1.3) § ¥ 8 (1.6) § ¥

Coxiella burnetii 11 (2.1) § ∆ 17 (0.7) § ¥ 2 (0.4) § ¥

Staphylococcus aureus 1 (0.2) 6 (1.2) 18 (0.7) 25 (4.3) 6 (1.2) 12 (8.3)

MSSA 1 (0.2) NR 9 (0.4) 18 (3.1) 4 (0.8) 9 (6.2)

MRSA 0 NR 9 (0.4) 7 (1.2) 2 (0.4) 3 (2.1)

Gram-negative enteric bacilli 1 (0.2) 2 (0.4) 23 (0.9) 15 (2.6) 3 (0.6) 4 (2.8)

Pseudomonas aeruginosa 1 (0.2) 1 (0.2) 37 (1.5) 12 (2.1) 12 (2.5) 8 (5.5)

> 1 pathogen 15 (2.9) ** 135 (5.4) 6 (1.0) 58 (11.9) 7 (4.8)

Ampicillin-Sulbactam 1.5 gm q6h IV OR

Clindamycin 600 mg q8h IV

Piperacillin-tazobactam 4.5 gm q6h OR

Piperacillin-tazobactam 4.5 gm q6h OR

Vancomycin 15 mg/kg q8-12h

Failure of outpatient antibiotic

Chronic severe liver disease X X X

Positive Legionella UAT result X¥ NA

Positive pneumococcal UAT

Sputum Gram stain 40%-100% depending 0%-100% depending on

Serologic testing for

• Influenza vaccination is recommended for the

Ricardo C. Zotomayor, M.D.

• S. aureus: 20%–30% • 50% MRSA

• Pseudomonas aeruginosa: 10%–20% • 19-26% resistant to piperacillin-

• Acinetobacter baumannii: 5%–10% • 56%–61% resistant to carbapenem

Sievert, DM et al. Infect Control Hosp Epidemiol 2013;34(1):1–14.

Adapted from Kalil, AC et al. Clin Infect Dis 2016;63(5):e61–111.

• Duration of mechanical ventilation ⩾7 days (OR 6.0)

• Local ICU ecology

Kalil, AC et al. Clin Infect Dis 2016;63(5):e61-111.

Kalil, AC et al. Clin Infect Dis 2016;63(5):e61-111.

G. Levy Hara et al. International Journal of Antimicrobial Agents 48 (2016) 239–246.

• Hospital settings with high rates of MDR pathogens (i.e. a

HAP/VAP: assess risk for MDR pathogens and mortality

No septic shock Septic shock

Antibiotic monotherapy: Single Gram-negative agent

No septic shock Septic shock

Single Gram-negative agent

No septic shock Septic shock

Single Gram-negative agent

Step 6: Shorten the duration of therapy

Step 6: Shorten the duration of therapy

Step 1: Start therapy using broad-spectrum

Step 1: Start therapy using broad-spectrum

Step 2: Stop therapy if the diagnosis of infection

Step 1: Start therapy using broad-spectrum

Step 2: Stop therapy if the diagnosis of infection

Step 1: Start therapy using broad-spectrum

Step 2: Stop therapy if the diagnosis of infection

• Past President, Philippine Society for Microbiology and Infectious Diseases

• Speaker, KOL , advisory board

• Correct and adequate antibiotic coverage is essential

• Most challenging in the critically ill/high risk pneumonia

• Choice of Empiric treatment