A rare case of ciprofloxacin-induced cholestatic hepatits in the newborn

Ciprofl oxacin is a fl uorinated quinolone antimicrobial agent that is widely used to treat a variety of gram positive and gramnegative infections among hospitalized children [2]. However, despite its high effectiveness and relative safety, severe adverse effects associated with its use include gastrointestinal symptoms such as nausea, vomiting, diarrhea, abdominal pain, skin rashes, photosensitivity, and liver injury [3,4]. Most commonly, liver damage related to ciprofl oxacin is limited to an asymptomatic elevation in liver enzymes. Acute fulminant hepatitis and cholestatic hepatitis are reported rarely in the literature [3]. Ciprofl oxacin at times causes acute liver injury within a period of two days to two weeks following initiation of treatment. Having a high index of suspicion is important for clinicians to recognize and discontinue any medication suspected of producing such reactions.


Discussion
Nosocomial infections are related to neonatal immune immaturity and the frequent use of invasive life sustaining devices mainly in preterm neonates. Also, the injudicious use of broad-spectrum antibiotics in neonatal units has led to high rates of resistance in fi rst line empiric antibiotics like penicillin and cephalosporin [5,6]. As multidrug-resistant organisms become more of a problem in neonatal intensive care units, there is a need to evaluate the use of other available antibiotics to treat serious neonatal infections.
Fluoroquinolones are potent, bactericidal antimicrobials against a broad spectrum of Gram-negative and Grampositive bacteria. They have been widely used in adult patients because of their excellent tissue penetration, including the cerebrospinal fl uid [7].
In neonatology, the use of ciprofl oxacin in life-threatening infections, although rare, is justifi ed by the fact that clinical benefi ts largely overweight the potential risks [8]. In the presence of meningitis, adequate cerebrospinal fl uid penetration of ciprofl oxacin has been established in adults and older children and available data in infected neonates although limited, showed that cerebrospinal fl uid concentrations were comparable to serum ciprofl oxacin concentrations A pharmacokinetic study performed in septic preterm neonates concluded that a dose of 20 mg/kg/d in 2 divided doses would be effective for common gram-negative infections except for Pseudomonas aeruginosa infections and ineffective for Staphylococcus aureus infections. Although this study is well conducted, it does not provide suffi cient data to establish the optimal dosing schedule of ciprofl oxacin in neonatal sepsis [9,10].
In paediatric patients, diarrhoea and rash are among the most common clinical adverse events and elevation in hepatic transaminases among the most common laboratory adverse events reported with use of ciprofl oxacin. Serum aminotransferase elevations have been reported in 1% to 6% of recipients of intravenous ciprofl oxacin. These elevations are usually transient, mild and asymptomatic; and rarely require dose adjustment. Ciprofl oxacin has also been linked to rare cases of cholestatic jaundice that usually arises after 1 to 3 weeks of therapy [11,12].
Ciprofl oxacin at times causes acute liver injury within a period of two days to two weeks following the initiation of antibiotic treatment. Although the precise mechanism of ciprofl oxacin-induced liver injury remains currently unknown, hepatocellular necrosis leading to elevated liver enzymes has been observed. The pattern of injury can be cholestatic, hepatocellular, or mixed. The more familiar pattern in the acute setting, is hepatocellular, which is associated with markedly elevated alanine transferase levels. The cholestatic pattern of liver injury, such as in our patient,usually occurs after a prolonged course of antibiotic use [13].
The pathogenic events that cause lesions due to the uses of drugs and toxins is either due to their direct toxic effect or an idiosyncratic immunoallergic reaction. The direct toxic effect is likely favoured by the high tissue levels of the drug or its metabolites. Drug-induced liver injury is typically idiosyncratic and is usually unpredictable until the drug is given [14]. Druginduced liver injury can be differentiated by the level of liver enzymes. The liver injury is termed cholestatic if only alkaline phosphatase is elevated more than two times its upper normal limit or, when both serum alanine aminotransferase and alkaline phoshatase are increased, if the ALT/ALP ratio is less than 2 [15,16].

Conclusions
In conclusion, the practitioners should be aware that Ciprofl oxacin is able to induce drug-induced liver injury, including a prolonged symptomatic course of cholestatic hepatitis, in order to recognize early an adverse reaction to the drug thus leading to its immediate withdrawal and avoiding a repeated future exposure.

Consent
Written informed consent was obtained from the patient for publication of this case report.

Disclosure
This clinical case was written based on clinical observation without any funding.