High-dose tigecycline-induced cutaneous hyperpigmentation

INTRODUCTION

Urinary tract infections (UTIs) are amongst the most common infectious diseases affecting people across age and gender. The rate of infection, mortality and morbidity of UTI is increasing with the greater use of antibiotics for various infections in hospital settings. The financial burden of UTI-associated hospitalisations and prolongation of hospital stays is substantial. Nosocomial UTIs are a common complication in healthcare systems worldwide. A UTI is defined as nosocomial when it is acquired in any healthcare institution or more generally when it is related to patient management. Particularly, high-risk groups include patients with indwelling urinary catheters, recurrent hospitalisation and those undergoing urological procedures amongst others. The most frequently isolated micro-organisms in patients with nosocomial UTIs are Escherichia coli, Candida spp., Klebsiella spp. and Enterococcus spp. Nosocomial pathogens causing UTIs tend to have a higher antibiotic resistance than community-acquired UTIs.^[1]

Enterococci are Gram-positive, facultatively anaerobic commensal organisms of the gastrointestinal tract. Multidrug-resistant (MDR) Enterococci spp. has become a leading cause of healthcare-associated infections, ranging from endocarditis to UTIs. Resistance to beta-lactams is almost universal amongst strains of Enterococcus faecium and there is frequent concomitant resistance to aminoglycosides and vancomycin. Vancomycin, daptomycin, linezolid, fosfomycin and tigecycline remain viable treatment strategies, depending on the sensitivity pattern.^[2]

Tigecycline – a glycylcycline is a tetracycline congener that inhibits bacterial protein synthesis by binding to the 30S bacterial ribosome and preventing access of aminoacyl tRNA (Ribonucleic acid) to the acceptor (A) site on the mRNAribosome complex. Tigecycline displays excellent activity against Enterococci, Enterobacteriaceae, Acinetobacter and Bacteroides fragilis. Tigecycline distributes rapidly and extensively into tissues, with an estimated wide apparent volume of distribution of 7–10 L/kg and a viable skin tissue concentration 3.9 times its serum level. Despite this pharmacokinetic feature of tigecycline, cutaneous adverse effects were uncommon and typically appeared in the form of rash and pruritus at rates of <4%. The main adverse effects of tigecycline include gastrointestinal (GI) disturbances such as nausea and vomiting, hepatotoxicity and irreversible brownish discolouration of teeth and may very rarely cause pseudotumor cerebri, stunted growth and various skin reactions.^[3]

Here, we report a clinical case of a woman who developed diffuse generalised cutaneous hyperpigmentation within 3 days of receiving high-dose tigecycline.

CASE REPORT

A 67-year-old Indian lady with hypertension, hypothyroidism controlled with levothyroxine (75 mcg once daily), oliguric chronic kidney disease – V (estimated Glomerular Filtration Rate [eGFR]- 14 mL/min/1.73 m²) on maintenance haemodialysis (HD), chronic coronary syndrome with history of recurrent recent hospitalisation with heart failure with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF]- 35%) and status post-primary coronary intervention to left anterior descending artery was admitted with complains of gradually worsening shortness of breath, even at rest for a few days without any associated fever or chest pain.

Initial examination revealed sinus tachycardia with a heart rate of 126/min, blood pressure of 186/112 mmHg, oxygen saturation (SpO₂) of 78% in room air, bilateral pitting pedal oedema and profuse inspiratory crackles on chest auscultation and jugular venous engorgement. A point-of-care ultrasound revealed profuse B lines in bilateral lung fields with bilateral pleural effusion and compromised cardiac contractility with dilated inferior vena cava with no respiratory variation. Chest X-ray showed diffuse pulmonary oedema with obliteration of bilateral costophrenic angles. The patient was provisionally diagnosed as HFrEF and put on non-invasive positive pressure ventilation with supplemental oxygen to maintain SpO₂ >90%; intravenous (iv) furosemide infusion was started at 4 mg/h after a bolus of 40 mg and glyceryl trinitrate was initiated intravenously at 10 mcg/min. Urgent HD with an ultrafiltrate of 3 L was started and empirical antibiotics in the form of piperacillin-tazobactam and doxycycline were initiated after collecting relevant cultures. Initial blood investigations revealed polymorphic leucocytosis with a marginally elevated C-reactive protein with normal procalcitonin, azotaemia and normal electrolytes. The patient showed clinical improvement with treatment and was gradually weaned of supplemental oxygen.

However, on the 5^th day of hospitalisation, she turned febrile with a T_max of 102.3°F. All invasive lines were changed; however, she remained persistently febrile - high grade, remission with paracetamol and no diurnal variation and haemodynamically stable. Blood and urine samples were sent for culture and sensitivity, and routine blood examinations were done which revealed worsened infective parameters (total leucocyte count – 19,400/cu mm with neutrophilic predominance, procalcitonin levels of 4 ng/mL). Antibiotics were empirically escalated to meropenem (M) and teicoplanin (T) and dose adjusted according to eGFR; however, the patient remained febrile. Urine cultures received on the 8^th day of hospitalisation revealed growth of E. faecium (>10⁵ cfu/mL), sensitive to only daptomycin and intermediately sensitive to tigecycline.

Tigecycline (Ti) 100 mg intravenously twice daily (high-dose tigecycline given the intermediate drug sensitivity) and daptomycin (D) 350 mg intravenously every alternate day (after HD) were started. The patient showed clinical and haematological improvement and she was afebrile from the 11^th day onwards [Table 1]. However, she developed a generalised diffuse skin hyperpigmentation from around the same time, mainly over the face, lips, neck and anterior trunk. This was not associated with pruritus, hair loss, scales, any aggravating or relieving factors, raised lesions or any pain/discharge [Figure 1]. There was no history of application of any topical formulation and there were no such events in her past.

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Figure 1:

Cutaneous hyperpigmentation observed over face, lips and neck 3 days after initiation of high-dose tigecycline.

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Tigecycline and daptomycin were the only two new drugs that were introduced, hence providing a temporal association with the adverse effect. However, since the patient showed clinical improvement and due to the unanimously decided non-serious nature of the adverse effect, a continuation of the above two drugs was decided in the best interest of the patient. Her other concomitant medications are enumerated in Table 2. On the 15^th day of hospitalisation, tigecycline was discontinued after a normal procalcitonin level was obtained. The patient was discharged in a haemodynamically stable state on the 18^th day of hospitalisation with advice to continue daptomycin intravenously for a total of 14 doses.

On her scheduled revisit a month later, a gradual, generalised lightening of skin hyperpigmentation was observed [Figure 2]. The patient was doing well during this period and her repeat urine cultures were sterile. Figure 3 depicts an even greater reduction in hyperpigmentation after 6 months though the baseline was not reached. Owing to the temporal association of symptoms and their waning off after stoppage, tigecycline is concluded to be the probable cause of this adverse drug reaction (ADR) [Tables 3 and 4].

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Figure 2:

Improvement of skin colour 1 month after stopping tigecycline.

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Figure 3:

Further betterment of skin colour 6 months after stopping tigecycline (though baseline has not been reached).

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DISCUSSION

In this case report, we describe the occurrence of cutaneous hyperpigmentation due to high-dose tigecycline. Minocycline, the parent compound of tigecycline is known to cause cutaneous adverse reactions in a dose-dependent manner at rates of 14%. This is postulated to be due to cutaneous deposition of black-coloured degradation products. Although it is unknown if tigecycline produces a similar effect by the same mechanism, literature documents very few such cutaneous hyperpigmentation as an ADR of tigecycline.^[4,5]

Vandecasteele et al. described skin hyperpigmentation of the upper trunk in a woman with osteomyelitis treated for 102 days with a conventional dose of tigecycline.^[4] A skin biopsy revealed melanin-containing macrophages; prognosis after stopping tigecycline was not reported.

Alsemari et al. reported a case of cutaneous hyperpigmentation with high-dose tigecycline 48 h after the onset of therapy. The patient had developed acute kidney injury during the treatment process which was treated aggressively with IV fluids and management of the underlying condition resulting in betterment of eGFR levels. The authors reported a betterment of skin tone about 10 days after dose reduction. Skin biopsy revealed a spongiotic epidermis, a dermal perivascular mononuclear infiltrate with scattered eosinophils and increased basal keratinocyte pigmentation consistent with drug-related skin changes.^[5]

Knueppel and Rahimian had reported cutaneous hyperpigmentation over the face, ears and upper trunk in two Hispanic men being treated with tigecycline and polymyxin B for bloodstream infection caused by MDR Klebsiella pneumoniae. The reactions occurred after a total of 29 and 22 days of tigecycline therapy, respectively. The hyperpigmentation subsided gradually; however, skin tone was not completely reversed even after 5 months of stopping the drug.^[6]

Contrary to that reported by Vandecasteele et al.,^[4] our patient developed cutaneous hyperpigmentation within 3 days of onset of high-dose tigecycline. Although there is no recommendation for dose adjustment of tigecycline in patients with renal impairment, 15% of the tigecycline dose is known to be excreted unchanged in the urine. This may explain the earlier onset of ADR in our patient of CKD-V. This may also explain the similarity with that reported by Alsemari et al.,^[5] where acute renal dysfunction had a temporal relationship with the cutaneous hyperpigmentation caused by high-dose tigecycline. Alsemari et al., and Knueppel and Rahimian et al also reported a betterment of skin tone after dose reduction/stoppage and/or betterment of renal function.^[4-6]

In our case, due to the clinical improvement and the perceived non-serious nature of ADR by both patient and physician alike, a unanimous decision to continue high-dose tigecycline was confirmed. The gradual betterment of skin colouration following the stoppage of tigecycline supports our initial assumption that tigecycline, being the 9- (N, N-dimethylglycylamido) derivative of minocycline is probably the causative drug. Cutaneous deposition of breakdown products in the wake of prolonged dosing or under-excretion in renal dysfunction may be the pathophysiologic mechanism. However, non-attainment of baseline skin tone even after 6 months of stoppage may be an indication that even after a complete washout of tigecycline and its degradational products, the cutaneous hyperpigmentation may not be completely reversible. Other concomitant medications like pantoprazole have been known to rarely cause cutaneous hyperpigmentation; however, their continuation during the evident improvement in skin colour lessens the likelihood of it being the offending drug. No significant drug interaction is noteworthy amongst the concomitant medications; however, any unreported drug–drug interaction occurring at high tigecycline concentrations cannot be entirely ruled out.

CONCLUSION

An objective causality assessment, using both the WHOUMC scale and Naranjo’s algorithm revealed a ‘probable’ relationship between the development of cutaneous hyperpigmentation and high-dose tigecycline therapy. The newer extensive use of high-dose tigecycline therapy in view of growing antimicrobial resistance warrants its reporting for future references, better patient communications, minimising psychological trauma and reducing litigations.