Addressing Neonatal CNS Infections: Case Report of Ceftaroline Therapy in Preterm Infant With Ventriculosubgaleal Shunt

Final diagnosis
Methicillin-resistant Staphylococcus epidermidis shunt-associated ventriculitis in a male neonate.

Clinical Course
A male neonate, born prematurely at 26 weeks' gestation at hospital 1, experienced significant complications early in life. By day 8, a head ultrasound revealed a grade 3 intraventricular hemorrhage. On day 19, he developed bacteremia caused by group B Streptococcus agalactiae, with head ultrasound findings suggestive of possible ventriculitis. The infection was managed with a 4-week course of penicillin. Despite receiving this therapy, the neonate’s hydrocephalus progressed, necessitating therapeutic transfontanelle taps. Due to worsening hydrocephalus, a ventriculosubgaleal shunt was inserted on day 38.

The patient’s course became complicated on day 56 by a cerebrospinal fluid (CSF) leak at the site of the subgaleal shunt, prompting a 48-hour course of cefepime and vancomycin; these were discontinued following negative CSF culture results. The subgaleal fluid collection was subsequently addressed with serial lumbar punctures. As illustrated in the FIGURE, critical clinical events unfolded over the subsequent weeks. On day 66, the patient’s condition deteriorated as he developed hypoxic hypercarbic respiratory failure, requiring intubation. Vancomycin and cefepime were reintroduced, and CSF analysis showed elevated white blood cell count, high protein levels, and low glucose level, though Gram stain result was negative. CSF culture results were positive for S epidermidis within 24 hours, revealing resistance to oxacillin and trimethoprim/sulfamethoxazole but susceptibility to rifampin.

Notably, the vancomycin minimum inhibitory concentration (MIC) was 2 µg/mL per the VITEK 2 system (bioMérieux), whereas ceftaroline’s MIC was measured at 0.5 mg/L via ETEST (bioMérieux). Although official MIC break points for ceftaroline in coagulase-negative staphylococci are not available, findings from studies indicate a MIC inhibiting 50% of bacterial isolates of 0.25 and MIC inhibiting 90% of bacterial isolates of 0.5 for ceftaroline against these isolates. After a low vancomycin trough level of 3.6 µg/mL was recorded following the fourth dose, vancomycin dosing was adjusted. When a repeat CSF culture yielded positive results for S epidermidis on day 68, ceftaroline (10 mg/kg/dose intravenously every 8 hours) and rifampin were added to the vancomycin regimen. The use of ceftaroline aimed to bridge the treatment gap as vancomycin levels remained subtherapeutic, allowing first-line therapy to continue without introducing potential antagonism or medications with uncertain central nervous system (CNS) dosing or safety profiles for neonates, such as linezolid or daptomycin. Subsequently, the patient was transferred to hospital 2 for surgical intervention.

At hospital 2, the patient’s therapy with vancomycin, rifampin, and ceftaroline was continued and the infected shunt was removed on day 70. An external ventricular drain (EVD) was placed, and both CSF and shunt tip cultures returned with negative results. Consequently, vancomycin and rifampin were discontinued on day 73 and ceftaroline therapy continued through day 83. At this point, ceftaroline was stopped in favor of cefazolin for EVD prophylaxis. In total, the patient’s antibiotic course included an initial 2-day treatment with vancomycin and cefepime followed by 7 days of vancomycin, ceftaroline, and rifampin and then 9 days of ceftaroline monotherapy. On day 87, vancomycin and ceftazidime were reintroduced due to an elevated CSF white blood cell count, but when CSF culture results remained negative on day 89, the EVD was removed and a right-sided ventriculosubgaleal shunt was inserted. Further complications included shunt migration, which necessitated removal and placement of a ventriculoperitoneal shunt on day 97. Throughout his hospital stay, the patient maintained clinical stability without any adverse drug reactions and was discharged to an inpatient rehabilitation facility on day 116.

Discussion
Organism Coverage Approved in 2010 by the US Food and Drug Administration, ceftaroline is a fifth-generation cephalosporin indicated for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia (CAP). Broadspectrum coverage includes the following gram-positive and -negative microorganisms: Staphylococcus aureus (including methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, S agalactiae, Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca. Oftentimes, it’s used off label for a wide spectrum of indications from nosocomial pneumonia to meningitis due to the broad scope of activity.^1,2 A major contributing factor to ceftaroline’s effectiveness against methicillin-resistant strains is its high affinity to the extra penicillinbinding protein PBP2a. Gene expression leading to the high expression of this protein has been associated with the proliferation of resistant strains that earliergeneration β-lactams and cephalosporins have been unable to inhibit.

Pharmacokinetics/Pharmacodynamics
Ceftaroline fosamil is the water-soluble prodrug of ceftaroline that is converted to its bioactive form through phosphatase enzymatic metabolism. This fifth-generation cephalosporin exhibits linear pharmacokinetics, where dose-dependent increases in maximal plasma concentrations yield increased drug exposure. Findings from repeated drug dose studies have shown no drug accumulation in adult patients with healthy renal function through a 14-day trial period.² However, dosing adjustments may be warranted in patients with reduced creatinine clearances of 50 mL/min or less.³ Ceftaroline has no cytochrome induction or inhibition, which reduces the risk of major drug-drug interactions. The largest pharmacodynamic predictor for ceftaroline is the percentage of serumfree drug concentrations above the MIC (%fT > MIC). Within pediatric patients, a dosing regimen of 8 mg/kg every 8 hours is recommended for patients older than 2 months but younger than 2 years. For patients 2 years or older, the dosing regimen is 12 mg/kg every 8 hours for patients with weight less than or equal to 3v3 kg and 400 to 600 mg every 8 to 12 hours for patients with weight greater than 33 kg.⁴ Currently approved regimens are generally predicted to have time-dependent target attainment for the majority of pediatric patients. However, in special cases, such as patients diagnosed with cystic fibrosis, higher clearances and reduced serum drug concentrations were reported. Despite observed suboptimal serum drug concentrations, patients were reported to have clinically improved outcomes.⁴ More ongoing pharmacokinetic studies are needed to optimize dosing in these special cases, which include osteomyelitis and CNS infections.

Adverse Effects
The most common adverse effects associated with ceftaroline are rash/ pruritus, gastrointestinal effects (nausea, vomiting, or diarrhea), and fever. Some serious adverse effects are incidences of Clostridioides difficile diarrhea as well as myelosuppression (reversible via granulocyte colony-stimulating factor administration). Additionally, it is important to note the occurrence of warm autoimmune hemolytic anemia when ceftaroline is administered concomitantly with vancomycin.⁵ Some laboratory abnormalities associated with ceftaroline are hepatotoxicity, elevated levels of aspartate aminotransferase/ alanine aminotransferase, and elevated creatinine levels that resolve upon discontinuation of ceftaroline.

Adjunctive Therapies and Outcomes
The current standard of care in treating bacterial methicillin-resistant S aureus (MRSA) infections is source control followed up by initiation of appropriate antibiotics. Vancomycin, linezolid, and daptomycin are among the few antibiotics with a spectrum of activity against methicillin-resistant Staphylococcus spp.⁶ Treatment outcomes were similar across studies, with improvement in status clinically and microbiologically. In line with the current standard of care, most studies to date use ceftaroline as salvage therapy when treatment failure occurs, with a combination of source control and other first-line antibiotics. This precludes providers from ascertaining a definitive conclusion regarding ceftaroline’s role in the management of MRSA infections. However, further data and research could provide a better insight on the trend toward sustained infection resolution upon the addition of ceftaroline.

References

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2. Teflaro. Prescribing information. Allergan; 2016.
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4.Varada NL, Sakoulas G, Lei LR, Chua J. Agranulocytosis with ceftaroline high-dose monotherapy or combination therapy with clindamycin. Pharmacotherapy. 2015;35(6):608-612. doi:10.1002/phar.1596
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