Here comes PCTHere comes PCT

David Gilbert, MDDavid Gilbert, MD

DisclosuresDisclosures

• Advisory/Consultant: Pfizer, Bayer, Schering-Plough, Pacific Bioscience, Advanced Life Science, Wyeth, Roche, Johnson and Johnson, Achaogen

• Speaker: Merck

Major ProblemMajor Problem

• Increasing resistance of major bacterial pathogens to licensed antibacterials

• Discovery and development of new antibacterials is at a low ebb.

• Hence, we need to be good stewards of the drugs that are still active.

How to reduce empiric use of How to reduce empiric use of antibacterials?antibacterials?

• Rapid point of care microbial diagnosis. Especially helpful in respiratory tract infections. Example: rapid test for gp.A streptococci

• Multiplex PCRs for common viral and bacterial pathogens would be ideal. A few are FDA approved. Clinical integration slow.

Surrogate Markers of Bacterial Surrogate Markers of Bacterial Invasive DiseaseInvasive Disease

• Until such time as multiplex PCRS are available, we are left with surrogate markers

• Have used fever, WBCs, C-reactive protein levels and ESR in this way for many years. Too insensitive and non-specific

• A new biomarker is procalcitonin (PCT). • See what you think?

ProcalcitoninProcalcitonin

• The 116-aminoacid precursor (prohormone) of the 32-aminoacid hormone—calcitonin

• Calcitonin produced in neuroendocrine C-cells of thyroid and K-cells of the lung

• Pro-CT produced in all parenchymal tissues and monocytes/macrophages

Crit.Care Medicine 2008; 36; 941&1684

Calcitonin vs ProCTCalcitonin vs ProCT

• Calcitonin lowers serum calcium

• Produced only in thyroid and selected lung cells

• Levels do not increase in response to bacterial infection.

• ProCT is intimately involved with the inflammatory process

• Produced by monocytes, fat cells, R-E system, adrenal, G-I tract and more

• Rapid large increases in serum levels within 3-6 hrs of onset of bacterial infection

What is physiologic role of PCT?What is physiologic role of PCT?

• Not yet completely understood

• Increases synthesis of nitric oxide

• Antibody to PCT increases survival of septic pigs

What elevates serum levels of What elevates serum levels of PCT?PCT?

• Acute local and invasive bacterial infections.• Low perfusion states that may allow

translocation of normal flora: major surgical procedures, trauma with shock, severe burns, severe cardiogenic shock, ischemic bowel

• Systemic fungal infections; falciparum malaria• Small cell lung Ca; Medullary thyroid Ca• Clinically, interested in PCT levels in RTIs and

Sepsis

PCT serum levelsPCT serum levels

• Levels rise within 3-6 hrs of onset of bacterial infection.

• Degree of elevation correlates with severity of bacterial infection

• FDA-approved Immunoassay is sensitive,rapid, and specific.

• Levels range from < 0.05 to over 1,000 ng/ml• Sequential levels useful in diagnosis, prognosis,

and assist in duration of therapy• Low levels have excellent negative predictive

value

PCT Levels as Guide to Therapy of PCT Levels as Guide to Therapy of Respiratory Tract Infections(RTIs)Respiratory Tract Infections(RTIs)

• Bulk of data from Switzerland

• Used sensitive PCT assay

• If randomized to PCT group, use of antibacterials encouraged or discouraged by PCT result

• Assumption: If patients recovered without an antibacterial, likely that no serious bacterial infection was present

PCT-Guided Therapy of AECB*PCT-Guided Therapy of AECB*

• Randomized controlled blinded trial at Univ. Hosp. in Switzerland

• Patients Admitted from ER with steroids and inhalers and then randomized

• Group 1. Standard therapy by attending MD. PCT levels kept blinded

• Group 2. PCT levels provided and, depending on result, discouraged or encouraged, use of antibiotics

Chest 2007; 131:9-19

PCT-Guided Therapy of AECBPCT-Guided Therapy of AECB

• PCT levels available within 1 hour, 24/7

• If PCT level < 0.1 ng/ml: “No bacterial infection. Discourage use of antibiotics”

• If PCT level > 0.25 ng/ml: “Use of antibiotics encouraged”

• Outcome assessment: Antibiotic use acutely and over 6 months. Need for ICU and other secondary endpoints

Results: AECBResults: AECBVariable PCT-

Guided(102)Not PCT-Guided (113)

Antibiotic 40% 72%

Clin. Success 84 89

ICU admit 8 11

Death, any cause 5 9

Positive sputum* 37 40

Viral studies None None

*Did not correlate with PCT levels

AECB study limitationsAECB study limitations

• One hospital; only inpatients

• Ultimately need large multicenter trial that includes both inpatients and outpatients

• Future study: If PCT serum level < 0.1 ng/ml, randomize to either placebo or antibiotic

• Hopefully include sputum cultures and viral studies

PCT Guidance of Antibiotic PCT Guidance of Antibiotic Therapy of CAP*Therapy of CAP*

• Randomized, controlled, blinded trial in Swiss University Hospital

• Patients admitted from ER with CAP

• All had PCT levels

• Controls: Treating MDs not given results of PCT serum level

• PCT group: Treating MDs given results with suggestions as to antibiotic use.

AJRCCM 2006; 174:84

Chest 2007;131:9

AJRCCM 2006; 174:84

High Levels of PCT in the “septic” High Levels of PCT in the “septic” patientpatient

• Increases likelihood of bacterial sepsis; Differentiates bacterial from viral infection

• Predicts prognosis of bacterial sepsis

• Differentiation of infectious and non-infectious etiologies of inflammation.

• As a guide to the duration of antibiotic therapy.

PCT: Marker of Sepsis in ICU*PCT: Marker of Sepsis in ICU*

*CCM 2000:28:977. PCT level of >0.5 ng/ml

How well does PCT differentiate How well does PCT differentiate bacterial and viral infections?*bacterial and viral infections?*

• 360 children admitted from ER with temperature > 38.5o C.

• Responsible pathogen identified.

• Divided into 3 groups:

• Gp. 1: Invasive bacterial infection

• Gp. 2: Localized bacterial infection

• Gp. 3: Viral infection

Ped. Inf. Dis. 1999; 18: 875-81

PCT: Bacterial or viral infection?PCT: Bacterial or viral infection?

Result Group 1 Group 2 Group 3

Diagnosis Meningitis or bacteremia

Local. Bacterial infection

Viral infections

Number of patients

46 78 236

Age range 1 mo-15 yr 2 mo-15 yr 1 mo-15 yr

Example pathogens

N.meningitidis, S.pneumo, E.coli

S.pyogenes, E.coli, Salmonella

Enterovirus, influenza, adenovirus,RSV, EBV

Correlation of Peak PCT Level and Correlation of Peak PCT Level and 90 Day Mortality*90 Day Mortality*

PCT: max. level, ng/ml Mortality, %

<1.0 5

1-5 11

6-20 28

21-50 37

51-1000 42

CCM 2006;34:2596

PCT is low in non-bacterial PCT is low in non-bacterial infectious causes of SIRS*infectious causes of SIRS*

• Viral infections: unless bacterial super-infection

• ARDS (CCM 1999; 27:2172)

• Sterile necrotizing pancreatitis (Gut 1997; 41:832)

• Post-liver transplant rejection (CCM 2000; 28:555)

SIRS= Systemic Inflammatory Response Syndrome

ARDS:Bacterial or not?ARDS:Bacterial or not?

CCM 1999;27:2175

Sequential PCT levels can shorten Sequential PCT levels can shorten antibiotic therapy in septic patients*antibiotic therapy in septic patients*

• Randomized, controlled, open intervention trail in ICU septic and septic shock patients.

• Daily PCT levels

• Standard of care vs. “stop” rules

• Stop if PCT fell 90% from baseline peak

• Stop if absolute value of < 0.25 ng/ml

• Stop if baseline < 1 and level now <0.1AJRCCM 2008;177:498

PCT levels at PPMCPCT levels at PPMC

• Ultra-sensitive, FDA-approved assay available 24/7 starting 9/15/08

• Results in < I hr.

• Cost: $68 (CBC $30; Antibiotic $20-120)

• Encourage use: ER, ICU, Hospitalists, Primary Care Physicians, and others.

Procalcitonin Levels: SummaryProcalcitonin Levels: Summary

• Sensitive and specific biomarker for bacterial infection

• PCT levels augment, do not replace, clinical assessment of patients with RTIs, suspected and proven sepsis

• Will hopefully result in reduced use of empiric antibiotics

• Sequential levels hopefully will decrease the duration of antibiotic therapy in some patients.

Antibiotic StewardshipAntibiotic Stewardship

• CDC,FDA, NIH, CMS all looking for ways to avoid overuse of antibiotics for non-bacterial Respiratory Tract Infections.

• Procalcitonin needs further study, but based on current evidence, low ProCT levels (<0.25 ng/ml), suggest a low priority for antimicrobial therapy in patients with upper and lower respiratory tract infections.

Can we rapidly discriminate Can we rapidly discriminate bacterial from viral RTI?bacterial from viral RTI?

• Sinusitis, otitis, acute bronchitis, AECB, and even CAP

• Clinical picture often does not allow discrimination

• ESR, CRP no help

• Eventually, point of care multiplex PCR

• For now, rapid procalcitonin (ProCT) assay available.

Procalcitonin Serum LevelsProcalcitonin Serum Levels

• FDA-approved antibody based assay system

• Very sensitive: quantifies levels from 0.05 to 1000 ng/ml

• Answers in less than 1 hour.

ProCT and Viral InfectionsProCT and Viral Infections

• Of 236 viral infections, only 3 had serum ProCT levels > 2 ng/ml

• Viral meningitis, < 1 ng/ml; bacterial meningitis, very high levels ( approx. 10 ng/ml)

• Stimulated European studies designed to determine if ProCT levels could guide antibiotic use for RTIs

Eur.resp.journal 2007;30:556

Main PointsMain Points

• Resistance is everywhere• Impressive array of mechanisms of

resistance• Vaccines can have a major impact on

incidence of invasive bacterial disease• To preserve activity of current drugs, need

less empiric use. How? Surrogate markers for bacterial infection or rapid ID of specific viral or bacterial pathogen

Resistance is everywhere: Resistance is everywhere: S.aureusS.aureus

• World-wide epidemic of CA-MRSA

• Roughly 50 % of S.aureus isolates at PPMC are MRSA

• In USA in 2005, 8987 cases of invasive disease with 13 % mortality. More deaths than from AIDS. (JAMA 2007;298:1763)

• Concomitant increase in vancomycin resistance

Anti-MRSA DrugsAnti-MRSA Drugs

• Licensed: Vanco, TMP/SMX, Doxy, Clinda, Linezolid, Quinupristin-dalfopristin

• In development: Dalbavancin, Telavancin, Ortivancin, Ceftobiprole, Ceftaroline, Iclaprim

Resistance is everywhere: Resistance is everywhere: S.pneumoniaeS.pneumoniae

• Changed in vitro criteria for resistance, and hence, reduced prevalence of resistance to penicillins

• Resistance to erythromycin, azithromycin, clarithromycin now roughly 50 %

• If allergic to penicillin and macrolide resistant isolate, treatment options: Fluoroquinolone, Clinda, Linezolid

Resistance is everywhere: FQs and Resistance is everywhere: FQs and Gram-negative BacteriaGram-negative Bacteria

• Resistance of N.gonorrhaeae to FQs

• Resistance of salmonella and camplyobacter to FQs

• Resistance of E.coli, P.aeruginosa, and Acinetobacter species to FQs

Resistance is everywhere: “R” of Resistance is everywhere: “R” of GNBs to beta-lactamsGNBs to beta-lactams

• Increasing resistance of aerobic GNBs to ESPs, ESCs, BL/BLIs, Carbapenems

• Mostly enzymatic: Chrom.-inducible cephalosporinases, ESBLs, KPCs(KIebsiella Producing Carbapenemases

• Empiric treatment of VAP in NYC: colistin and tigeclycline

• Pipeline drugs for P.aer., Acinetobacter: 0

How do bacteria survive in How do bacteria survive in presence of antibacterials?presence of antibacterials?

• Synthesis of enzymes that alter the drug

• Change the drug target

• Pump the drug out before target is reached

• Make the cell wall impermeable

• Make the target irrelevant; generative alternative synthetic pathways

Genetics of ResistanceGenetics of Resistance

• Resistance can occur from mutations. Once resistance present, spreads by genetic exchange, e.g.:

• Bacteriophages

• Transformation: update and incorporation of naked DNA (recycling)

• Spread of plasmids by conjugation (bacterial sex).

Vaccines to Prevent Invasive Vaccines to Prevent Invasive Bacterial DiseaseBacterial Disease

• Haemophilus influenza type b, protein conjugate vaccine

• Pneumococcal conjugate vaccine

19F to 19A: Watch Out!19F to 19A: Watch Out!

• Several reports of emergence of serotype 19A as a virulent and multidrug resistant pneumococcus:”replacement pneumococcal disease”

• Serotype 19F is in protein conjugate vaccine; 19A is not.

• Rate of Invasive Pneumococcal Disease in immunized alaskan children increased from 134 (2001-2003) to 245 (2004-2006) per 100,000.

In vitro susceptibility of 19A?In vitro susceptibility of 19A?

Drug MIC90 Suscept. Interpretation

Penicillin G 6 R

Amoxicillin 6 R

Ceftriaxone 2 Intermediate

Azithromycin >256 R

Vaccines are not the answerVaccines are not the answer

• H.influenza And pneumococcal vaccines successful, but no vaccines for S.aureus or common gram-negative bacteria

• Answer to resistance is to use antibacterials less often and, when used, for shorter periods of time.