adverse drug reactions ( adrs ) , including interactions , in older people are a common cause of admission to hospital1 and are also a common cause of disease in hospitalized patients .
frail elderly patients appear to be particularly at risk of adrs . in some cases , this is because insufficient account is taken of the effect of age and frailty on the pharmacokinetic and pharmacodynamic of the drug , especially in relation to hepatic2 and renal elimination.3 although many adrs are recognized during the drug development process and before licensing , this is not always the case , especially when they are uncommon or rare.3 moreover , patients with severe cognitive impairment may not be able to refer symptoms related to an adr , making the recognition of this clinical condition a medical problem.4 rhabdomyolysis is a clinical and laboratory syndrome that is caused by various etiologies , involving the skeletal muscle.5 rhabdomyolysis is characterized by the leaking of myoglobin and other intracellular proteins and electrolytes into the circulation , and may be associated with a wide variety of diseases , injuries , medications , and toxins.5 it is important to recognize drug - induced rhabdomyolysis because clinical effects are usually reversible.4 rhabdomyolysis related to macrolide - statin interaction has previously been described.68 clarithromycin , like other macrolides , is an inhibitor of cyp450 3a4 , the major enzyme responsible for the metabolism of several drugs , in particular some statins like simvastatin and atorvastain.69 to date , rhabdomyolysis related to clarithromycin has been reported in only one previous case report.10 we report the case of a 90-year - old caucasian male , admitted to the university hospital of pisa for dyspnea , who experienced rhabdomyolysis related to clarithromycin treatment .
a 90-year - old caucasian male was admitted to the university hospital of pisa for dyspnea .
he had experienced dyspnea for 2 weeks , and showed signs of pneumonia after a chest x - ray was performed .
the patient was affected by alzheimer s disease , in advanced phase , and did not take any home - medication as referred by his general physician . at admission in the emergency room ,
clinical workup revealed mental confusion ( the relatives referred progressive cognitive impairment for several months ) , sinus tachycardia ( 115 beats per minute ) , basilar wheezes , and rhonchi .
body temperature was 36.6c with normal systemic blood pressure ( 140/80 mmhg ) , diuresis , and blood oxygen saturation ( so2% 96.2% ) .
routine laboratory exams , including complete blood cell count , thyroid hormones , liver ( aspartate aminotransferase and alanine aminotransferase ) and muscle ( creatine kinase [ ck ] ) enzymes , as well as the coagulation pattern , resulted within normal limits .
serum brain natriuretic peptide was measured and a cardiac markers curve ( including myoglobin ) was also started , ruling out cardiogenic dyspnea .
blood potassium and creatinine concentrations were 4.96 meq / l ( reference range 3.55 meq / l ) and 122.8 mol / l ( reference range 4590
a diagnosis of acquired pneumonia was made and treatment with ceftriaxone ( 1 g four times daily , intravenous ) , hydration ( crystalloid 1.5 l / day ) , aerosol with salbutamol and oxitropium , o2 inhalation ( 3 l / minute ) , and dalteparin ( 2500 ui , subcutaneous ) was started .
after the geriatric ward admission , clarithromycin ( 500 mg two times daily , intravenous ) was also started .
on the second day of hospitalization , for continuing sinus tachycardia , in the absence of any evident causes ( fever , hypotension , arterial - venous fistula , thyrotoxicosis , suspected drug treatments , etc ) beta - blocker treatment ( bisoprolol 1.25 mg , daily ) was added and a cardiac markers curve was restarted ( figure 1 ) .
the second point of the curve , almost 6 hours after the third clarithromycin dose , revealed a huge myoglobin increase ( 1144 ng / ml ; 8.5 times the upper normal range [ 28138 ng / ml ] ) without electrocardiogram modifications .
u / l ; 6.5 times the upper normal range [ 38180 u / l ] ) along with a mild creatinine increase ( 152.9 mol / l ) , in the absence of liver enzyme alterations ( aspartate aminotransferase , alanine aminotransferase ) .
urine color concomitantly changed toward dark brown and hemogasanalysis revealed a slight respiratory insufficiency type 1 with normal ph .
a diagnosis of rhabdomyolysis was made and clarithromycin was stopped , while the concomitant therapy with ceftriaxone , bisoprolol , and aerosol with salbutamol and oxitropium was continued .
the patient was immediately treated with intravenous crystalloid hypotonic solution ( 80 ml / hour ) and corticosteroid ( 40 mg methylprednisolone , intravenous ) .
serum ck and myoglobin levels decreased within a few days and a chest x - ray showed significant improvement .
the patient was discharged home on the sixth hospital day ( figure 1 ) with the diagnosis of iatrogenic rhabdomyolysis and acquired pneumonia of unknown etiology .
indeed , serum and urinary antigen and antibody exams excluded the presence of legionella pneumophila , streptococcus pneumoniae , and mycoplasma pneumoniae while virus infection assessments were not performed .
clarithromycin , like other macrolides , is an inhibitor of cyp450 3a4 , the major enzyme responsible for the metabolism of several drugs , in particular some statins as simvastatin and atorvastatin.3,69 rhabdomyolysis related to macrolide and statins interaction has previously been described ; however , rhabdomyolysis related to clarithromycin has been reported in only one previous case report.8,10 in our case , there was an evident temporal sequence between clarithromycin exposure - withdrawal and the onset - recovery from rhabdomyolysis biochemical signs , while other potential causes of muscle damage were reasonably excluded .
accordingly , the naranjo probability scale confirmed a probable relationship ( score 6/9).13 a general physician and a nurse followed the patient at home , thus we are confident the home care was carried out in a correct manner , ruling out mistakes and accidental drug intake .
moreover , an interaction with other concomitant medications was improbable considering the rapid resolution after clarithromycin withdrawal and the elimination pathways of the concomitant drugs ( both bisoprolol and ceftriaxone have hepatic and renal elimination routes).11,12 in addition , bisoprolol was administered at the minimal dose ( 1.25 mg ) and both bisoprolol and ceftriaxone , as single therapy , were never related to an adverse drug reaction like rhabdomyolysis .
we ruled out infection as the possible cause of muscle damage considering the sequence of the events .
in fact , the patient was admitted to the hospital for dyspnea developed at home since 2 weeks , while serum ck suddenly increased 2 days after hospital admission .
if rhabdomyolysis had been caused by the infection we would have expected that serum ck increased earlier , thus being already evident at hospital admission . moreover ,
the diagnosis of rhabdomyolysis , unless there is a high index of suspicion , can be missed since muscular pain , swelling , and tenderness may not be prominent or even absent .
the definitive diagnosis should be made by laboratory tests including serum ck and urine myoglobin.5 in our case , the patient had advanced cognitive impairment making him unable to easily refer any symptom , and the diagnosis was made by the huge elevation of biochemical markers ( 6.5 times the upper normal value for ck , 8.5 times for myoglobin ) .
overall , these findings allowed us to make the diagnosis of rhabdomyolysis with sufficient warranty .
although clarithromycin associated rhabdomyolysis is mainly due to pharmacokinetic interactions , a direct muscle toxicity might be postuled.5,10
 rhabdomyolysis is a clinical and laboratory syndrome that is caused by various etiologies , involving the skeletal muscle . 
 clarithromycin , like other macrolides , is an inhibitor of cyp450 3a4 , the major enzyme responsible for the metabolism of several drugs , in particular some statins . 
 rhabdomyolysis related to macrolide  statin interaction has previously been described . to date , rhabdomyolysis induced by clarithromycin has been described in only one previous report . 
 we describe the case of a 90-year - old caucasian male , admitted to the university hospital of pisa for dyspnea , who developed rhabdomyolysis associated with clarithromycin administration . 
Introduction
Case report
Discussion