Cefditoren pivoxil associated rash and arthralgia in a child.

Cefditoren pivoxil is an oral antimicrobial used increasingly in pediatric bacterial infections. We report a case of rash and arthralgia following administration of cefditoren pivoxil for lower respiratory tract infection in a four-year-old female child. On discontinuation of the antibiotic, the child recovered full function of the knee joint within seven days. The causality of the event assessed as per the WHO-UMC system for standardized case causality assessment criteria can be considered as 'probable'. Analyzed by the Naranjo's ADR probability scale, the score was 7, which also makes it a 'probable' event.

Introduction

Cefditoren pivoxil is a third-generation oral cephalosporin with a broad spectrum of activity against pathogens, including both Gram-positive and Gram-negative bacteria, and is stable to hydrolysis by many common β-lactamases. Cefditoren pivoxil is indicated in the treatment of lower respiratory tract infections, acute exacerbations of chronic bronchitis (AECB), mild-to-moderate community-acquired pneumonia (CAP), acute maxillary sinusitis, acute pharyngitis/tonsillitis and uncomplicated skin and soft tissue infections. It is of particular use in Streptococcus pneumoniae infections with decreased susceptibility to penicillin or β-lactamase-mediated resistance among the common community-acquired pathogens.[1]

Cefditoren pivoxil demonstrates some cephalosporin class-related adverse effects, which include allergic reactions, Stevens-Johnson syndrome, serum sickness-like reaction, erythema multiforme, toxic epidermal necrolysis, etc.[2]

Case Report

A four-year-old girl (body weight 16 kg) presented with fever for three days. On examination, she showed fine crepitations over both lower lung fields (anterior and posterior). A plain X-ray of the chest on PA view demonstrated non-homogenous opacities in both lower lung zones. Blood examination report showed a normal hemoglobin and RBC count. Total WBC counts were 12,400/μl (N - 79%, L - 18%, E - 2%, M - 1%, B - 0). The diagnosis of lower respiratory tract infection was made and she was prescribed cefditoren pivoxil 10mg/kg/day (75 mg twice daily) for 10 days and an ambroxol-salbutamol combination elixir. She was also advised paracetamol 15mg/kg/dose (250 mg thrice daily) for fever.

Her fever subsided within the first two days of therapy after which paracetamol was discontinued. On the fourth day of therapy with cefditoren, she developed wide spread maculopapular rash [Figure 1]. She also complained of pain over the right knee joint and refused to walk. There was no history of fall or injury to the knee. Local pain and tenderness were noted on flexion and extension of the right knee joint. There was erythema but no appreciable swelling. X-ray showed no bony or joint space abnormality [Figure 2]. Other joints like hips, elbows, and wrists were not involved.

Figure 1

Distribution of maculopapular rash in a child receiving cefditoren pivoxil

Figure 2

Digital X-ray showing normal right knee joint (AP and lateral view) of the patient

All medicines that the child was receiving including cefditoren pivoxil were discontinued promptly. Paracetamol 15 mg/kg three times a day was prescribed again to provide relief from pain. The rash, local pain, and tenderness resolved within three days. However, there was still some residual discomfort with joint mobility and difficulty in walking. She eventually recovered full function of the knee joint and started walking without any discomfort on the seventh day following discontinuation of cefditoren pivoxil.

Causality assessment

The child was suspected to have suffered an episode of rash and arthralgia with cefditoren pivoxil treatment. None of the concomitant medications, e.g., ambroxol, salbutamol, and paracetamol is known to cause arthropathic symptoms or joint damage. An exanthematous febrile illness of viral origin, albeit rarely, is known to usually affect older teens and adults. Known as the fifth disease as the rash appears on the fifth day of the fever, it is also characterized by swelling and pain of joints.[3] The clinical presentation in this patient excludes the diagnosis of fifth disease. In this case there was reasonable temporal relationship between the adverse event and drug exposure. Also, pain disappeared and functional joint disability was resolved on dechallenge. Rechallenge did not occur. Further, no alternative cause, including any disease, was likely to have caused the adverse event. As per the WHO and Uppsala Monitoring Center standardized case causality assessment criteria,[4] this event can be considered as a “probable” reaction to due to cefditoren pivoxil. The Naranjo's ADR probability score,[5] 7, also confirmed this causality as “probable”.

Discussion

Arthralgia and arthropathy are known side effects with many antimicrobials including cephalosporins. During a period of six years, since the first notification in 1989, the Adverse Drug Reactions Advisory Committee (ADRAC), received 42 reports of arthritis or arthralgia associated with the use of the second generation cephalosporin drug, cefaclor. The majority of the reports concerned pediatric patients: 36 of the 42 patients were under 16 years of age.[6]

Since cefditoren pivoxil has been an effective and safe drug in pediatric bacterial infections,[7] clinicians are increasingly using this antimicrobial agent. Although post-marketing experience has shown that it can cause rare cases of arthralgia, thrombocytopenia, and acute interstitial or eosinophilic pneumonia,[8] an extensive literature search could not reveal any report of rash and arthropathy associated with use of cefditoren pivoxil in children in India. The presence of joint pain or frank arthritis in children treated with cefditoren pivoxil is of clinical importance, and may be overlooked or misinterpreted. It is important for prescribers to be aware of a possibility of cefditoren-induced rash and arthralgia and consider withdrawing this drug if such as adverse event occurs.