In their study, Bernal et al1 conclude that CYP2C19 genotypes influence the metabolism of proton pump inhibitors (PPIs), thereby affecting the future infection rates. Although CYP2C19 is the predominant enzyme, CYP3A4 is also important in the metabolism of PPI although to a lesser extent. Thus, variations in genotypes of both CYP2C19 and CYP3A4 may affect PPI metabolism. Whereas normal metabolizers (NMs) experienced more total infection events as compared to rapid or ultrarapid metabolizers (RM/UMs) in the study by Bernal et al,1 the rate of respiratory tract infections and gastrointestinal tract infections was similar in both groups. Additionally, the infection rates were similar between poor or intermediate metabolizers (PM/IMs) and NMs. It is possible that variation in CYP3A4 genotypes may explain this lack of difference in the rates of gastrointestinal tract infections and respiratory tract infections despite differences in metabolizer phenotypes among the study subjects.
CYP2C19 activity undergoes developmental maturity. The activity of CYP2C19 is reduced between birth to 6 months of age, and adultlike enzyme activity is seen by early infancy.2 This initial lack of CYP2C19 activity may result in reduced metabolism of PPI and hence increased risk of future infection events in these young infants. Stratifying the study population by age may have provided more information regarding the effect of the developmental immaturity of CYP2C19 enzyme activity on PPI metabolism and the risk of future infection events across various age groups.
The data regarding the type of PPI agent used in the study subjects were not presented in this article. There is wide variation in the contribution of CYP2C19 enzyme to the metabolism of PPI agents. In some studies, both esomeprazole and rabeprazole were less affected by genotypic variations of CYP2C19 than other PPI agents.3,4 This may again affect the exposure of study subjects to PPI agents, thereby influencing the risk of future infection events.
Although the annual weighted average of PPI use was calculated in the study, the duration of acid suppression in each PPI course might have also been important to evaluate. Infants with the same annual weighted average dosing of PPI may differ with respect to the length of time PPI was used during each treatment cycle. Logically, an infant with continuous acid suppression over an extended period may have a higher risk of future infection events as compared with an infant who receives frequent but intermittent short bursts of acid suppression. The time in between the PPI courses in the latter scenario may allow for partial correction of dysbiosis and possibly reduce the risk of future infection events.
Finally, it would also be interesting to know if the authors have collected data on other adverse effects associated with PPI use including but not limited to bone mineralization, electrolyte imbalance, and kidney function.
CONFLICT OF INTEREST: The author has indicated he has no potential conflicts of interest to disclose.