# Presentation: 033682

## Primary bloodstream infection as an indication: Regulatory perspective

**Primary bloodstream infection as an indication: Regulatory perspective**

**FDA/IDSA/ISAP Workshop**
**April 15, 2004**
**David Ross, M.D., Ph.D.**

## Outline

**Regulatory history**
**Defining anti-infective (AI) indications**
**Primary bloodstream infection as an AI indication**

## Bloodstream infection (BSI): history

**10 drugs indicated for bacteremia or septicemia**
**All labeled prior to 1992**
**Labeling based on variable or unspecified clinical manifestations in different studies**
**Includes bacteremia associated with focal infection and bacteremia of unknown origin**
**Patients pooled from trials of other indications**

## 9/93 Anti-Infective Drugs AC meeting

**Bacteremia did not affect outcome in a large NDA dataset**
**Bacteremia is due to infection at a primary site**
**Bacteremic SIRS patients form a heterogeneous population**
**Unclear if bacteremic SIRS patients were sicker than nonbacteremic patients**

## 9/93 AC conclusions

**Bacteremia less important than site of infection for classifying infections**
**Study of ‘bacteremic sepsis’ as a separate indication not feasible given heterogeneity of patient population**
**Labeling should include bacteremia in the context of site-specific infections, e.g., “pneumonia with associated bacteremia”**

## Reconsidering BSI as an indication

**Increased incidence of BSI:**
**with resistant pathogens (e.g., VRE, MRSA)**
**without identifiable primary source**
**Issues in measuring drug effect in BSI . . .**
**Patient heterogeneity**
**Differences in natural history for different pathogens**
**Differences in pathogen epidemiology/virulence**
**Need to define an identifiable clinical syndrome**
** ****	****. . . before considering as an indication**

## Does bacteremia equal destiny?

**28 yo female with patchy infiltrate in one lobe.  No comorbidities.**
**HR 80, RR 16.  **
**SCx ****→**** *****S. pneumoniae***** BCx ****→**** *****S. pneumoniae*****.**
**Mortality risk <0.1%**

**52 yo male with multilobar pneumonia. Chronic renal failure, uncontrolled DM **
**HR 130, RR 35. Intubated.**
**SCx ****→**** *****S. pneumoniae  *****BCx ****→**** negative**
**Mortality risk 27%**** **

## Not all bacteremias are the same

**A 76 yo nursing home resident was admitted for altered mental status, hypotension, hypo-thermia, obtundation, and neck stiffness.  A CXR showed bi-lateral infiltrates.  An LP showed 4,218 WBC/****μ****L**** (89% segs) and glucose of less than 20 mg/dL. Blood and CSF Cx grew MRSA. **
**	****	****Despite MICU transfer, therapy with vancomycin and rifampin, and aggressive supportive care, the patient deteriorated and died 11 days after admission.**

**A 67 yo M with chronic renal failure receiving hemodialysis via an arteriovenous graft was admit-ted for fever to 38.0°C; the patient was otherwise well.  No murmur was found and the graft was non-tender. The fever resolved and vancomycin was started.  BCx grew MRSA.**
**There was no further fever or other sx.  A repeat BCx was positive. A transesophageal echocardio-gram was negative, as was a Doppler ultrasound of the graft.**
**The patient received 4 weeks of IV vancomycin and did well. Repeat BCx were negative.**

## Site-based anti-infective (AI) indication

**Site-based anti-infective (AI) indication**

**“****Infection at a specified body site due to a specified, susceptible microorganism”. (Points to Consider, 1992)**
**Accounts for differences in drug efficacy for infections at different sites**
**Allows demonstration of efficacy from adequate and well-controlled studies**
**Allows description of drug effect in labeling**

## Essentials of an AI indication

**Essentials of an AI indication**

**Must be a recognized disease or condition, or an important manifestation of a disease**
**Definable syndrome with specific clinical manifestations, diagnostic criteria, and therapeutic requirements**
**Drug treatment effect demonstrable via adequate and well-controlled trials using clinically relevant endpoints**
**Describable in labeling**

## AI indications vs. non-indications

**AI indications vs. non-indications**

_**AI indications**_
**Urinary tract infection**
**Osteomyelitis**
**Bacterial meningitis**
**Streptococcal pharyngitis**
**Community-acquired pneumonia**
**Prophylaxis against post-operative infection**

_**Non-indications**_
**Dysuria**
**Elevated ESR**
**Coma**
****** ****throat culture for GAS**
**Pleuritic chest pain**
**Decrease in skin colonization**

## Slide 12

## BSI vs. bacteremia

**Candidal BSI (candidemia) **
**Accepted AI indication**
**Frequently primary BSI (no identifed underlying infection)**
**Definable clinical syndrome**
***Escherichia coli***** bacteremia**
**Not accepted AI indication**
**Virtually never primary BSI **
**Variety of potential underlying infections (e.g., GI, GU)**
**Variety of clinical manifestations**

## BSI vs. (pseudo)bacteremia

|  | Peripheral BCx (n = 1408) | Catheter BCx         (n = 1408) | p value |
| --- | --- | --- | --- |
| True BSI | 13.7% | 14.4% | 0.59 |
| Contamination | 1.8% | 3.8% | 0.001 |
| Indeterminate | 0.9% | 1.6% | 0.09 |
| Negative | 83.6% | 80.1% | 0.02 |

**Everts RJ *****et al*****. J Clin Microbiol. 2001; 39:3393-3394**

## Bacteremia as a surrogate endpoint

**Chaisson R *****et al*****. Ann. Intern. Med. 1994; 121:905-11**

|  | Clarithromycin dose |  |  |
| --- | --- | --- | --- |
|  | 500 mg bid | 1000 mg bid | 2000 mg bid |
| Bacterial load at 2 weeks (cfu/mL) | 145 | 34 | 25 |
| Mortality at 12 weeks | 5.7% | 25.5% | 28.0% |

## Questions

**Questions**

**Is there a distinct patient population with primary bacterial BSI that can be identified at the time of randomization into a clinical trial?**
**If yes, how should patients with bacterial BSI who demonstrate evidence of metastatic infection post-randomization be classified with regard to a) whether the BSI was primary or secondary at the time of randomization; b) outcome?  **
**What combination of clinical manifestations, diagnostic criteria (including those excluding other primary infections), therapeutic requirements, and clinically relevant endpoints would define primary BSI due to a specified bacterial pathogen as a unique indication in labeling?**