Table 2 Results of causality assessment on ciprofloxacin and hypoglycemia in patients without diabetes using Hill’s criteria

1.

Strength of association

IC value was negative (no statistical signal).

2.

Consistency of the cases

Cases of hypoglycemia associated with ciprofloxacin in patients without diabetes have been reported to the WHO global database from different geographical areas. Moreover, there is a similar published case report of hypoglycemia in an elderly patient without diabetes following intake of ciprofloxacin. In many of the cases, hypoglycemia manifested shortly (within 4 days) following used of ciprofloxacin and recovered on de-challenge in a substantial number of cases.

3.

Specificity of the association

In 48.5% of the cases, patients took ciprofloxacin and shortly encountered hypoglycemic episodes without other coreported reactions.

4.

Temporal relationship

The time to reaction onset of hypoglycemia in a majority of the cases was within 4 days following intake of ciprofloxacin and when patients had no history of such events before. This shows that the association had a plausible temporal relationship.

5.

Dose-response relationship

No evidence of dose-response relationship was found on this association.

6.

Biological mechanism or plausibility

The possible mechanism that explains the causal association of ciprofloxacin and hypoglycemia could be increased insulin release via blockade of ATP-sensitive potassium channels in the beta-cells of the pancreas [21, 22].

7.

Experimental evidence

Two experimental studies in rat islet cells exposed to quinolones showed increase in insulin secretion via blockade of ATP-dependent potassium channels [21, 22]. Besides, the facts that hypoglycemia abated in ten cases following withdrawal of ciprofloxacin and that there was recurrence of the same event in one case after subsequent exposure to ciprofloxacin support the association.

8.

Analogy

Hypoglycemia is a well-known adverse effect of fluoroquinolones that have structural analogues with ciprofloxacin.

9.

Coherence

Taking into consideration the effect of fluoroquinolones in causing hyperinsulinemia in rat islet cells and the aforementioned preexisting knowledge, the association is coherent with today’s knowledge.