# Presentation: 917175

## CIPROFLOXACIN FOR PROPHYLAXIS OF CLINICAL DISEASE DUE TO INHALED B. anthracis

**Anti-Infectives Advisory Committee Meeting**
**July 28, 2000**
**Andrea Meyerhoff MD MSc DTMH**
**Division of Special Pathogens, US FDA**

## Overview

- Inhalational anthrax
- Drugs for anthrax
- Microbiology of *Bacillus anthracis*
- Cipro pharmacology-animal and human
- Studies of post exposure prophylaxis

## Inhalational anthrax

- First described British textile mills 19th c
- Woolsorters’ or ragpickers’ disease
- Largely an industrial / occupational infection
- Rare; US ~20 cases since 1900
- Hemorrhagic mediastinitis, with involvement of RES, CNS, and development of sepsis syndrome

## Inhalational anthrax

- Clinical entity resulting from intentional use of aerosolized spores *B. anthracis*
- Mortality 80-100% clinically recognizable disease, even with appropriate therapy
- Penicillins and/or tetracyclines historically drugs of choice
- Reports of engineered *B. anthracis* strains PCN-R, TCN-R

## Drugs for anthrax:regulatory status

- No drug is approved for **prophylaxis** of **inhalational** anthrax
- PCNs, TCNs with indications for **treatment**** **of clinical disease due to *B. anthracis*
- Programs for large scale use in civilian or military personnel, in contrast with practice of medicine, require an approved NDA indication or IND

## Cipro

- First formulation (oral) approved US 1987
- Approved indications (17) include
- lower respiratory tract infections
- complicated intraabdominal infections
- bone and joint infections
- typhoid fever
- Used by >100 million patients in US

**Notes:**
Discussion of use and safety data presented by Bayer

## Cipro oral

- Approved doses 100-750 mg q 12 hour
- Proposed regimen anthrax prophylaxis:
- Adult 500 mg q 12 hour
- Pediatric 10-15 mg/kg q 12 hour
- Duration 60 days

## B. anthracis: Microbiology

- Spore forming
- Germinates into vegetative state under certain environmental conditions
- Vegetative state
- encapsulated, toxin-producing: PA, EF, LF
- generally PCN, TCN susceptible, 3% PCN-R
- bioengineered strains with PCN-R, TCN-R

**Notes:**
Mechanism of R -PCN: B-lactamase production
Mechanism of R-TCN not known?

## B. anthracis: Microbiology

**Notes:**
Clinical and laboratory isolates, geographically diverse- series presented from UK, 33/70 strains were epidemiologically unrelated
submission included a reference that described an additional 22 strains that were clinical isolates from Turkey
over 90 strains total

## Cipro pharmacology: overview

- Peak and trough serum concentrations
- Macaque monkey
- Human
- Comparison macaque and human

## Ciprofloxacin Peak Concentrations - Monkeys(Kelly et al 1992)

**Notes:**
These data come from the 10 animals that were exposed to aerosolized spores and received ciprofloxacin for 30 days

## Ciprofloxacin Trough Concentrations - Monkeys(Kelly et al 1992)

## Ciprofloxacin Oral Steady State Pharmacokinetics

**Notes:**
Combines data from study under review and studies done during the development of ciprofloxacin

## Ciprofloxacin Peak Concentrations - All

## Ciprofloxacin Trough Concentrations - All

## Comparison of drug levels with MIC90 B. anthracis

- Fluoroquinolones: killing is concentration dependent rather than time dependent
- Cmax/MIC _>_ 10 desirable range
- Cipro: *B. anthracis*
- Cipro peak macaque ~33x MIC90
- Cipro peak human ~50x MIC90

## Inhalational anthrax: early theories of pathogenesis

- Theory #1: Persistent spores
- germination pulmonary macrophage (MØ)
- toxin production/ early pathology mediastinal lymph nodes
- Theory #2: Acute bacterial infection
- erosion bronchial mucosa
- rapid germination pulmonary parenchyma
- early pathology pneumonia

## Early studies inhalational anthrax: post-exposure drug administration

- Post exposure PCN (Henderson et al 1956)
- PCN 24 h post exp macaques for 5, 10, 20 days with controls
- survival curves same slope as controls
- only delay death

## Survival curves(Henderson et al 1956)

**Notes:**
Both y axes represent # survivors
group C large # non-anthrax deaths before day 42, on which day all remaining animals in this group were sacrificed to do counts of spores remaining in lungs
as a result, only 2 deaths attributable to anthrax, survival curve extrapolated

## Spore clearance(Henderson et al 1956)

## Early studies inhalational anthrax: spore clearance from lung (Ross 1957)

- Guinea pig: # spores reaching regional LN **<<< **# deposited pulmonary epithelium
- Differential staining: distinction of stages of spore development and vegetative state
- Different modes of spore exit from lung
**transported to regional LN via pulmonary MØ **
**phagocytosed spores passed into bronchioles**
**?spores lysed and destroyed in phagocytic cell**

## Inhalational anthrax: post-exposure drug administration (Friedlander et al 1993) 

- 6 groups/10 animals each
- 30 days antimicrobial: 1) ciprofloxacin, 2) doxycycline, 3) penicillin, 4) doxy + vaccine
- 5) vaccine, 6) control
- Survival following aerosol challenge days 0-120
- Mortality rates
- at 90 days (evaluable population)
- up to 130 days (ITT population)

## Challenge (from Friedlander et al 1993)

- Challenge (from Friedlander et al 1993)

- Survival

**TOC**

**End of treatment**

**Notes:**

3 animals in the cipro cohort died
1 died at d 36 from anthrax
1 died at d 5 following accidental instillation of drug into trachea, micro and path negative for anthrax
1 died at d 103 with urinary tract obstruction- no evidence of anthrax microbiology or histology

Other deaths
PCN 3 anthrax deaths days 9, 12, 20
DCN 1 anthrax death day 58
DCN + VAX 1 death day 36, no anthrax, myocardial degeneration

## Challenge (from Friedlander et al 1993)

- Challenge (from Friedlander et al 1993)

- Survival

**TOC**

**End of treatment**

**Notes:**
Y-axis survival rate, x-axis days post exposure
two vertical lines 1) end of abx administration, 2) test of cure

Deaths clustered at 30-60 days period

Other deaths
PCN 3 anthrax deaths days 9, 12, 20
DCN 1 anthrax death day 58
DCN + VAX 1 death day 36, no anthrax, myocardial degeneration 

## Intent-to-treat Analysis:Including all cause of death up to re-challenge

**Notes:**
Using different statistical analyses, looking at both ITT and evaluable populations, consistent demonstration of efficacy of ciprofloxacin compared with placebo

## Evaluable Population Analysis:Cause of death proven to be due to Anthax (TOC=90)

**Notes:**
*One animal died 5 days after exposure from aspiration pneumonia, had no evidence of anthrax at autopsy, and was excluded from this analysis.  Another animal died 73 days after antibiotic treatment.  This death was not thought to be anthrax related and was not included in this analysis.
One animal died 6 days after discontinuing doxycycline with no evidence of anthrax on autopsy.  Cause of death remains unknown: the animal was excluded from this statistical analysis.

## Prevention of inhalational anthrax: duration of drug administration

- 5, 10, 20  days too short
- 30 days look better
- Of the ciprofloxacin cohort, one anthrax death at 36 days
- Spore load decreases over time
- Is there a minimum?

## Prevention of inhalational anthrax:human epidemiology

- Sverdlovsk 1979 published account: longest incubation fatal case 43 days
- Patient #42
- Industrial exposure
- nonimmunized mill workers inhale 150-700 anthrax-contaminated particles _<_ 5μ/ shift
- clinical disease rare
- likelihood of development of anthrax independent of duration of employment

## Summary: Inhalational anthrax

- Rare, rapidly progressive disease with very high mortality
- Little opportunity to improve outcome with treatment once clinical disease recognized
- Identified as a clinical manifestation of a biological agent of highest potential concern

## Summary: Inhalational anthrax

- Currently no drug approved for prophylaxis
- Cannot be studied in humans
- Non-human primate model demonstrates similar pathology and mortality as humans

## Summary: Ciprofloxacin

- Post-exposure administration in primate model shown to  significantly improve survival compared with placebo
- Comparable blood levels achieved with
- dose used* for successful prophylaxis in primate model of inhalational anthrax
- 500 mg po q 12 hours in adults
- 15 mg/kg po q 12 hours in children
- Blood levels achieved experimental animals and humans ~30-50x MIC90 *B. anthracis*
- *250 mg followed by 125 mg q 12 hr

## Summary: Ciprofloxacin

- Broad array of indications with substantial clinical experience
- Well-characterized safety database

## Summary: Prophylaxis of inhalational anthrax

- Prophylaxis an effort to reduce risk
- Ciprofloxacin survival better than placebo following 30-day regimen
- Epidemiologic data suggest duration of drug administration at least 45 days
- Duration of proposed regimen is 60 days

**Notes:**
Cipro pk similar in monkeys and humans
Monkey model inhalational anthrax closely approximates human disease...

## Question #1 for committee

- Do the data presented support the safety and efficacy of ciprofloxacin for post-exposure prophylaxis of inhalational anthrax?

## Question #2 for committee

- If yes, is 60 days an appropriate duration of ciprofloxacin administration for this indication?

## Acknowledgements

- Peter Dionne, M.S., Microbiology Reviewer
- Shukal Bala, Ph.D., Microbiology Reviewer
- Stephen Hundley, Ph.D., DABT, Pharmacology-Toxicology Reviewer
- Joette Meyer, Pharm.D., Clinical Pharmacology and Biopharmaceutics Reviewer
- Karen Higgins Sc.D., Biometrics Team Leader
- Valerie Jensen R.Ph., Regulatory Project Manager
- Leo Chan R.Ph., Regulatory Project Manager