The amendment was added: - To clarify the timing interval between ciprofloxacin and infant formula (2 hours before or after) - To correct discrepancies among the age groups referred to - To delete a reference to a data collection instrument other than a care report form - To provide clarification on performance of required gait/joint examinations and the category of professional (i.e, evaluator) required to perform the exams (physical therapist or rheumatologist) - To specify the type of intervention (i.e., imaging) to evaluate cases presenting with signs and/or symptoms suggestive of arthropathy - To add a cap on enrollment of subjects in the adolescent age group (a single center should not have enrolled more than two subjects aged 12 to 16 years of age) - To clarify the categorization and reporting of adverse events during the long term follow-up

The second amendment provided for the following: - Extended the permissible window for a subject's pre-therapy gait/joint examination from 48 hours prior to initiation of study drug therapy up to 24 hours after receipt of the first dose of study drug. This permitted study enrollment in the overnight hours when children presented through the emergency department and qualified physical therapy personnel might not have been available. - Allowed for enrollment of children reliant on infant formula provided they were treated with IV medication only; - Corrected a typographical error in the dose strength of the 5 percent (%) suspension; - Clarified the exclusion of all children with a diagnosis of cystic fibrosis whether or not this current infection was an exacerbation of the underlying disease; - Clarified that subjects enrolled into the 100169 complicated urinary tract infection study could be enrolled into the observational study provided informed consent was provided to allow for retrospective collection of the initial year’s data.

The purpose of the third amendment was to: - Allow for enrollment of subjects up to 72 hours after initiation of study drug treatment; - Specify provisions for performance of the gait/joint examination when a certified physical therapist was not available; - Clarify the expectation for documentation of the Range of motion examination within the case report form; - Allow for enrollment of children with febrile neutropenia receiving ciprofloxacin prophylaxis pending recovery of white blood cell (WBC) count to greater than or equal to (>=) 500 cells per millimeter^3; - Clarify the exclusion of children with cystic fibrosis from the protocol; - To provide a gait/joint examination flow diagram.

The purpose of the fourth amendment was to incorporate the following changes, as requested by the Food and Drugs Administration (FDA): - Add a non-quinolone arm to the present study. The objective was to obtain information (i.e., assess the “background noise”) on musculoskeletal adverse events that could have occurred in this pediatric population had they received treatment with a non-quinolone antibiotic and to monitor these adverse events for the same duration as the ciprofloxacin-treated subjects. - Shorten the long-term follow-up period from 5 to 10 years to 1 to 5 years. Pre-pubescent and pubescent children were to be followed for 5 years and post-pubescent children were to be followed for 1 year. Subjects who experienced a musculoskeletal adverse event during therapy were to be followed for 5 years regardless of their stage of pubescence. - Revise downward the total number of subjects to be enrolled from 3,000 to approximately 900 subjects. Approximately half (450) of these 900 subjects were to be in the ciprofloxacin arm and approximately half (450) in the non-quinolone antibiotic arm. This sample size would provide 95% probability of seeing at least one event that had the event rate of 1 in 250. This was based on combining these 900 subjects with at least 600 subjects available from another pediatric ciprofloxacin trial. - Demographic and baseline characteristics were to be summarized by treatment group as well as type of ciprofloxacin treatment (IV versus oral), age group (>= 2 months to less than [<] 24 months; 2 years to < 6 years; >= 6 years to < 12 years; >= 12 years to < 17 years). - The decision to treat with ciprofloxacin or a non-quinolone antibiotic was made prior to a subject's enrollment in the study and was based on the particular infection, type of subject, medical history and the clinical evaluation by the prescribing physician.

The purpose of the fifth amendment was to incorporate the following change, as requested by the FDA: Shorten the follow-up period for the non-quinolone arm from five years to up to two years. This change was made because the FDA no longer required a follow-up for musculoskeletal events in pediatric subjects receiving non-quinolone treatment. At the time of this amendment, the study dataset included data collected for subjects up to two years, so this data was analyzed.