# Presentation: 217754

## STREPTOCOCCAL PHARYNGITIS AND TONSILLITIS

- Nasim Moledina, M.D.
- Mamodikoe Makhene, M.D., M.P.H.
- Medical Officers
- Division of Anti-Infective Drug Products

- July 1998

## Regulatory Synonyms

- Upper respiratory tract infection due to* Streptococcus pyogenes.*

- July 1998

**Notes:**
The clinical entity addressed in this guideline is pharyngitis as a result of S. pyogenes,  because it is the most  important of all the pathogens. 

Clearly, there are other bacteria, and specifically other streptococci which cause pharyngitis but because they are rarely associated with sequelae and specifically only AGN, and not ARF, these pathogens are not addressed here. 

In addition, this document does not address pharyngitis secondary to viral infection.

## Study Considerations

- One statistically adequate and well-controlled multicenter trial is suggested
- Adequate microbiologic data and specific human pharmacokinetic/dynamic data supportive of clinical effectiveness should be provided.
- includes tissue distribution studies to demonstrate diffusion into tonsillar tissues

- July 1998

## Study Considerations

-  microbiologic eradication is the primary outcome parameter
- study should establish correlation between clinical cure and bacterial eradication
-  Any product with an absolute eradication rate of <85% should not ordinarily be approved as first-line therapy

- July 1998

**Notes:**
Although  microbiologic eradication is the primary outcome parameter, the study should establish correlation between bacterial eradication and clinical cure; essentially then patients would be microbiologically and clincally evaluable.

## Enrollment

- Male and female patients of any age may be enrolled
-  *clinical* diagnosis of acute streptococcal pharyngitis and/or tonsillitis based on history and physical examination, with attention to the ear, nose and throat
- scarlet fever

- July 1998

**Notes:**

Streptococcal pharyngitis is an infection of school age children between 5-11 years primarily, however, all age groups are susceptible

For inclusion, patients should have a clinical diagnosis......

Other than rash, the epidemiology, clinical presentation, and sequelae of scarlet fever are no different from those of strep pharyngitis 

## Inclusion Criteria  Clinical Features

- abrupt onset of sore throat accompanied by headache, fever
- pain on swallowing
- nausea, vomiting and abdominal pain are common in children
- erythema and thick exudate of pharynx/ tonsils

- July 1998

## Inclusion Criteria  Clinical Features

- Anterior cervical nodes may be enlarged, often tender
- cough, rhinorrhea, hoarseness, conjunctivitis, and diarrhea are more suggestive of viral etiology

- July 1998

**Notes:**
Certain clinical features can help exclude patients with viral pharyngitis at the time of enrollment  

## Inclusion Criteria  Streptococcal fever 

- young child, 1-3 years
- classic presentation uncommon
- seromucoid rhinitis
- moderate fever, anorexia
- more generalized adenopathy
- protracted course more likely

- July 1998

**Notes:**
In addition, when enrolling younger patients,  it  is important to note that younger paitents may not have the classic presentation

## Inclusion Criteria Laboratory Criteria

- specimen for culture obtained from the posterior pharynx and  tonsils
- expect  *Streptococcus pyogenes* at baseline
- organism should be susceptible to the study drug(s)

- July 1998

**Notes:**

despite the characterics which are associated with strep pharyngitis, the clinical presentation may be indistinguishable from that due to other pathogens including viruses

therefore, lab confirmation of a streptococcal infection is should be provided by a throat culture at baseline

## Inclusion Criteria Rapid Antigen tests 

- often used for screening
- not as reliable as culture because of low/variable sensitivity (70-85%)
-  results should be confirmed by culture

- July 1998

**Notes:**
although the specificity-->95%
sensitivity---variable/low--60-85%---associated with frequent false negatives and failures to diagnose a streptococcal pharyngitis

In this infection where concern about sequelae is paramount and knowing that adeuqate treatment of GAS infection virtually eliminates the sequelae, we don’t want to miss any patients with this infection that can be easily treated.  

## Exclusion CriteriaCarriage 

- upper respiratory tract persistently colonized with *Streptococcus pyogenes *
- multiple culture-positive episodes, with mild or atypical symptoms

- July 1998

**Notes:**

it is important to identify and exclude carriers before enrollment to minimize confounding of  the efficacy  results

low risk for spread GAS to contacts
low risk for suppurative and non-suppurative complications

## Study Drugs 

- To be evaluable, the patient should receive within 80-120% of the prescribed dose and/or dosing regimen.
- Control drug---any approved drug and dosing regimen

- July 1998

## Study visits

- Entry
- On therapy visit
- End of therapy visit (not applicable)
- Post-therapy visit-test of cure visit
- Late post-therapy visit

- July 1998

## Entry Visit

- document acute episode of streptococcal pharyngitis (with consistent clinical presentation)
- physical examination with emphasis on ears, nose, throat exam
- throat culture for GAS isolation and susceptibility testing

- July 1998

**Notes:**
pharyngeal or tonsillar culture to document the presennce of GAS

## On-Therapy Visit 

- This visit is strongly recommended for good study conduct.
- to assess early clinical response to therapy
- perform history, physical examination,  throat culture as necessary

- July 1998

**Notes:**
This visit is strongly recommended ..........
because it gives the opportunity to assess ........

## On-Therapy Visit

- document telephone contact (specific questions and responses)
*Note:  IDSA/FDA guidelines recommend a visit or telephone contact 3-5 days after the initiation of therapy *

- July 1998

## Post-therapy (Test-of-Cure) Visit 

- assessment of primary outcome
- ~14-18 days after the start of therapy
- clinical evaluation
- Repeat throat culture and antimicrobial susceptibility testing
*Note:  The IDSA/FDA guidelines recommend a visit 4-7 days post therapy.*

- July 1998

## Late Post-therapy Visit

- ~38 to 45 days after the start of therapy
- assess for relapse, or the presence of non-suppurative sequelae (glomerulonephritis or acute rheumatic fever)
- clinical evaluation

- July 1998

**Notes:**
Of note is that the assessment for sequelae is based on the clinical features at this visit since there is no serologic documentation being done at this visit.

## Late Post-therapy Visit 

- results of throat culture and susceptibility testing
*Note:  IDSA/FDA guidelines recommend a visit 2-4 weeks post therapy to assess for carditis and nephritis*

- July 1998

## Assessment of Outcome

- dependent on the eradication of *S. pyogenes* from the pharynx and the resolution of clinical signs and symptoms

- July 1998

**Notes:**
To make an assessment of outcome it is important to remember that:
making dagnosis with certainty on clinical grounds often not possible, verify or rule out diagnosis with culture 
positive throat culture does not distinguish acute streptococcal infection from carrier with pharyngitis from a other source (eg virus, other, bacteria)
Therefore, the response should be evaluated both clinically and microbiologically--eradication of the organism and resolve clinical signs and symptoms 

## Microbiologic Outcome

- Documented Eradication
- baseline pathogen absent from the test-of-cure culture
- Persistence
- original pathogen present in the test-of-cure culture

- July 1998

## Microbiologic Outcome 

- Recurrence
- culture negative for *S. pyogenes* at the test-of-cure visit,  but positive at the late post-therapy visit
- Continued Eradication
- negative culture for *S. pyogenes* at both the test-of-cure and late post-therapy visits

- July 1998

## Clinical Outcome

- 	Cure
- resolution of signs and symptoms at the test-of-cure visit
- no antimicrobial agents, other as specified in the protocol, are given

- July 1998

## Clinical Outcome

- Failure
- received at least 72 hours of therapy
- persistence of signs or symptoms/ appearance of new signs and symptoms
- additional antimicrobial agents given,  or antimicrobial therapy is changed

- July 1998

## Clinical Outcome  Late post-therapy visit 

- evaluate for post-streptococcal sequelae (ARF and AGN)
- comments about the status of signs and symptoms (e.g., continued cure, recurrence, etc.) of the acute infection may be made

- July 1998

**Notes:**
expect  to see AGN  ~ 10 days after the antecendent GAS infection
expect to see ARF 2-4 weeks after the antecendent GAS infection

## Bacteriologic Outcome

- Pichichero PIDJ 1993  Meta-analysis of 19 studies done between 1970-1990
- bacteriologic failure rates
- penicillin---16%
- cephalosporins---8% (P<0.0001)
- other reports of bacteriologic failure rates as high as 20-30%

- July 1998

## Bacteriologic Outcome 

- Is there a temporal trend in bacteriologic failure rates with oral penicillin?
- Shulman et al, PIDJ 1994  Review of 51 studies between 1953-1979 and 22 studies between 1980-1993
- no significant difference in bacteriologic treatment failure rates (~10% in both eras)

- July 1998

**Notes:**
Even with the recommended 10 days of oral therapy, the failure rates with penicillin may be high
reports of bacteriologic failure rates as high as 20-30%

## Issue for Discussion

- With reports of high failure rates, is penicillin still an adequate comparative agent?

- July 1998

## Bacteriologic FailuresPossible Reasons 

- enrollment of carriers, especially if entry criteria are not strict enough
- non-Group A beta-hemolytic streptococci
- non-compliance, frequent dosing
- reacquisition of GAS from family member or close contact

- July 1998

## Bacteriologic FailuresPossible Explanations

- penicillin tolerance
- inactivation of penicillin by beta-lactamase producing oral flora
- cryptogenic infection within tonsils
- lack of bacterial interference

- July 1998