Skin is the largest organ of the adult human body and serves several essential functions. ^{1 , 2} Drugs may cause undesirable or unfavorable effects that may limit their use and effectiveness, known as adverse drug reactions (ADRs), ³ and the risk of ADRs ranges from almost nothing to severe with substantial financial and quality of life costs. ⁴ One of the most commonly used and general classifications of ADRs is the World Health Organization (WHO) classification, also known as the mnemonic classification. ⁵

Cutaneous adverse reactions (CADRs) are prevalent and account for about 10% to 30% of all ADRs and affect 2-3% of hospitalized patients. ⁶ CADRs can be fatal if sufficient emergency care is not delivered. ⁷ While there are several risk factors for developing CADRs, antibiotics are responsible for 40 to 60% of instances, ^{5 , 8} and according to the WHO, around 2% of dermatologic CADRs are deemed severe. ⁹ Severe CADRs (SCARs) include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), erythroderma or exfoliative dermatitis (ED), and drug reaction with eosinophilia and systemic symptoms (DRESS). ¹⁰

Pharmacovigilance (PV) plays a crucial role in determining the safety profile of medications over their complete life cycle through two primary approaches, spontaneous surveillance and active surveillance. ¹¹ While spontaneous reporting systems (SRS) have their limitations, they are vital for the early discovery of novel reactions in terms of their clinical nature, severity, or frequency. ¹² The WHO utilizes VigiBase as its worldwide database, which relies on the collection of spontaneous reports to facilitate the timely identification of possible safety signals. ¹³

VigiLyze and VigiGrade are a tool and method, respectively, that are integrated with other tools and methods with VigiBase. VigiLyze is an online resource that provides a quick and clear overview of VigiBase, while VigiGrade represents report quality, it provides a completeness score for the amount of clinically relevant information provided in an individual case safety report (ICSR). ^{14 – 16}

A signal emerges from information gathered from one or more sources. It is a hypothesis suggesting a potential causal relationship or a new aspect of a known relationship between an active ingredient and an event or a set of related events. The hypothesis should have enough likelihood of being true to justify further investigation. ^{17 , 18}

Signal management encompasses a series of activities aimed at evaluating potential new or modified risks associated with the utilization of a medicinal product. These activities encompass signal prioritization, which involves ongoing assessment of risk impact; signal detection, which involves qualitative analysis utilizing disparity and case report analysis; signal validation; and signal inspection. ¹⁹

The objective of this research was to assess the data obtained and uploaded to VigiBase about adverse medication responses affecting the skin and surrounding structures, with a specific focus on identifying any possible signals linked with Meropenem that are not currently indicated on the medicine label.

Meropenem – Erythroderma was the DEC with the highest impact on public health, found to be category “A” according to Waller et al., tool, ²⁸ a high-priority signal that needs further investigation, calculation of evidence and public health scores is shown in Table 4. In the 11 years of study, a total of 65 cases were found in the global database, and only 53 met the inclusion criteria. Table 5 shows the country distribution of the reports.

There was a slight male predominance in the affected patients with a M:F ratio of 1.3:1 ( Figure 2) and an average age of 58.5 ± 25.5 years (range newborn through 95 years), the largest share of cases was of the (45-64) years age group ( Figure 3).

Statistical parameters, IC ₀₂₅, ROR ₀₂₅, and PRR ₀₂₅ were calculated manually for the included cases to estimate the strength of the association, values are listed in Table 6.

The use of quantitative analysis has shown a robust correlation between the administration of Meropenem and the occurrence of exfoliative dermatitis. This association has been substantiated by the meticulous examination of individual cases. Tables 7 and 8 validate the discovered signal using the WHO-UMC causality criteria and Bradford Hill criteria, respectively.

In the present study, ED led to the death of one of the patients and caused disability in two other patients, cases outcome is listed in Figure 3A, while the seriousness assessment was weighed up according to WHO criteria ²³ and listed in Figure 3B.

Since Exfoliative dermatitis is a type-B ADR, it is not predictable nor dose-dependent and was found to be not preventable after evaluation using Schumock and Thornton scale ³⁷ and to assess the severity, Hartwig’s Severity Assessment Scale ³⁸ was used with results listed in Table 9.

Erythroderma is one of the rarely encountered and diagnostically challenging conditions. ^{39 , 40} Erythroderma, often known as ED, is a syndrome with a non-specific clinical picture and is considered as a dermatological emergency associated with a significant mortality rate among hospitalized patients. ^{41 , 42}

In Iraq, there were only 3 cases of Meropenem-erythroderma DEC, and from what was clear from all the 4,510 reports of Iraqi patients that have been reviewed, some syndromes were recorded as separate symptoms and while, even a minority, there were some mistermed reactions and ICSRs missing essential details that are vital in analyzing the case at hand. Moreover, underreporting significantly impedes the Pharmacovigilance system worldwide, drastically reducing the number of reports submitted to VigiBase. ^{43 , 44}

From 65 cases of Meropenem–Erythroderma DEC, only 53 were included, as 12 ICSRs had a completeness ratio of less than 50% which led to their exclusion. In more than 50% of the cases, Meropenem was the sole administered drug, and 28 patients had a positive dechallenge; together with the results of the various assessment tools that were used and the solid statistical evidence, there’s strong evidence of a relationship between Meropenem and ED.

Several studies that discussed and researched genetic susceptibility to SCARs showed higher susceptibility in Thai and Chinese populations due to specific Human Leukocyte Antigens (HLAs), ^{45 – 49} and that might explain why Thailand and China ranked first and second in the number of reports.

In the present study, male preponderance was seen, and the average age was in the 5 ^th decade; these findings agree with other studies. ^{10 , 50 , 51}

Drug-induced ED is rapid in onset and progresses faster than ED caused by primary skin disease with faster resolution. ^{35 , 52} In the current study, the average time for the onset of symptoms was 10 days, ranging between 0 days (the day Meropenem started) to 30 days, and this is comparable with Sindi et al. findings. ⁴⁰ There was a single female patient whose beginning was documented as occurring 120 days before. However, it remains unclear if she began experiencing signs and symptoms after this four-month period or whether she had entirely recovered, with the reported date being her final follow-up appointment.

Histopathologic and laboratory data that may aid in the diagnosis of the cases were not available, in addition to previous allergy and medical history that could explain if there is a possible drug-drug or drug-disease interactions, as these can insidiously modulate how the body reacts to different drugs by various mechanisms causing aggravation of pre-existing dermatoses or forms an antigenic complex that triggers an immune response. ^{53 , 54}

Due to the voluntary nature of ADR reporting, the main limitations faced in our research were underreporting and incomplete reporting, primarily caused by a lack of sufficient pharmacovigilance knowledge and practice or finding the reporting process a time-consuming and fairly complicated procedure. Additionally, some healthcare providers do not report because of the fear of legal consequences, which was also seen in several studies. ^{55 – 58}

Although Erythroderma is a rare reaction, death may occur if the patient has not received rapid management and the underlying trigger was treated, this can be challenging due to the variable course and non-specific symptoms of erythroderma.

This study found a strong link between Meropenem and ED supported by statistical evidence and data from analyzing case series.

The influence of genetic and ethnic variations on drug hypersensitivity reactions (DHRs) is significant, as it alters the body’s response to various medications, resulting in a wide range of symptoms or modifying the vulnerability of certain groups.