{"id":3221,"date":"2017-03-14T06:30:36","date_gmt":"2017-03-14T10:30:36","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=3221"},"modified":"2025-09-20T19:11:26","modified_gmt":"2025-09-21T01:11:26","slug":"efficacy-treatment-duration-tipping-point","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2017\/03\/14\/3221\/efficacy-treatment-duration-tipping-point\/","title":{"rendered":"Efficacy and Treatment Duration: Where is the Tipping Point?"},"content":{"rendered":"

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Development pf antibacterials differs in several important ways from drug development in other areas, and the lack of standard dose-finding is just one of them.<\/p>\n

Dose-finding in its most basic form involves ascending amounts of drug for efficacy and safety; for antibiotics, however, an effective dose can be predicted nowadays with sufficient accuracy based on PK\/PD considerations. This then becomes the dose for testing\u00a0in Phase 2.<\/p>\n

Duration of treatment is not part of the test protocol; the antibiotic is usually administered for an arbitrary number of days based on historical standards.<\/p>\n

Occasionally testing a shortened treatment regimen becomes a Phase 4 life cycle management activity. Such was the case with moxifloxacin\u2019s sinusitis program which evaluated shorter treatment courses after the 7-day regimen was approved. These studies can provide valuable information but they rarely go far enough to define the \u201cinflection\u201d or \u201ctipping point\u201d, i.e., the minimal duration of therapy before non-inferiority becomes inferiority.\u00a0 For obvious reasons, few marketing departments are interested in finding out.<\/p>\n

We are talking about antibacterials, not antibiotics in general. For the recent batch of HCV therapeutics 8-wk therapy has been compared with more standard 12-wk regimens<\/span><\/p>\n<\/div>\n

However, others take on what antibiotic companies shy away from: clinician researchers showed for cIAI that a 4-day treatment course is sufficient\u00a0[1]<\/a>, and those with a stake in PCT have studied it as a tool to shorten therapy[2]<\/sup><\/a>. For nosocomial pneumonia and CABP, we now have studies demonstrating that shorter treatment does not negatively affect outcomes. While not everyone subscribes to recommendations to shorten VAP therapy as suggested by Chastre and Hedrick\u00a0[3]<\/a>, the trend to shorter therapy makes sense from the standpoint of antibiotic stewardship and avoidance of unnecessary exposure or costs. But none of these trials were structured to find the \u2018efficacy cliff\u2019, none of them determined – by step-wise shortening of therapy \u2013 where the steep part of the efficacy time curve begins.<\/p>\n

\"\"<\/a>
Catastrophe Plot for the Antibiotic Efficacy Duration relationship. CR \/ BR = Clinical \/ Bacteriological Response<\/figcaption><\/figure>\n

In this context, failed studies become important sources of information as they help us demarcate the lower end of the efficacy spectrum.<\/p>\n

A recent publication comparing different lengths of ceftidoren treatment for uUTI reminded us of this issue, a topic which seems to get little attention\u00a0[4]<\/a>. Below see some examples of drugs and indications for which treatment duration made a difference in outcomes. Please send us more examples, if you are familiar with them; we would appreciate your\u00a0help in creating a more comprehensive list.<\/span><\/p>\n

Penicillin<\/strong> for Tonsillitis \/ Pharyngitis
\n<\/strong>Textbooks recommend a 10-day course of penicillin for streptococcal pharyngitis. Can one get well with shorter treatment? A series of studies by mainly Dutch clinicians showed rather convincingly that a 7-day course is similarly effective, but a 5-day course is not. Note that these studies were not done as parallel direct comparison trials; therefore, the data – while suggestive – still requires confirmation.<\/p>\n

Amoxiclav for Acute Otitis Media
\n<\/strong>A 5-day treatment course was not as efficacious as a 10-day course in toddlers aged 1-23 months in a recently published well-designed prospective trial.[5]<\/sup><\/a>\u00a0 Just about every outcome variable was improved more in the 10-day treatment group than in the\u00a05-day antibiotic treatment course: symptom score, severity of illness, pain, fever, bulging of the TM, and numbers of ears affected by AOM.<\/p>\n

Uncomplicated UTI (uUTI)
\n<\/strong>This is probably the only indication for which we have good study data showing that duration matters both for clinical as well as bacteriologic response. Numerous studies of cephalosporins in uUTI showed that 3-day treatment courses were superior to 1-day or single dose therapy [6]<\/a>. Here a sampling, by no means complete:<\/p>\n