# Presentation: 229268

## Acute Sinusitis

**Eric A. Mann, M.D., Ph.D.**
**Division of Anti-Infective Drug Products**
**July 30, 1998**

## Acute vs. Chronic Sinusitis

**Clinical Presentation**
**Microbiology**
**Role of Antibiotic Therapy**

- July 1998

## Revisions to the February 1997 Draft Guidance Document for Acute Sinusitis

## Inclusion Criteria

**Addition of fever to diagnostic signs/symptoms of acute sinusitis**

**•   ****12-63% incidence previously reported**
**•   ****specificity= 83%, sensitivity =16%**
-       ( *Ann Intern Med *1992;117:705-710.)

- July 1998

## Inclusion Criteria (cont’d)

**Allergic rhinitis patients**
**may have different clinical response rates**
**may be difficult to distinguish allergic vs. infectious symptoms**
**should document baseline allergy-related symptomology during the two week period prior to onset of sinusitis**

- July 1998

## Inclusion Criteria (cont’d)

**Industry Comment:****	**
**“****It is not clear why the Division recommends that patients with acute sinusitis have a history of signs and symptoms for ‘longer than 7 days.’”**

- July 1998

## Inclusion Criteria (cont’d)

**Kaliner et al. (1997)**
**0.5% to 2.5% of adult patients with viral URIs will develop acute bacterial sinusitis.**
**“****...persistence of the URI for more than 7 to 10 days usually indicates the development of sinusitis.”**

- July 1998

## Inclusion Criteria (cont’d)

**Radiologic Documentation**
- “Radiographic documentation should include either roentgenography...and/or CT or ultrasound examination of the affected sinuses and should comment about the sinus abnormalities such as mucosal thickening, air-fluid levels...”

- July 1998

## Plain Films vs. CT Scan  in Sinusitis

- Davidson et al. *Head Neck *1989; 11:405-9.
- McAlister et al. *Am J Roentgenol *1989;153:1259-1264.
- Burke et al. *Acad Emerg Med* 1994;1:235-9.
- Iinuma et al. *Rhinology* 1994; 32:134-6.
- Kaliner et al. *Otolaryngol Head Neck Surg *1997; 116: S13.

- July 1998

## Inclusion Criteria (cont’d)

- International Rhinosinusitis Advisory Board (1997)
-           “Discordance between plain x-rays and computed tomography scans in detecting sinus abnormality has ranged from 13%...to 75% with conventional x-rays underestimating the presence and extent of the sinus abnormality. CT results are currently regarded as the ‘gold standard’ for diagnosing sinus abnormality for most infectious processes.”

- July 1998

## Revised Guidance Document

**“****CT scan is the preferred imaging technique when available”**
**Pre- and post-treatment imaging modalities should be the same**

- July 1998

## Microbiological Diagnosis

**“ ****The microbiological diagnosis of acute sinusitis is based on isolating a bacterial pathogen from a specimen obtained by direct sinus aspiration at baseline.”**

- July 1998

## Industry Comments: Antral Puncture

**Possible selection bias by the investigators favoring more severe infections**

- July 1998

## Industry Comments Regarding Antral Puncture (cont’d)

**Possible therapeutic effect of antral aspiration / lavage**

- July 1998

## Industry Comments Regarding Antral Puncture (cont’d)

**Problems with antral puncture (cont’d)**
**Difficulty recruiting patients to undergo the procedure**

- July 1998

**Are endoscopically-directed cultures of the middle meatus an acceptable means of documenting microbiological diagnosis of acute sinusitis?**

- July 1998

## Endoscopic Cultures

**Talbot et al.  (1995)**
**47 evaluable patients with acute maxillary sinusitis**
**overall sensitivity = 65%, specificity =40%**
**better performance with *****Streptococcus pneumoniae,***** *****Haemophilus influenzae, Moraxella catarrhalis***
**increased isolation of staphylococcal species with endoscopic cultures***** ***

- July 1998

## Endoscopic Cultures (cont’d)

**Klossek et al. (1996)**
**Endoscopic cultures from middle meatus of 139 normal, healthy subjects**
**81.3% cultured positively (189 total isolates):**
**74  Coagulase negative staphylococci**
**34  Corynebacteria**
**19  *****Staphylococcus aureus***
**18  *****Propionibacterium acnes***
**  ****2  *****Haemophilus influenzae***
**  ****2  *****Streptococcus pneumoniae***

- July 1998

## Revised Guidance Document

- “... **endoscopically guided cultures are not a currently acceptable means of establishing microbiological diagnosis because they may be contaminated by nasal cavity flora (particularly staphylococcal species). Further studies are required to define the role of this procedure in clinical trials.”**

- July 1998

## Microbiological Diagnosis

**“****Documentation should include gram stain examination with WBC and bacterial morphotype semiquantitation, quantitative bacterial cultures, and antimicrobial susceptibility testing.”**

- July 1998

## Industry Comments Regarding Quantitative Bacterial Cultures (cont’d)

**No standard methodology for measurement of bacterial density in sinus aspirate fluid**
**Lack of adequate breakpoints for CFU/ml**
**Difficulty diluting viscous secretions**

- July 1998

## Industry Comments Regarding Quantitative Bacterial Cultures

**Sinuses are normally sterile; recovery of relevant pathogens should be considered significant regardless of bacterial counts**

- July 1998

## Revised Guidance Document

**“****Isolation of the common pathogens, *****Streptococcus pneumoniae, Haemophilus influenzae, *****and***** Moraxella catarrhalis***** from a maxillary sinus aspirate is considered significant independent of colony count data. *****Staphylococcus aureus***** is considered an etiologic agent when isolated in pure culture with bacterial counts**_**>**_**10****4 ****CFU/mL.”**

- July 1998

## Inclusion Criteria (cont’d)

**“****The pathogens should be susceptible to the study and control drugs.”**
** ****Industry Comments:**
**“****runs counter to trials designed to assess empirical (real world) therapy”**
**would interfere with assessment of outcome in patients with resistant strains****	**

- July 1998

## Revised Guidance Document

**“****The pathogens should be susceptible to study and control drugs. However, should the patient show clinical improvement, despite isolation of a non-susceptible organism by *****in vitro***** testing, the investigator may elect to continue treatment with the study drug and to collect all protocol-specified data.”**

- July 1998

## Clinical Outcomes

**Clinical Cure:**
** “...****at least improvement in the radiographic appearance of the sinuses” changed to “...at least no worsening in the radiographic appearance of the sinuses.” **

- July 1998

## Summary:

**Fever added to list of diagnostic signs/symptoms consistent with acute sinusitis**
**CRF should document baseline allergy-related symptoms for the two weeks preceding acute sinusitis**
**CT scan is the preferred imaging modality to support the diagnosis of acute sinusitis**

- July 1998

## Summary (cont’d):

**Pre- and post-treatment imaging modalities should be the same**
**Endoscopically guided cultures are currently not an acceptable means of establishing microbiological diagnosis**
**Isolation of *****Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis *****from sinus puncture will be considered significant independent of colony count data**

- July 1998

## Summary (cont’d):

***Staphylococcus aureus*****  is considered an etiologic agent only when isolated in pure culture with counts **_**>**_** 10****4**** CFU/mL**
**Investigators may continue study drug treatment in patients showing clinical improvement, despite isolation of a resistant organism by *****in vitro***** testing**
**Clinical cure: no worsening in the radiographic appearance of the sinuses**

- July 1998