Rhabdomyolysis Associations with Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS)

Introduction: Daptomycin, macrolides, trimethoprim-sulfamethoxazole, linezolid, fluoroquinolones, and cefdinir are known to be associated with rhabdomyolysis. Other antibiotics may also lead to rhabdomyolysis, but no study has systemically compared rhabdomyolysis associations for many available antibiotics. Objectives: The objective of this study was to evaluate the association between rhabdomyolysis and many available antibiotics using the FDA Adverse Event Report System (FAERS). Methods: FAERS reports from January 1, 2004 to December 31, 2017 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify rhabdomyolysis cases. Reporting Odds Ratios (RORs) and corresponding 95% confidence intervals (95%CI) for the association between antibiotics and rhabdomyolysis were calculated. An association was considered statistically significant when the lower limit of the 95%CI was greater than 1.0. Results: A total of 2,334,959 reports (including 7,685 rhabdomyolysis reports) were considered, after inclusion criteria were applied. Daptomycin had the greatest proportion of rhabdomyolysis reports, representing 5.5% of all daptomycin reports. Statistically significant rhabdomyolysis RORs (95% CI) for antibiotics were (in descending order): daptomycin 17.94 (14.08-22.85), cefditoren 8.61 (3.54-20.94), cefaclor 7.16 (2.28-22.49), erythromycin 5.93 (3.17-11.10), norfloxacin 4.50 (1.44-14.07), clarithromycin 3.95 (2.77-5.64), meropenem 3.19 (1.51-6.72), azithromycin 2.94 (1.96-4.39), cefdinir 2.84 (1.06-7.62), piperacillin-tazobactam 2.61 (1.48-4.61), trimethoprim-sulfamethoxazole 2.53 (1.52-4.21), linezolid 2.49 (1.47-4.21), ciprofloxacin 2.10 (1.51-2.92). Conclusions: This study confirms prior evidence for rhabdomyolysis associations with daptomycin, macrolides, trimethoprim-sulfamethoxazole, linezolid, fluoroquinolones, and cefdinir. This study also identifies previously unknown rhabdomyolysis associations with meropenem, cefditoren, cefaclor, and piperacillin-tazobactam.


Introduction
Rhabdomyolysis is a clinical syndrome of skeletal muscle injury associated with myoglobinuria, electrolyte abnormalities, and acute kidney injury [1].
The severity of rhabdomyolysis can range from an asymptomatic elevation in creatinine kinase (CK) to severe life-threatening symptoms associated with Ivyspring International Publisher high CK levels and renal failure. The most common presenting symptoms include myalgia, weakness, and tea-colored urine.
Some antibiotics have been shown to play a role in developing rhabdomyolysis. Multiple case reports have shown an association between daptomycin and rhabdomyolysis [2][3][4]. The use of macrolides alone or in combination with statins was reported to be related to rhabdomyolysis [5,6]. A review of 53 cases showed rhabdomyolysis associated with concomitant use of statins and azithromycin [7]. Additionally, case reports indicated that trimethoprim-sulfamethoxazole induced rhabdomyolysis occurred in both immunocompetent and immunocompromised patients [8,9]. There have been case reports linking the use of linezolid to serious cases of rhabdomyolysis [10,11]. Fluoroquinolones have also been shown to be associated with rhabdomyolysis in case reports when fluoroquinolones were used alone or in combination with statins [12,13]. Rhabdomyolysis is listed as an adverse drug reaction (ADR) of cefdinir in its United States Food and Drug Administration (FDA) label [14]. Rhabdomyolysis was also associated with certain medications, such as statins [15].
Antibiotics are frequently prescribed home medications, so it is imperative to know which classes and specific agents within classes are more likely to be associated with rhabdomyolysis. Although some antibiotics are known to be associated with rhabdomyolysis, no study has systematically compared rhabdomyolysis associations for common antibiotics. The objective of this study was to evaluate the association between rhabdomyolysis and common antibiotics using the FDA Adverse Event Report System (FAERS).

Data Source
FAERS is a publicly available database, which is composed of adverse event reports that were submitted to the FDA [16]. FAERS data contain drug information (drug name, active ingredient, route of administration, the drug's reported role in the event) and reaction information. Each report has a primary suspected drug with one or more ADRs and may include other drugs taken by the patient.

Study Design
The methods of data mining were previously used in other published FAERS studies [17][18][19]. FAERS data from January 1, 2004 to December 31, 2017 were included in the study. Some reports were submitted to FDA multiple times with updated information. Therefore, duplicate reports were removed by case number, with only the most recently submitted version included in the study. Another step of removing duplicate reports was performed by matching age, sex, event date, and reporter country.

Drug Exposure Definition
Each antibiotic was identified in FAERS by generic and brand names listed in the Drugs@FDA Database [17][18][19][20]. Drugs with a reported role coded as "PS" (Primary Suspect Drug) were evaluated for inclusion. Antibiotics with less than three ADR reports were excluded from data analysis [21].

Adverse Drug Reaction Definition
FAERS defines ADRs using Preferred Terms (PT) from the Medical Dictionary for Regulatory Activities (MedDRA) [22]. Preferred Term "Rhabdomyolysis" was used to identify rhabdomyolysis cases. Standardised MedDRA Queries (SMQs) are groupings of MedDRA terms, usually at the PT level, which relate to an adverse drug reaction. Hepatic disorders (SMQ) was used to identify cases with hepatic disorders. Acute renal failure (SMQ) and the term "Renal failure acute" were used to identify acute kidney injury cases.

Statistical Analysis
A disproportionality analysis was conducted by computing Reporting Odds Ratios (ROR) and corresponding 95% confidence intervals (95%CI) for the association between rhabdomyolysis and each antibiotic class or individual antibiotic or each statin [23]. ROR was calculated as the ratio of the odds of reporting rhabdomyolysis versus all other ADRs for a given drug, compared with this reporting odds for all other drugs present in FAERS [23]. An association was considered to be statistically significant if the lower limit of 95%CI was above 1.0 [23]. A higher ROR suggested a stronger association between the antibiotic and rhabdomyolysis. An adjusted ROR was calculated after removing reports of potentially confounding statins from the data analysis.
A case report demonstrated that cefditoren pivoxil induced hypocarnitinemia and hypoglycemia in a 6-year-old girl with Fukuyama-type congenital muscular dystrophy [26]. In our study, a 5-year-old girl on cefditoren had both rhabdomyolysis and decreased carnitine level. Although there were commonalities between these two cases, more data would be necessary prior to making any conclusions between hypocarnitemia and rhabdomyolysis. In addition, hypocarnitemia may be a sign of Long-Chain 3-Hydroxyacyl-Coenzyme A Dehydrogenase (LCHAD) deficiency which can cause rhabdomyolysis. In this respect, it is possible that the cefditoren did not cause the rhabdomyolysis, but these patients had underlying illness that caused them to have rhabdomyolysis.
There were three cefaclor-associated rhabdomyolysis reports in our study. Two of these reports had concomitant NSAIDS. NSAIDS are known to be associated with acute kidney injury [27] and acute kidney injury might increase the cefaclor exposure which led to rhabdomyolysis. However, since acute kidney injury was used to diagnose rhabdomyolysis, the association between rhabdomyolysis and cefaclor was confounded by acute kidney injury.
In our study, twelve piperacillin-tazobactam reports listed rhabdomyolysis as an ADR. Three of these reports had acute kidney injury as well. Rhabdomyolysis ROR for piperacillin-tazobactam reports with and without acute kidney injury were statistically similar.

Limitations
A causal relationship between a drug and an ADR cannot be determined by FAERS. Significant bias may occur because of the spontaneous and voluntary reporting of ADRs. Media attention and recent publication of an ADR in the literature might affect the reporting behaviors. The association between a drug and an ADR is confounded by comorbidities and concomitant drugs [19]. Despite the limitations, FAERS has a large sample size and is suitable for discovering new and rare drug-ADR associations.

Conclusions
This study confirms prior evidence for rhabdomyolysis associations with daptomycin, macrolides, trimethoprim-sulfamethoxazole, linezolid, fluoroquinolones, and cefdinir. This study also identifies previously unknown rhabdomyolysis association with meropenem, cefditoren, cefaclor, and piperacillin-tazobactam. Results obtained from FAERS should be interpreted with caution in the context of data limitations. Antibiotic stewardship is needed to prevent rhabdomyolysis and to improve health outcomes. Monitoring of baseline and weekly CK levels for daptomycin and other antibiotics which were associated rhabdomyolysis is warranted.