The last three decades of the sixteenth century, including the final years of Cirillo's tenure as commendatore, encompassed a period of considerable change for Rome, and specifically for the Hospital of Santo Spirito. Between Cirillo's death in 1575, and 1600, the leadership of the Hospital passed to six new commendatori in relatively quick succession. The buildings bear witness to the fact that several of them were keen to make their mark physically. Further, the consolidation of the ideals of the Council of Trent was starting to take effect.

Much important information about this period in the history of Santo Spirito is found in the retrospective report written by Virgilio Spada in 1660 entitled Stato della Casa dell’Archiospedale di Santo Spirito di Roma. Spada's tenure as commendatore of the Hospital in 1660–1662 was brief, but provides a neat bookend to that of Cirillo a century earlier. Thanks to his character and education, his observations are of considerable value. Like Cirillo's Relatione della fabrica e casa di S. Spirito di Roma written nearly a century earlier, and the more generic report on all the institutions of Rome written in 1624 for Urban VIII, Spada's Stato della Casa was probably required by the papal authorities as a report in response to an Apostolic Visitation to present a justification of expenditure. This four-inch-thick manuscript book held in the Archivio di Stato in Rome considers the ways in which all aspects of the institution were run, including their costs. The account on the one hand looks backward, giving an overview of the institution's history, and on the other, describes how the institution was operating at the time at which it was written. It thus offers scope for comparison with earlier periods; a point of reference for activities in the decades that followed it; and an overview of the running of both the church and the hospital in the mid-seventeenth century. Though neither Spada nor Stefano Vai, the other commendatore of major importance in the mid-seventeenth century, mention the Tridentine reforms specifically, it is evident from what they do say that it was a fundamental consideration in their respective periods of governorship.