In recent years, AAD has become a global concern due to the emergence of highly virulent strains and the widespread use of antibiotics such as clindamycin and cephalosporins [26]. Studies have shown that the incidence rate of AAD is increasing every year in China and other countries. Research on AAD and CDI has gained attention recently, with findings supporting the strong relationship between AAD and CD [27]. Clostridium difficile is a major cause of infectious diarrhea during antibiotic administration. Given the constant development and widespread use of novel antibiotics, understanding the connection between antibiotics and AAD is crucial.
However, the previous real-world study conducted from 2015 to 2017 only included a small number of antibiotics [17]. As a result, the data needs to be updated. Our study screened more reports of AAD following the use of antibiotics from 2004 to September 2022, including novel antibiotics in recent years. Above all, the onset times and outcomes of AAD induced by various antibiotics have not been previously reported.
Our study represents the largest data collection of real-world research to date, using data collected in the FAERS database to examine differences in AAD produced by various antibiotics in terms of correlation, onset time, prognosis, and more. Our findings showed that patients aged 65 years or older had a higher ROR value, indicating that their probability of developing AAD was higher. We hypothesized that the reason why elderly individuals are more susceptible to AAD may be due to a weakened immune response, resulting in a poorer ability to produce a serum IgG antitoxin A antibody response to C [28]. Additionally, females accounted for a larger proportion than males in all reports (51.49% vs. 36.85%). This result suggests that females may be more susceptible to AAD than males, potentially due to differences in gut flora between genders [29]. These findings are consistent with recent research in the relevant literature [17].
The study found that nearly all antibiotics were strongly associated with AAD events, consistent with a clinical retrospective study [30]. When the ROR value was calculated for each antibiotic, cefditoren (ROR = 58.59; 95%CI: 45.68–75.15), cephradine (ROR = 42.06; 95%CI: 12.90–137.14), and lincomycin (ROR = 41.65; 95%CI: 21.05–82.39) had the highest ROR values. When the ROR value was calculated by antibiotic class, lincomycins (ROR = 29.19; 95%CI: 27.06–31.50) had the highest value, with most β-lactam antibiotics having higher ROR values, as described in previous studies [17]. Notably, the study revealed that the rank correlation between the different classes of antibiotics and AAD was as follows: lincomycins > third-generation cephalosporins > first/second-generation cephalosporins > β-lactamase inhibitors > carbapenems > fourth-generation cephalosporins > penicillins > fluoroquinolones > novel cephalosporins > erythromycins > tetracyclines > aminoglycosides. In a meta-analysis, the ranking was as follows: third-generation cephalosporins > clindamycin > second-generation cephalosporins > fourth-generation cephalosporins > carbapenems > trimethoprim-sulfonamides > fluoroquinolones > penicillin combinations [31]. Third-generation cephalosporins had the highest ROR value compared to β-lactam antibiotics, while new cephalosporins had the lowest. The results were consistent with previous research indicating that broad-spectrum antibiotics such as lincomycin, cephalosporin, and penicillin were more likely to result in AAD [32,33,34]. This may be due to C. difficile isolates being completely resistant to clindamycin, most cephalosporins, and penicillin. There is no comparison with cephalosporins, although previously published studies suggested that fluoroquinolones were similarly significant risk factors for causing AAD [26, 35, 36]. The probable explanation for this finding is that nearly all fluoroquinolones exhibit a high minimum inhibitory concentration (MIC) against C. difficile, thereby leading to a high resistance rate. In our study, ROR for AAD with fluoroquinolones was 6.42, implying that the signal of AAD induced by fluoroquinolones was significantly lower than that of β-lactam antibiotics, which has not been previously reported. We hypothesize that the reason for this may be that fluoroquinolones are not as widely utilized as beta-lactam antibiotics due to their restricted usage to avoid adverse effects.
The ROR value for AAD caused by the same class of antibiotics also varied greatly, with the ROR values for first/second-generation cephalosporins ranging from 11.47 to 42.06, those for third-generation cephalosporins ranging from 9.97 to 58.59, and those for penicillins ranging from 6.50 to 34.92. Therefore, the degree of AAD induced by the same class of antibiotics can differ. These findings provide a strong foundation for choosing antibiotics.
A recent study found that patients treated with enzyme inhibitor antibiotics had a significantly higher incidence of AAD (35.36% vs. 21.43%) than those treated with non-enzyme inhibitor antibiotics (P = 0.013) [34, 37]. This could be attributed to the frequent use of enzyme inhibitor antibiotics in the treatment of multidrug-resistant bacteria among critically ill patients who require extended treatment periods. Studies have shown a correlation between the duration of enzyme inhibitor antibiotic therapy and the occurrence of AAD in critically ill patients. Additionally, prolonged use of enzyme inhibitor antibiotics may lead to alterations in the intestinal microbiota, thereby increasing the likelihood of AAD. [34]. Our findings similarly revealed differences in ROR values between β-lactamase inhibitors and their corresponding β-lactamase drugs. For example, amoxicillin-clavulanate (ROR = 13.31; 95%CI: 12.09–14.65) and amoxicillin (ROR = 6.50; 95%CI: 5.69–7.44), ampicillin-sulbactam (ROR = 20.32; 95%CI: 14.97–27.59) and ampicillin (ROR = 8.60; 95%CI: 5.32–13.90), ceftazidime-avibactam (ROR = 3.32; 95%CI: 1.24–8.87) and ceftazidime (ROR = 15.29; 95%CI: 10.63–22.00).
The abuse of antibiotics, particularly broad-spectrum antibiotics, is commonly believed to be the main cause of AAD. It is noteworthy that antifungal drugs are also included in broad-spectrum antibiotics. A recent retrospective study has revealed a higher incidence of antifungal-associated diarrhea (AAD) in patients within the intensive care unit who were treated with antifungals. This outcome is likely attributed to the fact that antifungals are commonly administered alongside other antibiotics, increasing the likelihood of inducing AAD [37, 38]. In our study, amphotericin b and fluconazole were the existing antifungals in the antibiotics that met the inclusion criteria. Their ROR values and 95% Cl were (ROR = 1.70, 95%CI: 0.97–3.00) and (ROR = 3.07, 95%CI: 2.36–4.00), respectively, suggesting that these two antifungal drugs were associated with AAD.
The period between drug intake and symptom onset varies but is typically short [39]. A previous study published in 2012 showed that the most contagious times for potential donors to support the transmission of C. difficile were ≤ 1 week (65%), ≤ 4 weeks (82%), and > 8 weeks (only 10%) [40]. Our study found that the onset times of AAD associated with all involved antibiotics were ≤ 1 week (52.47%), ≤ 4 weeks (91.35%), and > 8 weeks (3.49%), which was consistent with previous study results. Notably, we also examined the separate onset times of each antibiotic, and the result was that the onset times of AAD caused by the same class of drugs also varied. The onset times of AAD induced by cephalosporins ranged from 3 days (cefazolin) to 8.5 days (ceftazidime). This may be due to the varying abilities of different antibiotics to disrupt the intestinal flora or inhibit the activity of C. difficile, resulting in differing periods of AAD onset. We should therefore analyze the onset times of AAD caused by antibiotics separately for each drug.
Most cases of antibiotic-associated diarrhea (AAD) are mild and self-limiting, typically resolving within 5 to 10 days after discontinuing antibiotics therapy. However, one type of AAD called Clostridioides difficile infection (CDI) can result in severe gastrointestinal disease, ranging from diarrhea and fever to colitis, toxic megacolon, multi-organ failure, or death [11]. Hence, it is essential to monitor the prognosis of AAD caused by antibiotics. This study utilized the FAERS database to determine the real-world prognosis of AAD for the first time. The findings indicated that mild and moderate AAD cases constituted the majority of cases, consistent with previous reports [11]. Yet, death due to AAD still occurs, with a high mortality rate associated with C. difficile antibiotic diarrhea (CDAD), particularly in patients over 65 years with underlying or severe diseases [41]. The study discovered that 12.3% of AAD cases were classified as “Death” cases (grade 5). In the United States, CDI has an approximate incidence rate of 453,000 cases and 29,000 deaths in 2011 [9], calculating a mortality rate of 6.4%. The population included in our study came from a variety of countries, some of which had lax antibiotics regulation, which could account for the mortality rate of our research findings. Another finding is that lincomycins had the lowest mortality rate (6.4%) while new cephalosporins had the highest mortality rate (37.5%). This result may be related to the patient’s own disease and the management of antibiotics. Novel antibiotics are frequently subject to strict regulations and limited to patients experiencing severe infections. This patient population typically presents with multiple comorbidities, complex diseases, and a high mortality rate.
Limitations
Although the study had advantages in data mining utilizing the FAERS database, it had inherent limitations, such asthe inability to establish whether the drug caused the event [42]. Additionally, some antibiotics could be combined with other drugs, increasing the probability of AAD. Despite these limitations, this study suggests that FAERS serves as a pharmacovigilance tool for alerting individuals to the varying degrees of AAD resulting from different antibiotics.
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