This study examined the relationship between the susceptibility for cefotaxime and penicillin to predict oral beta-lactams susceptibility. Given the importance of appropriate and timely transition from intravenous to oral therapy, determining the utility of cefotaxime MIC as a reliable marker for oral agents is paramount. However, in this study, the ability of cefotaxime MIC to predict categorical susceptibility of oral cephalosporins was only 77%. Variability in correlating MICs was most notable in the higher range of cefotaxime susceptible MICs (0.25–2 μg/ml). Interestingly, using the CLSI meningitis breakpoint for cefotaxime does have overall good predictability of categorical oral cephalosporins. The use of meningitis breakpoints could be considered as a future marker for oral cephalosporins, but this might cause confusion with clinicians with terms of “meningitis” and oral therapy, as the two are not associated together.
An example of the clinical implications is the most commonly used third-generation oral cephalosporin in the US, cefdinir . In this study, cefdinir had an unfavorably high MIC profile compared to amoxicillin reducing its predictive performance to the commonly tested penicillin or cefotaxime. In addition, cefdinir has poor pharmacokinetic/pharmacodynamic properties, low bioavailability, and short half-life that is unlikely to overcome the higher MIC distribution that was seen in the study [13,14,15]. Furthermore, there have been limited efficacy and PK studies of cefdinir in the treatment of pneumonia or IPD . These limitations may increase the risk for treatment failure especially in the cefotaxime higher MIC isolates. Similar limitations may apply for the lesser-used cefpodoxime and cefuroxime [17,18,19,20].
Using surrogates to infer or predict susceptibility is common in clinical practice with not only Streptococcus pneumoniae but essentially any bacterial pathogen that is susceptible to β-lactams [21,22,23,24]. It has previously been questioned with other pathogens, notably the Enterobacterales family to cephalosporins. First-generation cephalosporins are similarly used to predict oral cephalosporins against Enterobacterales and has had conflicting results depending on the specific oral cephalosporin tested [22, 23]. With a more recent study proposing routine use of oral cephalosporin, cefpodoxime, susceptibility testing to Enterobacterales as an optimal way to represent susceptibility to other oral cephalosporins (cefdinir, cefixime) . Our data further adds the collection of studies that caution the use of surrogates to represent susceptibility of oral cephalosporins and the first specifically for Streptococcus pneumoniae.
CLSI currently only provides interpretation of oral beta-lactam susceptibility when penicillin MIC ≤0.06 μg/ml. What is not offered is when there is mild beta-lactam resistance with a penicillin MIC > 0.06 μg/ml. With antimicrobial resistance rates ever-rising  and 37% of our current isolates exhibiting penicillin MIC > 0.06 μg/ml, it is imperative to provide guidance on an efficient way to predict oral beta-lactam susceptibility. Amoxicillin did correlate well with penicillin MIC and would be reasonable to use as a marker for susceptibility. However, in this study, neither penicillin nor cefotaxime was a good predictor for oral cephalosporin susceptibility. If no prediction method can be developed, then routine cefdinir susceptibility may need to be considered as part of standard of care.
There are a few limitations to our study. This was a single center pediatric study which may limit the generalizability to other centers including adult patients that may have different resistant patterns. Additionally, of the sample size studied, most were very penicillin and cefotaxime susceptible limiting the correlation and predictive value of the agents which may wane with higher MIC but susceptible isolates.