Linezolid Add-On Rescue Therapy Cured MRSA Necrotizing Pneumonia: a case report in a preterm infant

Necrotizing pneumonia due to Methicillin-Resistant Staphylococcus Aureus (MRSA) is devastating and difficult to treat in preterm infants. We report a case of severe MRSA necrotizing pneumonia in a preterm infant. As an add-on rescue therapy to vancomycin, linezolid rapidly cured this case after the failure of vancomycin plus rifampicin. This rapid cure suggests that adjunctive rather than rescue linezolid may be considered in such cases.


Introduction
Methicillin-Resistant Staphylococcus Aureus (MRSA) was the causative organism in 1.4% of the neonatal late-onset sepsis (LOS) in Arab states in the Gulf region [1]. MRSA colonization is a risk factor for invasive MRSA infections. Preterm infants born at < 32 weeks' gestation or weighing < 1500 grams are at two-fold increased risk of MRSA colonization [2].
Moreover, combining linezolid with vancomycin is controversial as in-vitro studies have shown that linezolid decreased vancomycin activity [24][25][26][27]. Thus, we aimed to report linezolid as an add-on rescue treatment for severe MRSA necrotizing pneumonia in a preterm infant. Hoping this report will increase awareness of newborn infant caregivers on the appropriate use of linezolid for invasive MRSA infections.

Case Report
The patient was a female very preterm newborn infant with a birth weight of 1440 grams. She was born at 30 weeks' gestation by emergency Cesarean section due to maternal pre-eclamptic toxemia. The mother was 26 years old primigravida who received adequate intrapartum antibiotic prophylaxis as she had Group B streptococcus bacteriuria at 22 weeks' gestation. Apgar scores were 5 and 8 at 1 and 5 minutes, respectively. The infant was started on ampicillin and cefotaxime, which were discontinued on the 3 rd day of life (DOL) when her blood culture was reported negative. She required two doses of surfactant and invasive conventional mechanical ventilation (ICMV) for 3 days. The cord screening for glucose-6-phosphate dehydrogenase showed that she is deficient. Her metabolic screen was not remarkable.
On the 8 th DOL, she developed progressive respiratory distress for which she required ICMV again. LOS was entertained, and she was investigated and treated accordingly. The chest X-ray showed a small pneumatocele in the left middle lung zone. Vancomycin and ceftazidime were started empirically. Analysis of the cerebrospinal fluid was normal and its culture as well as the urine culture were sterile. The blood culture on the 8 th DOL grew MRSA sensitive to vancomycin and rifampicin. Vancomycin plus rifampicin combination cleared the bacteremia but failed to treat the progressive necrotizing pneumonia. Repeated trough vancomycin levels were within the therapeutic range. Her respiratory status continued to deteriorate until day 17 post-MRSA necrotizing pneumonia when rifampicin was replaced by intravenous linezolid (10 mg/kg every 8 hours). After that, she showed a rapid, significant improvement; CRP dropped to 49 mg/L and platelets' count normalized three days after adding linezolid. The infant was weaned gradually from the respiratory support and was on room air on day 37 post-MRSA necrotizing pneumonia. Figure 1 summarizes the timeline events and Figure 2 shows serial chest radiological images. Cranial ultrasound scans revealed no evidence of intraventricular hemorrhage. Ophthalmology screening for retinopathy of prematurity was negative. Hearing assessment by otoacoustic emissions was normal bilaterally. The infant had no central line before acquiring MRSA infection.
She was discharged home on 52 nd DOL (37 3/7 postmenstrual weeks). On discharge, she was on room air, feeding orally well, and weighing 2185 grams. A repeated chest X-ray at four months of age was completely normal (Figure 2-C). She had normal growth and development when she was discharged from the high-risk newborn clinic at nine months of age.

Discussion
As an add-on rescue therapy to vancomycin, linezolid rapidly cured severe MRSA necrotizing pneumonia in a preterm infant after the failure of vancomycin plus rifampicin. This rapid cure suggests that adjunctive rather than rescue linezolid needs to be considered in such cases.
During the last two decays, linezolid was the only approved anti-MRSA on infants among the other new antibiotics that have been approved in adults [8]. Linezolid has several advantages over vancomycin, including oral route, less renal toxicity, less sensitivity reaction, and no need for therapeutic drug monitoring [12,14,18]. On the other hand, linezolid is associated with more thrombocytopenia and anemia than vancomycin [8, 18-20, 22, 28]. Thus, it is recommended to monitor platelets and hemoglobin levels during linezolid treatment [18,20]. Pediatric and adult literature have reported the following side effects of linezolid: peripheral and optic neuropathy [11,29]; cataract [28]; hyperlactatemia [19,29,30]; serotonin syndrome [29]; and dental discoloration [31]. It seems that these side effects are transient and cumulative dose-dependent [22,28,29].
Linezolid inhibits bacterial growth by binding to the bacterial 50S ribosomal subunit preventing the formation of the 70S ribosomal complex [8,16,19]. So, linezolid is a bacteriostatic antibiotic, whereas vancomycin and rifampicin are bactericidal antibiotics [8,9,11]. The dogma of bacteriostatic antibiotics antagonize bactericidal antibiotics [32] has been demonstrated by in-vitro studies on combining linezolid with vancomycin [24][25][26][27]. Despite that rifampicin penetrates cells, tissues, and biofilms better than vancomycin [9], vancomycin plus rifampicin failed to treat MRSA necrotizing pneumonia in our case. We have no plausible explanation of why the combination of two bactericidal antibiotics failed whereas a bactericidal plus a bacteriostatic antibiotics succeeded except that tissue penetration of linezolid is better than rifampicin. An in vitro study has demonstrated that linezolid plus rifampicin is more potent than linezolid plus vancomycin [26]. On the other hand, MRSA resistance to linezolid has been reported in Saudi Arabia [33], thus using linezolid needs to be through a stewardship program or individualized after consulting the infectious diseases team [11].
In conclusion, linezolid, as an add-on rescue therapy to vancomycin, rapidly cured severe MRSA necrotizing pneumonia in a preterm infant after the failure of vancomycin plus rifampicin. Proper hand hygiene is the best way to prevent healthcare-associated MRSA infections and, subsequently, improve preterm infants' outcomes.

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Conflicts of interest:
There are no conflicts of interest.