Cephalosporins belong to β-lactam class of antibiotics and have been developed to the fifth generation at present. Cephalosporins are widely used in the world for their broad antibacterial spectrum, low toxicity, penicillinase resistance and rich varieties. The subsequent adverse drug reactions (ADRs) have also become the focus of public concern. In China, an ADR is defined as the harmful reaction of qualified drugs under normal usage and dosage, which has nothing to do with the purpose of drug use (2011). The annual reports of national ADR monitoring in China from 2017 to 2019 all showed that ADR reports of cephalosporins were the most in the reports of anti-infective drugs, which also had the most reports of serious ADRs (Administration, N.M.P, 2018; Administration, N.M.P, 2019; Administration, N.M.P, 2020).

With the implementation of the two-child policy in 2015 and the three-child policy in 2021, the number of children (0–14) in China has increased rapidly, and the safety of children’s medication has become a key point to improve the health of children. G. M. Park found that antibiotics were the most common ADR causing drugs in children, among which the third cephalosporin was the most common (Park et al., 2012). Jung also believed that antibiotics were the most common drugs that might cause ADRs in children (n = 5,159), among which cephalosporins were the most common drugs (n = 5,101). Gastrointestinal tract and skin clinical features were the most frequently reported ADR (Jung et al., 2017). In 2015, the National Medical Products Administration warned that cefathiamidine could cause severe ADRs like anaphylactic shock, and a high proportion of ADRs of cefathiamidine have been reported in the ADR reports of children (Administration, S.F.a.D, 2015). Children, as a special medication population, are prone to ADR due to their underdevelopment of liver, kidney and central nervous system and poor ability of metabolism, excretion and tolerance of drugs.

Cephalosporin ADRs in children is a public health problem that deserves attention. It is difficult to carry out clinical trials in children, and there is no strong evidence of safety. And the use of cephalosporins is mostly based on long-term clinical practice. Therefore, it is necessary to re-evaluate the safety of cephalosporins in children after marketing. The purpose of this study was to analyze the provincial spontaneous reporting system (SRS) database to investigate the safety of cephalosporins in children from all aspects of ADRs.

According to statistics, in recent 6 years, the ADR reports of cephalosporins in children aged 0–14 reported by SRS were mainly concentrated in children aged 0–3. Jiang found that among the people who had ADRs after taking cephalosporins, young children were the most prominent (Jiang et al., 2021). Zheng’s investigation on a hospital found that the number of children with ADRs to cephalosporins was mainly 0–3 years old (Zheng et al., 2018). The above results were consistent with the results of this study, which suggested that the physiological function of children, especially newborns and infants, was not fully mature; drug metabolism was slow; and drug accumulation was easy to occur, resulting in a high incidence of ADR. Due to the limitations of data collection, it was not possible to know the frequency of cephalosporin use by age group.

The patient’s allergy history may be incomplete, making it difficult to make a meaningful analysis. However, a study involving 13,153 cases of cefazolin skin testing in South Korea found that 15% of patients with a history of β-lactam allergy were positive for the skin test; 1.35% of the patients without a history of β-lactam antibiotic allergy were positive, indicating that the history of β-lactam allergy may be associated with the occurrence of cephalosporin allergic reactions (Kwon et al., 2019). In addition, there may also be cross-reactivity in cephalosporin allergy (Li et al., 2019). Perfecting the records of allergic history will be helpful to the prediction of allergic reactions.

Combined with the severity of ADRs, the results showed that there was no significant difference in the distribution of the severity of ADRs between different sexes. Notably, although there were many ADR reports in children aged 0–4 years, the proportion of severe ADRs is the lowest. The likely reason was that doctors were more cautious in using cephalosporins when treating newborns and infants, prioritizing safety over efficacy (Lu et al., 2018). The reported rate of severe ADRs generally increased with age. Children at this age were in a period of rapid growth and development, and their physical conditions fluctuated greatly, so it was difficult to determine the appropriate dose. This may have something to do with the difficulty in accurately estimating the appropriate dose from experience and the increasing confidence of doctors in medication as children age. It was suggested that doctors strictly followed the drug instructions and antibiotic medication guidelines, comprehensively analyzed the state of the children, strictly controlled the dosage and prevented the inducing of drug resistance.

This study found that the use of cephalosporin compound preparations in children was more prominent in severe ADRs, and the proportion of severe ADRs in most cephalosporin compound preparations was higher than the average. At present, there were few studies on ADRs of cephalosporin compound preparations, among which the research of cefoperazone/sulbactam was the most abundant. In China, a number of retrospective studies on efficacy and ADRs reported that the efficacy of cefoperazone/sulbactam was significantly higher than that of ceftazidime in the control group, and the incidence of ADRs was considered lower than that of the control group (Zhu, 2019; Wang et al., 2020). The subjects in these studies were all older than 20 years. The noninferiority trial conducted by Liu on pneumonia patients over 18 years old showed no significant difference in the mortality rate and proportion of severe ADRs in the cefoperazone/sulbactam group compared with the cefepime group, suggesting that the two groups had the same efficacy and safety (Liu et al., 2019). In adults, ADRs and severe ADRs caused by cephalosporin compound preparations appeared to be no different or better than those caused by other conventional cephalosporins. Few studies have been conducted on ADRs of cephalosporin compound preparations in children. But the only studies that have been done on children seem to come to a different conclusion than adults, Pareek et al. compared the efficacy and safety of cefotaxime/sulbactam with amoxicillin clavulanate (conventional treatment) and found that one patient in the cefotaxime/sulbactam group reported a severe ADR to convulsion, except that both drugs were safe and well tolerated in the study population (Pareek et al., 2008). A clinical study involving 986 patients treated with cefotaxime/sulbactam found a higher incidence of ADRs in children than adults (12.73 vs. 6.46%, p < 0.05) (Chen et al., 2017). The ADRs of cephalosporin compound preparations in children may have different characteristics from that of adults. In addition, the pharmacokinetic trials of cephalosporin compound preparations in human volunteers were conducted in healthy adults, and the results showed no pharmacokinetic interaction between the two components, but it was not clear whether the it was consistent in children (Ma et al., 2003; Mingjie et al., 2008; Yang et al., 2011). ADRs, severe ADRs, factors and other aspects related to the safety of cephalosporin compound preparations in children may need more and in-depth studies.

In this study, it was found that the proportion of severe ADRs of most cephalosporin compound preparations was higher than that of the corresponding single formulations. Cephalosporins in compound preparation can effectively prevent bacteria from synthesizing cell wall and inhibit bacterial division, but is easily hydrolyzed by β-lactamase. Sulbactam and tazobactam are β-lactamase inhibitors, which can inhibit the activity of hydrolase but have weak antibacterial effect. Combined use of the two can increase the stability of cephalosporins and enhance the antibacterial effect. Many in vitro and in vivo experiments at earlier times have confirmed that cephalosporin compound preparations have better antibacterial effect than the corresponding single preparations (Crosby and Gump, 1982; Knapp et al., 1990; Fu et al., 2002; You et al., 2003; Prakash et al., 2005; Yong et al., 2006; Li et al., 2010). However, no comparative studies on safety between compound preparations and single preparations have been found, and only comparative studies on toxicity reactions were identified. Li investigated the difference of toxicity reaction between cefoperazone/tazobactam and single component. Acute toxicity test showed no abnormal reaction and no death in the tested animals; The long-term toxicity test showed no significant differences in hematology, blood biochemistry, coefficient of vital organs and pathology between the cefoperazone/tazobactam group and the single component group (Li et al., 2003). This study suggested that the use of cephalosporin compound preparations in children may increase the efficacy as well as ADR compared with the single preparations, probably because the impurity profile of compound preparations is not the simple summation of impurity profile of single formulations, but there are more new impurities and change quickly, indicating more allergic reactions.

ADRs of Cephalosporins in children mainly involved skin and accessory damage, systemic damage and gastrointestinal system damage, including rash, pruritus, urticaria, allergic reaction, vomiting, and nausea. There were only a few ADRs such as liver function damage, hematuria, and leucopenia. Misreporting was a common problem in SRS. Reactions of skin, gastrointestinal tract and the whole body were easy to detect, while ADRs related to liver, kidney, and blood may need to be reflected by biochemical indicators. And it was possible that medical institutions and doctors may choose not to report serious ADRs out of self-interest.

After treatment and intervention, ADRs of most patients have been improved or cured, but a few patients still left sequelae or died. Anaphylactoid reaction and anaphylactic shock accounted for the majority of the death reports, among which three cases of death reports used ceftriaxone from the same manufacturer. So it cannot be ruled out that ADRs may be caused by product quality problems. Besides, the safety of ceftriaxone has been a prominent problem. In the pharmacovigilance database of Iran from 1998 to 2009, ceftriaxone had the highest number of deaths (49 cases) (Shalviri et al., 2012); Ceftriaxone was the main drug in 112 cases of anaphylactic shock reported by SRS of Republic of Crimea from 2010 to 2018. Some literature analysis on severe ADRs of ceftriaxone showed that there were more cases of severe allergic reaction and anaphylactic shock, and anaphylactic shock was the main cause of death (Zhang et al., 2010; Lu et al., 2011). The safety of ceftriaxone still needs extra attention. Doctors should strictly follow the medication indications, strengthen the monitoring and treatment of allergic reactions, and actively carry out anti-allergy treatment.

In this study, ADR signals obtained from signal mining in the background of medication use in children may have child specificity. Combined with the drug instructions, 73 off-label ADRs were found. The off-label ADR signals of ceftezole with the largest number of reported cases were analyzed one by one.

De-Sarro reported that ceftezole was characterized by the presence of a tetrazole nucleus similar to pententytetrazole at position seven, and thus has convulsion activity. Tremor, convulsion and limb spasm occurred in both rats and dogs after intravenous administration (De Sarro et al., 1995). No cases of tremor after using ceftezole have been found in children, but a documented case of tremor and convulsion after intravenous ceftezole in an adult woman with uremia has been reported (Jin, 2009). Due to uremia, drug excretion was slowed down; plasma half-life was prolonged; the blood-brain barrier was damaged; and drugs accumulated in the central nervous system. Patients with uremia were more likely to develop antibiotic encephalopathy, or in severe cases of grand mal epilepsy. Given the six cases reported in this study and the fact that renal function and blood-brain barrier were not fully developed in children, tremor may be associated with the drug.

The occurrence of dizziness appeared to be a rare ADR of ceftezole, and few cases have been identified in related studies. When Geng evaluated the efficacy of a drug in children with ceftezole as the control group, dizziness occurred in three out of 40 cases (Geng, 2017). In the drug efficacy studies without age limits, Wang found dizziness in four cases (n = 40) and Yang found dizziness in three cases (n = 136) (Yang et al., 2010; Wang and Zeng, 2021). However, the specific mechanism of ceftezole induced dizziness remained unclear and more research was needed.

No facial edema has been reported with ceftezole. In this study, facial edema was mainly presented as facial and eyelid edema. Given the positive signals and description of the reported data, more studies were needed.

Anxiety with ceftezole was not common. Ma used the SF-36 score to evaluate the mental state of patients (without age limit) after the use of ceftezole. The higher the score, the better the state. The study obtained a low mental state score of 61.29 (Ma, 2018). It was difficult to judge whether the anxiety and restlessness was caused by the drug, because it seemed understandable that the child was anxious in an unfamiliar environment and in a state of physical discomfort.

Reports of ADRs such as cyanosis, pallor, chill, and palpitation with ceftezole have occasionally been seen. Wei analyzed 113 cases of ADRs of ceftezole in a hospital, and found two cases of chill (Jiao et al., 2010). Guo reported a case of elderly patients with sudden palpitations, pallor, and cold extremities after the injection of ceftezole (Guo and Sun, 2005). Since there were few studies related to children, there were no reported cases of these ADRs in children, and the relevant mechanism studies were even less.

In cephalosporin instructions, ADRs are well documented, most of which include the data of clinical trial and passive monitoring. In the process of examining the instructions, it was found that the ADR items of each cephalosporin were approximately consistent with the statistics for the number of ADRs in the study. However, there are few ADR annotations and clinical trial reports of ADRs related to medication in children in cephalosporin instructions. Due to economic and ethical issues, clinical trials of medicines for children are limited, resulting in a lack of efficacy and safety data for children. Some European countries have introduced relevant policies and regulations that allow manufacturers to enrich clinical trials of drugs with children as research subjects when conditions permit (Marinovic et al., 2016; Ciato et al., 2017). In addition, ADR signals of cephalosporins with children’s particularity could be obtained by data mining, which could be used as data support of ADRs in the instructions to enrich the label of ADRs related to medication in children.

The statistical results and ADR signals obtained in this study are helpful in guiding the safe use of cephalosporins for children in the clinic, and might be clues for ADR mechanism research, even providing advice for modifying drug labels based on results that may be special to children and the detection of off-label ADRs. In addition, this study has potential limitations. The effect estimated in the study is based on the data of a single province. Although the data are considerable, the external validity of the conclusion still needs to be improved. Due to the limitation of the selected signal mining method, the combination of drugs is not considered, and the conclusions may be biased.

ADRs were common but not serious in children aged 0–4 years. And the reported rate of serious ADRs in children aged over 4 years increased with age, possibly because the body fluctuated greatly at this stage and it was difficult to determine the appropriate dose with empirical medication. ADR reports of ceftezole, ceftazidime, cefoperazone/sulbactam, cefotaxime, ceftriaxone were numerous, and serious, which deserved attention. Studies on the safety of cephalosporin compound preparations in children were few, and the safety of cephalosporin compound preparations in children was doubtful. ADR signal mining was helpful to identify off-label ADRs. Ceftezole may cause off-label ADRs including tremor, face oedema, cyanosis, pallor, rigors, and palpitation. It was also found that the labeling of ADRs in children in cephalosporin instructions and the record of allergic history need to be improved.