Keywords
Colistimethate - neonate - extremely low-birth-weight - multidrug resistant
Neonatal infections remain a major cause of morbidity and mortality among extremely
low-birth-weight (ELBW) infants. The emergence of multidrug-resistant (MDR) pathogens
are increasingly reported and remain a treatment challenge with resistance to standard
antimicrobial treatments.[1]
[2]
[3] Multidrug-resistant Acinetobacter baumannii (MDR-Ab) isolates, one of the most serious therapeutic problems worldwide, are an
indicator of poor clinical outcomes and an important cause of ventilator-associated
pneumonia, bacteremia, and sepsis in the critically ill patient.[1]
[3]
[4]
[5]
[6]
[7]
Case Report
A 535-g female infant was born at 23 weeks' gestational age. She was intubated in
the delivery room. Her Apgar scores were 1, 6, and 6 at 1, 5, and 10 minutes. Her
neonatal intensive care unit course prior to MDR-Ab was complicated by hyaline membrane
disease, electrolyte imbalances, apnea of prematurity, anemia, bilateral grade III
to IV intraventricular hemorrhage with infarction of the right cerebral hemisphere,
a 7-day course of ampicillin and cefotaxime for suspected early onset sepsis and suppurative
chorioamnionitis as diagnosed on placental pathology, and a patent ductus arteriosus
that spontaneously closed without treatment. She later developed bronchopulmonary
dysplasia, Enterococcus faecalis bloodstream infection (on day 67 of life), retinopathy of prematurity, seizures,
porencephaly, and posthemorrhagic hydrocephalus requiring placement of a ventriculoperitoneal
shunt.
On day of life 11, the patient deteriorated, requiring increased ventilator support
and abdominal distension was noted. A full sepsis workup was completed and empiric
antibiotic coverage was initiated, which included vancomycin, cefotaxime, and metronidazole.
Fluconazole prophylaxis was also initiated per unit protocol. The C-reactive protein
and white blood cell count were markedly elevated at 46.66 mg/L and 41.6 K/mm3, respectively, but blood and cerebrospinal fluid cultures remained negative. Chest
X-ray revealed patchy opacities of both lungs superimposed on granular opacities.
Respiratory (sputum) cultures were positive for MDR-Ab. Culture sensitivities revealed
a complete resistance to the entire antimicrobial panel, which included cephalosporins,
aminoglycosides, fluoroquinolones, carbapenems, and beta-lactamase inhibitors. E-test
for colistimethate and tigecycline were reported as sensitive (0.5 mCg/mL, 4 mcg/mL
respectively). The patient was placed in isolation due to these findings. No other
patients were concomitantly positive for MDR-Ab.
The infectious disease team was consulted and in view of worsening findings and marked
increase in ventilator support, colistimethate sodium (CMS) was initiated at a dose
of 2 mg/kg/dose of colistimethate base activity intravenously (IV) every 12 hours.
Synergistic rifampin as reported[8]
[9] was added 72 hours later per infectious disease team recommendation. Serum blood
urea nitrogen and creatinine prior to initiation of treatment were 34 and 0.8 mg/dL,
respectively. The baseline urine output was ~4 mL/kg/h. By day 4 of treatment, serum
blood urea nitrogen and creatinine increased to 55 and 1.3 mg/dL, respectively, with
a significant decrease in urine output. The patient also developed jerking movements,
which were suspected to be seizures. She was started on phenobarbital and no further
seizure episodes were noted. An electroencephalogram was not feasible at that time
due to high-frequency oscillation. Due to signs of nephrotoxicity, the dose of CMS
was adjusted to 2 mg/kg IV every 24 hours with close monitoring of renal function.
Serum creatinine decreased to 1 mg/dL 2 days later and returned to baseline 5 days
later. The patient completed a 10-day course of dose-adjusted CMS and rifampin. The
ventilatory support was slowly weaned during the course of treatment, and chest X-ray
showed improvement. A repeat respiratory culture after treatment showed no pathogens.
The patient had a complicated hospital course but was subsequently discharged home
at 5 months of age.
Discussion
MDR-Ab is emerging as an important nosocomial pathogen that can cause severe and life-threatening
infections and thus increase morbidity and mortality rates in intensive care units.[1]
[7]
[10] The increase of MDR-Ab strains has rendered traditional antimicrobials ineffective.[2]
[3]
[10] In addition, due to the decline of new broad-spectrum antibiotics in the pharmaceutical
pipeline, combating these MDR strains has prompted the reevaluation of older antibiotics
such as the polymyxins.[2]
[10]
[11]
Polymyxin, a cyclic polypeptide, binds to phospholipids, altering the permeability
and causing damage to the cytoplasmic membrane and leakage of intracellular contents.
Polymyxins are widely distributed in body tissues such as liver, kidneys, heart, and
muscle but do not penetrate into cerebrospinal fluid or synovial fluid or cross the
placenta.[8] Reported toxicities associated with polymyxins include renal insufficiency, acute
tubular necrosis, and neurotoxicity in the form of apnea, seizures, and neuromuscular
blockade.[5]
[6]
[12]
[13]
[14] The mechanism of renal toxicity is partly due to its D-amino acid and fatty acid
component, which can increase membrane permeability resulting in an increased influx
of cations, anions, and water, leading to cell swelling and lysis.[5] Renal toxicity has been reported in up to 11% of cases but is considered to be dose-dependent
with previous reports at considerably higher doses used than currently recommended.[5]
[14] Recent data on polymyxin-induced toxicity in patients without cystic fibrosis has
shown lower and less severe toxicity.[5]
[12] The proposed mechanisms of CMS neurotoxicity include a noncompetitive myoneuronal
presynaptic blockade of acetylcholine release and hypocalcemia-induced prolongation
of depolarization. Reported contributing factors to neurotoxicity have included high
doses of CMS, hypoxia, hypocalcemia, and renal disease.[5]
Dosing of CMS in neonates or pediatric patients has varied widely due to the lack
of published pharmacokinetic data in this population. Our patient developed signs
of toxicity associated with use of intravenous CMS with a Naranjo score of 6 for adverse
drug reaction assessment (defined as probable).[15]
Although our patient's renal function improved with dose adjustments, there are no
published studies or recommendations for dosing in ELBW neonates. We suspect that
renal compromise induced during CMS treatment was due to extreme prematurity, immature
kidneys, and lack of data regarding dosing in the ELBW neonate.
Recent advances in neonatal care have improved the survival and outcomes of ELBW infants.
However, infection-related causes of death remain to be a significant issue. Emerging
MDR organisms and lack of available drugs to combat these infections has led to the
increase in complications.[16] This case report highlights a 23-week gestational-age neonate with MDR-Ab pneumonia
who appeared to respond to CMS therapy but who developed suspected CMS-associated
nephrotoxicity and neurotoxicity. Due to the paucity of pharmacokinetic data in the
neonatal population, toxicities associated with polymyxins must be closely monitored.
Further studies in neonates are urgently needed to determine population pharmacokinetics,
pharmacodynamics, and efficacy of CMS in this critically ill population.
