Use of linezolid in pediatrics: a critical review☆

Introduction 

Linezolid is a synthetic antibacterial agent of the oxazolidinone class with in vitro activity against aerobic Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (MRCoNS), vancomycin-resistant enterococci (VRE), penicillin-resistant Streptococcus pneumoniae (PRSP), and other drug-resistant Gram-positive bacteria.1, 2 It is chemically unrelated to other antibacterial agents and selectively inhibits bacterial protein synthesis through binding to domain V of the 23S rRNA on the bacterial 50S ribosomal subunit, and prevents the formation of a functional 70S-initiation complex, an essential component of the translation process. Due to this unique mechanism of action, the development of cross-resistance with other antibacterial agents is difficult. Linezolid has a predominantly bacteriostatic action rather than a bactericidal effect. In addition, it has a good oral bioavailability, and parenteral therapy can be switched to oral therapy while treating serious infections.

An increasing incidence of serious infections due to resistant Gram-positive bacteria in children has become particularly evident in recent years in neonatal, pediatric intensive care, and hematology/oncology units. Resistant phenotype spread has become a difficult therapeutic problem and linezolid appears to be a very promising alternative for the treatment of resistant pathogens.3 The indications for administration of linezolid to children so far include the treatment of VRE, nosocomial and community-acquired pneumonia due to MRSA or PRSP, and complicated skin/soft tissue infections due to MRSA and MRCoNS.2, 3 While linezolid use in the pediatric population is increasing, information about its use mostly derives from adult studies, a few studies in children, and some case reports; in particular there are very few data available in the neonatal population. The aim of this comprehensive review was to summarize all the data available in the English language literature regarding the effectiveness and safety of linezolid use for its approved and off-label indications in children.

Literature review and methods 

Articles on linezolid therapy in children, published in the English language literature, were retrieved by use of the term ‘linezolid’ as either a keyword or MeSH (medical subject heading) with the limitation ‘all child: 0–18 years’ in searches of the PubMed bibliographic database (US National Library of Medicine, Bethesda, MD) from January 2001 to August 2008. The references cited in the above articles were screened for additional cases. Articles were stratified into three categories: clinical trials, case series (if they had at least two pediatric cases), and case reports.

Results 

A total of 133 articles were found in PubMed. Additional cases screened in the references cited in these articles had already been identified in the first 133 articles; thus, no further cases were added. From these 133 articles, 103 were excluded based on the exclusion criteria detailed above. Specifically, 30 articles were pharmacokinetic/pharmacodynamic studies, 24 were reviews, 14 were studies with patients >18 years of age, 13 were clinical trials with no specific data for children or analyzing the same patient data, 13 were in languages other than English, and nine were excluded due to no original data. Based on the inclusion criteria, a total of 30 articles were studied and analyzed; 18 articles were case reports, nine were case series, and three were clinical trials.

In these 30 articles, a total of 597 children were reported as having received linezolid; 529 children (263 males) with ages ranging from 0 to 17 years were found in clinical trials; 50 children with an average age of 5.8 years (ranging from 0 to 17 years) were found in case series; and 18 children (10 males) with a median age of 7.8 years (ranging from 0 to 18 years) were found in case reports (Table 1).

Table 1. Analysis of the findings of clinical trials, case series and case reports

	Clinical trials (N=529)
	Age range, (n)	0–1 year (77), 1–17 years (452)
	Sex	M/F: 263/266
	Case series (N=50)
	Age average (range)	5.8 years (0–17 years)
	Primary disease	12/28 without, 5/28 hydrocephalus, 2/28 prematurity, 2/28 CGD, 2/28 hyper-IgE syndrome, 2/28 congenital heart disease, 2/28 trauma, 1/28 leukemia; NR in 22
	Microorganisms	18 MRSA, 13 VRE, 6 CoNS, 3 Enterococcus spp, 2 Nocardia spp, 1 MSSA, NR in 7
	Type of infection	15 bone infections (6 with bacteremia), 7 CNS infections, 8 pneumonia (including 1 with sepsis, 1 pyopneumothorax, 2 tracheitis), 5 neutropenic fever, 4 bacteremia, 3 endocarditis (1 with urinary tract infection), 3 peritoneal abscess, 2 skin infections, 1 urinary tract infection, 1 necrotizing enterocolitis, NR in 1
	Antibiotics given before linezolid	Yes=32; no=18
	Linezolid dose and route of administration	42 appropriate dose, 1 inappropriate dose, NR in 2; 30mg/kg/day continuous intravenous infusion in 2, 400mg/bid po in 1, 15mg/kg/day bid po in 1, 22.5mg/kg/day bid po in 1.
	Linezolid duration (range)	48.3 days (7–365 days)
	Linezolid adverse effects	8 dermatological–hematological–hepatic adverse effects, 2 anemia, 2 possible drug interactions due to MAOI activity, 1 rash, 1 diarrhea, none in 12, NR in 24
	Adjunctive therapy	Yes=15, no=13, NR in 22
	Other antibiotics given with linezolid	Yes=15, no=18, NR in 17
	Outcome	31 survival, 5 failure, 5 undetermined, NR in 9
	Case reports (N=18)
	Age mean (range)	7.84 years (0–18 years)
	Sex	M/F: 10/8
	Primary disease	4 prematurity, 3 without, 2 transplantation, 2 trauma, 2 cystic fibrosis, 1 congenital heart disease, 1 hydrocephalus, 1 HIV, 1 single cell anemia, 1 TB
	Microorganism	4 MRSA, 2 MRSE, 3 VRE, 1 Staphylococcus capitis, 1 Enterococcus faecalis, 1 Gemella haemolysans, 1 Mycobacterium fortuitum, 1 Mycobacterium abscessus, 1 XDR-MTB, 1 Nocardia farcinica, 2 unspecified
	Type of infection	8 CNS infections (3 VP-shunt, 2 brain abscesses, 2 meningitis (± ventriculitis), 1 ventriculitis), 4 bacteremia (± endocarditis), 3 skin/soft tissue infections (complicated or not), 2 pneumonia, 1 bone infection
	Antibiotics before linezolid	Yes=13, no=3, NR in 2
	Reason to start linezolid	7 in vitro data, 3 intolerance, 3 refractory to current therapy, 3 initial therapy, 1 bioavailability, 1 in vitro data + intolerance
	Linezolid dose and route of administration	11 appropriate dose, 4 inappropriate dose, NR in 2; 15mg/kg/bid in 1
	Linezolid duration, average (range)	122 days (10–657 days)
	Linezolid adverse effects	Anemia, pancytopenia, lactic acidosis, optic neuropathy, serotonin syndrome, discoloration of teeth
	Linezolid resistance	1/18
	Adjunctive therapy	5/18 (VP shunt, removal of VP shunt, surgical drainage, ventriculostomy)
	Other antibiotics with linezolid	Yes=13, no=3, NR in 2
	Outcome	15 survival, 3 failure

M, male; F, female; CoNS, coagulase-negative staphylococci; MRSA, methicillin-resistant Staphylococcus aureus; MRSE, methicillin-resistant Staphylococcus epidermidis; MSSA, methicillin-sensitive Staphylococcus aureus; VRE, vancomycin-resistant enterococci; XDR-MTB, extensively drug-resistant Mycobacterium tuberculosis; CGD, chronic granulomatous disease; CNS, central nervous system; TB, tuberculosis; VP, ventriculoperitoneal; HIV, human immunodeficiency virus; MAOI, monoamine oxidase inhibitor; bid, twice daily; po, per os; NR, not reported.

Clinical trials 

A total of three clinical trials available in the literature were studied, including 529 children (263 males/266 females) with ages ranging from 0 to 17 years. The clinical trials are presented in Table 2.

Table 2. Clinical trials available in the literature

	Ref./study type	No of patients, age, sex	Exclusion criteria	Organism	Type of infection	LNZ dose	LNZ duration	LNZ adverse effects	LNZ resistance	Adjunctive therapy	Clinical/ microbiological efficacy
	4/efficacy study	17 pts: 12–24m; 47 pts: 2–6 y; 2 pts: >6 y; 36M/30F	Lung abscess, seizures, absolute neutrophil count <500/μl or hemoglobin <9g/dl and other standard exclusion criteria	MRSA, Streptococcus pneumoniae, PRSP, group A streptococci	Pneumonia	10mg/kg/d tid iv and 10mg/kg/d bid po	Range 6–41 d; 58 pts >9 d	Fever, rash, vomiting, abdominal pain, neutropenia, eosinophilia, ALT elevation	N	Chest tubes	Clinical: S: 61; F: 1; I: 4
											Microbiological: all with S. pneumoniae and group A streptococci were cured
	2/RCCT	43 pts: 0–90 d; 34 pts: 91 d–<1 y; 88 pts: 1–4 y; 50 pts: 5–11 y; 117M/98F	Pulmonary conditions (CF) or inflammatory skin conditions (superinfected eczema or atopic dermatitis), decubitus or ischemic ulcers, necrotizing fasciitis, gas gangrene, burns involving >20% of total body surface, endocarditis, skeletal infections, CNS infections, and other standard exclusion criteria	Staphylococcus aureus, MRSA, Streptococcus pyogenes, S. pneumoniae, CoNS, Enterococcus faecium, vancomycin-resistant Enterococcus faecalis	Nosocomial pneumonia, skin/ complicated skin structure infections, catheter-related bacteremia, bacteremia of unknown source, other infections	10mg/kg/d 3 d iv and 10mg/kg/d po 3 d	Range 10–28 d	Diarrhea, vomiting, thrombocytopenia, loose stools, rash, nausea, anemia, eosinophilia, oral candidiasis, fever, red man syndrome, pruritus	N	N	Clinical: S: 135/150
											Microbiological: S: 82/93
	6/RCCT	146 pts: 5–11 y; 102 pts: 12–17 y; 110M/138F	Chronic inflammatory skin conditions (superinfected eczema), decubitus and ischemic ulcers, necrotizing fasciitis, gas gangrene, burns involving >20% of total body surface, orbital–buccal–facial cellulitis, endocarditis, osteomyelitis/septic arthritis, CNS infections, leukemia, HIV patients with CD4 <200 cells/mm3 and other standard exclusion criteria	MSSA, MRSA, S. pyogenes, Streptococcus agalactiae, Streptococcus dysgalacticae	Skin and soft tissue infection	10mg/kg/d 2 d, 600mg bid po	Range 10–21 d	Diarrhea, fever, headache, vomiting, cough, nausea, abdominal pain	N	N	Clinical: S: 201; F: 20; I: 3
											Microbiological: S: 142; F: 15; I: 2

LNZ, linezolid; RCCT, randomized comparator controlled trial; CF, cystic fibrosis; CNS, central nervous system; HIV, human immunodeficiency virus; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus; PRSP, penicillin-resistant Streptococcus pneumoniae; CoNS, coagulase-negative staphylococci; ALT, alanine aminotransferase; pts, patients; y, years; m, months; d, days; M, male; F, female; po, per os; iv, intravenous; bid, twice daily; tid, three times daily; N, no; S, survival; F, failure; I, indeterminate.

The first reported clinical trial of linezolid was a non-comparator controlled phase II, open label multicenter study.4 This study enrolled 78 children aged between 1 and 17 years who had been admitted to the hospital with community-acquired pneumonia. Sixty-six children completed treatment that consisted of intravenous linezolid followed by oral linezolid. The mean total duration of intravenous and oral administration was 12.2±6.2 days. Pathogens isolated from blood or pleural fluid cultures were S. pneumoniae including PRSP strains, group A streptococci, and MRSA. At the follow-up visit 7–14 days after the last dose of linezolid, 92.4% of patients were cured, including all the patients with proven pneumococcal pneumonia; one failed and four were considered indeterminate.

The second reported clinical trial was a randomized, open label, comparator controlled, multi-center trial of linezolid versus vancomycin for the treatment of resistant Gram-positive infections in children.2 This study enrolled 321 children from birth to 4 years of age, diagnosed with nosocomial pneumonia, complicated skin or skin structure infections, catheter-related bacteremia, bacteremia of unknown source, or other infections caused by Gram-positive bacteria. A total of 215 children had received linezolid intravenously followed by oral linezolid. Treatment lasted for 10–28 days and clinical cure was achieved in 79% and 89% for linezolid in intent-to-treat and clinically evaluable patients, respectively. Pathogen eradication rates in microbiologically evaluable patients were 95% for methicillin-sensitive S. aureus (MSSA), 88% for MRSA, and 85% for MRCoNS.

In a separate analysis of the neonatal population that was enrolled in this study, a total of 43 neonates were included in the intent-to-treat group of linezolid.5 Clinical cure was achieved in 78% and the corresponding cure rate in clinically evaluable patients was 84%. Pathogen eradication rates were as follows in the linezolid group: 67% for S. aureus, 88% for coagulase-negative staphylococci (CoNS), and 71% for enterococci. Drug-related adverse effects in neonates were fewer in the linezolid-treated than in the vancomycin-treated neonates. The conclusion of this study was that linezolid was well tolerated and as effective as vancomycin in treating serious Gram-positive infections in both neonates and children.

A third randomized, blinded, comparator controlled, multinational trial compared the efficacy and safety of linezolid and cefadroxil for the treatment of uncomplicated skin/skin structure infections in pediatric patients.6 From the 508 patients enrolled, with ages ranging between 5 and 17 years, 248 received linezolid. Therapy lasted for 10–21 consecutive days with a follow-up visit 10–21 days post-therapy. At follow-up the cure rate was 88.7% for linezolid-treated intent-to-treat patients and 91% for clinically evaluable patients. S. aureus was eradicated in 89.6% of microbiologically evaluable patients. Thus, linezolid was well tolerated and as effective as cefadroxil in treating uncomplicated skin infections in pediatric patients. In addition, linezolid effectively treated infections caused by MSSA, MRSA, and Streptococcus pyogenes.

Case series 

A total of nine case series articles were studied. Specifically, five articles included children with ages ranging from 1 month to 17 years, two articles included neonates, one article was about adverse effects, and one article was about the development of resistance to linezolid. A total of 50 children with an average age of 5.8 years were found in these case series. The analysis of the findings is presented in Table 1 and the case series available in the literature are presented in Table 3.

Table 3. Case series available in the literature

	Ref.	Age/sex	Primary disease	Organism	Type of infection	ABs before LNZ	LNZ dose, route of administration	LNZ duration	LNZ adverse effects	LNZ resistance	Adjunctive therapy	Other ABs with LNZ	Outcome
	7	4 y, F	No underlying disease	Unspecified	Pneumonia	Y	30mg/kg/d continuous iv infusion	20 d	NR	N	Evacuation of pleural effusion	Y	S
		3 y, M	No underlying disease	Unspecified	Pneumonia	Y	30mg/kg/d continuous iv infusion	23 d	NR	N	N	Y	S
	11	6 y, M	CGD	Nocardia	Pneumonia	Y	10mg/kg/d bid iv	40 d	NR	N	N	Y	S
		9 y, M	CGD	Nocardia	Pneumonia	Y	400mg bid po	12m	NR	N	N	Y	S
	15	16 y, NR	Hyper-IgE syndrome	MRSA	SSTI	Y	15mg/kg/d bid po	6m	NR	Y	N	Y	F
		11 y, NR	Hyper-IgE syndrome	MRSA	NR	Y	22.5mg/kg/d bid po	9m	NR	Y	N	Y	F
	12	1.5m, F	Prematurity	Enterococcus faecium (glycopeptide -sensitive)	Pneumonia and sepsis	Y	10mg/kg/d tid iv	16 d	NR	N	N	Y	S
		12 d, F	Prematurity	E. faecium (glycopeptide -sensitive)	Necrotizing enterocolitis	Y	10mg/kg/d tid iv	14 d	NR	N	N	Y	S
	9	3m, M	CHD	MRSA	Bone infection	Y	10mg/kg/d tid iv	33 d	Rash	N	N	N	S
		4.8m, F	CHD and Down syndrome	MRSA	Bone infection	Y	10mg/kg/d tid iv	22 d	NR	N	N	N	S
		7.8 y, M	Trauma, femur fracture	VRE and CoNS	Bone infection	Y	10mg/kg/d tid iv	15 d	NR	N	Y	N	S
		9 y, M	Trauma, fibula fracture	MSSA	Bone infection	Y	10mg/kg/d tid iv	28 d	NR	N	Y	N	S
		2 y, F	No underlying disease	MRSA	Bone infection	Y	10mg/kg/d tid iv	20 d	NR	N	Y	N	S
		2.6 y, M	No underlying disease	MRSA	Bone infection and bacteremia	Y	10mg/kg/d tid iv	15 d	Diarrhea	N	Y	N	S
		6.5 y, M	No underlying disease	MRSA	Bone infection	Y	10mg/kg/d tid iv	36 d	Anemia	N	N	N	F
		9.2 y, F	No underlying disease	MRSA	Bone infection and bacteremia	Y	10mg/kg/d tid iv	18 d	NR	N	Y	N	S
		9.5 y, M	No underlying disease	MRSA	Bone infection	Y	10mg/kg/d tid iv	32 d	NR	N	Y	N	S
		11.4 y, F	No underlying disease	MRSA	Bone infection and bacteremia	Y	10mg/kg/d tid iv	32 d	Anemia	N	Y	N	F
		11.8 y, M	No underlying disease	MRSA	Bone infection and bacteremia	Y	10mg/kg/d tid iv	9 d	NR	N	N	N	S
		12.6 y, F	No underlying disease	MRSA	Bone infection and bacteremia	Y	10mg/kg/d tid iv	15 d	NR	N	Y	N	S
		14.1 y, M	No underlying disease	MRSA	Bone infection and bacteremia	Y	10mg/kg/d tid iv	20 d	NR	N	Y	N	S
	10	<15 y, NRa	NRb	Vancomycin-resistant E. faecium	Bone infection	N	NRc	NRd	NRe	N	NR	NR	S
		<15 y, NRa	NRb	Vancomycin-resistant E. faecium	Peritoneal abscess	N	NRc	NRd	NRe	N	NR	NR	F
		<15 y, NRa	NRb	Vancomycin-resistant E. faecium	Urinary tract infection	N	NRc	NRd	NRe	N	NR	NR	S
		<15 y, NRa	NRb	Vancomycin-resistant E. faecium	Abdominal collection	N	NRc	NRd	NRe	N	NR	NR	S
		<15 y, NRa	NRb	Vancomycin-resistant E. faecium	Endocarditis and urinary tract infection	N	NRc	NRd	NRe	N	NR	NR	S
		<15 y, NRa	NRb	Vancomycin-resistant Enterococcus faecalis	Pyopneumothorax	N	NRc	NRd	NRe	N	NR	NR	S
		<15 y, NRa	NRb	None	Neutropenic fever BMT (VRE colonization)	N	NRc	NRd	NRe	N	NR	NR	Uh
		<15 y, NRa	NRb	None	Neutropenic fever BMT (VRE colonization)	N	NRc	NRd	NRe	N	NR	NR	Uh
		<15 y, NRa	NRb	Vancomycin-resistant E. faecium	Intraabdominal (subphrenic) abscess	N	NRc	NRd	NRe	N	NR	NR	S
		<15 y, NRa	NRb	Vancomycin-resistant E. faecium	Bacteremia	N	NRc	NRd	NRe	N	NR	NR	S
		<15 y, NRa	NRb	Vancomycin-resistant E. faecium	Catheter-associated bacteremia	N	NRc	NRd	NRe	N	NR	NR	S
		<15 y, NRa	NRb	No enterococci	Neutropenic fever BMT (VRE colonization)	N	NRc	NRd	NRe	N	NR	NR	Uh
		<15 y, NRa	NRb	No enterococci	Neutropenic fever BMT (VRE colonization)	N	NRc	NRd	NRe	N	NR	NR	Uh
		<15 y, NRa	NRb	Vancomycin-resistant E. faecium	Burn patient	N	NRc	NRd	NRe	N	NR	NR	S
		<15 y, NRa	NRb	Vancomycin-resistant E. faecium	Neutropenic fever BMT (VRE colonization)	N	NRc	NRd	NRe	N	NR	NR	Uh
	8	1.5m, NR	NR	Staphylococcus epidermidis	Endocarditis	Y	10mg/kg/d tid iv	6 w	NR	NR	NR	Y	NR
		2m, NR	NR	S. epidermidis	Endocarditis	Y	10mg/kg/d tid iv	6 w	NR	NR	NR	Y	NR
		11.5m, NR	NR	MRSA	Tracheitis	Y	10mg/kg/d tid iv	10 d	NR	NR	NR	N	NR
		5m, NR	NR	MRSA	CNS infection and cellulitis	Y	10mg/kg/d tid iv	7 d	NR	NR	NR	N	NR
		8m, NR	NR	MRSA	CNS infection	Y	10mg/kg/d tid iv	12 d	NR	NR	NR	N	NR
		6m, NR	NR	MRSA	Tracheitis and pneumonia	Y	10mg/kg/d tid iv	10 d	NR	NR	NR	N	NR
		12m, NR	NR	MRSA	Bacteremia	Y	10mg/kg/d tid iv	10 d	NR	NR	NR	N	NR
	14	17 y, M	Lymphoblastic leukemia	VRE	Bacteremia	N	NR	NR	Possible drug interactions due to MAOI activity	N	N	NR	NR
		7 y, M	No underlying disease	NR	Bone infection	Y	NR	NR	Possible drug interactions due to MAOI activity	N	N	Y	NR
	13	Neonate, NR	PHH	S. epidermidis	CSF infection	NRf	10mg/kg/d tid iv	NR	N	NR	Subcutaneous tunneled EVD	NRg	S
		Neonate, NR	PHH	S. epidermidis	CSF infection	NRf	10mg/kg/d tid iv	NR	N	NR	Subcutaneous tunneled EVD	NRg	S
		Neonate, NR	PHH	S. epidermidis	CSF infection	NRf	10mg/kg/d tid iv	NR	N	NR	Subcutaneous tunneled EVD	NRg	S
		Neonate, NR	PHH	E. faecalis	CSF infection	NRf	10mg/kg/d tid iv	NR	N	NR	Subcutaneous tunneled EVD	NRg	S
		Neonate, NR	PHH	Staphylococcus haemolyticus	CSF infection	NRf	10mg/kg/d tid iv	NR	N	NR	Subcutaneous tunneled EVD	NRg	S

ABs, antibiotics; LNZ, linezolid; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus; VRE, vancomycin-resistant enterococci; CoNS, coagulase-negative staphylococci; BMT, bone marrow transplantation; CNS, central nervous system; MAOI, monoamine oxidase inhibitor; EVD, external ventricular drainage; SSTI, skin and soft tissue infection; CHD, congenital heart disease; CGD, chronic granulomatous disease; PHH, post-hemorrhagic hydrocephalus; CSF, cerebrospinal fluid; y, years; m, months; w, weeks; d, days; M, male; F, female; po, per os; iv, intravenous; bid, twice daily; tid, three times daily; NR, not reported; Y, yes; N, no; S, survival; F, failure; U, undetermined.

a Average age 7 years old, nine male and six female. b Five transplanted patients (four bone marrow and one liver transplantation), three were undergoing oncological treatment, and six had undergone surgical procedures. c The linezolid doses were correct in 14 cases and incorrect in three by default (0–11 y 10mg/kg/d every 8h and >12 y 600mg/dose every 12h). d 47.1% received linezolid 14–28 d, 23.5% received linezolid <14 d, and 29.4% received linezolid >28 d. e Eight of 15 presented with dermatological, hematological and hepatic adverse effects (rash, neutropenia, leukopenia, thrombocytopenia, elevated transaminases). f Three out of five received antibiotics prior to linezolid. g Four out of five received other antibiotics with linezolid, one out of five received linezolid as monotherapy. h So reported by the author.

Case reports 

A total of 18 case reports were studied, including 10 males and eight females with a median age of 7.8 years, ranging from 0 to 18 years. A further analysis of the findings is presented in Table 1 and case reports available in the literature are presented in Table 4.

Table 4. Case reports available in the literature

	Ref.	Age/sex	Primary disease	Organism	Type of infection	ABs before LNZ	Reason to start LNZ	LNZ dose, route of administration	LNZ duration	LNZ adverse effects	LNZ resistance	Adjunctive therapy	Other ABs with LNZ	Outcome
	20	12.7 y, M	Kidney transplantation	Nocardia farcinica	Brain abscess	Y	Bacterium sensitivity to LNZ (in vitro data)	600mg bid po	NR	Anemia	N	N	Y	S
	17	18 y, F	Trauma	MRSE	CNS shunt infection and bacteremia	Y	Neutropenic episode due to vancomycin (intolerance)	10mg/kg/d tid iv	17 d	NR	N	VP shunt	Y	S
	21	17 m, M	Congenital heart disease	Gemella haemolysans	Meningitis	Y	Antimicrobial susceptibility test (in vitro data)	100mg/kg/d iv	10 d	NR	N	N	Y	S
	27	4 y, F	Cystic fibrosis, short bowel syndrome	MRSE	Bacteremia	Y	Skin rash due to vancomycin and teicoplanin (intolerance)	10mg/kg/d bid iv	20 d	NR	N	N	N	S
	18	4 y, M	Developmental delay-seizure disorder	MRSA	CNS infection (VP shunt infection)	Y	Indeterminately susceptible to vancomycin (in vitro/ refractory)	10mg/kg/d bid iv	NR	NR	N	N	Y	S
	22	1.5 m, F	Prematurity	VRE	Ventriculitis–meningitis	Y	Antimicrobial susceptibility test (in vitro)	10mg/kg/d tid iv	5 w	NR	N	Removal of VP shunt	Y	S
	19	17 y, M	No underlying disease	Unspecified	Brain abscess–sinusitis	Y	Clinical deterioration and CT findings (refractory to current therapy)	10mg/kg/d bid iv	7 w	NR	N	Surgical drainage	Y	S
	23	4 y, F	PHH	Enterococcus faecalis	VP shunt infection	Y	Failure of initial therapy (refractory)	10mg/kg/d tid iv	4 m	NR	N	Ventriculostomy	Y	S
	24	4.5 m, M	Prematurity, tracheostoma, atrial septal defect, extended NICU stay, indwelling CVC, multiple antimicrobials	VRE	Bacteremia and endocarditis	Y	Microorganism susceptibility to LNZ (in vitro data)	15mg/kg/d tid iv	9 w	NR	N	N	Y	S
	29	Infant, M	Prematurity–RDS	Staphylococcus capitis	Sepsis	Y	Persistent S. capitis septicemia (refractory)	NR	21 d	NR	N	N	Y	S
	31	13 y, F	HgbSS anemia	Mycobacterium fortuitum	Bacteremia	N	Initial therapy	NR	2 m	Lactic acidosis	N	N	Y	F
	28	10 y, F	Cystic fibrosis	MRSA	Pneumonia	Y	Initial therapy (repeated and prolonged courses of LNZ)	10mg/kg/d tid iv, 600mg bid po	1.8 y	NR	Y	N	NR	S
	32	6 y, M	No underlying disease	MRSA	Bone infection	NR	Allergic to penicillin and vancomycin (intolerance)	170mg bid po	1 y	Optic neuropathy	N	N	Y	S
	26	4 y, F	Severe burn injuries	Unspecified	Burn injuries	NR	Initial therapy	140mg bid po	NR	Serotonin syndrome	N	N	NR	F
	25	11 y, M	HIV	MRSA	Cellulitis	N	Not permanent intravenous access (bioavailability)	600mg bid po	28 d	Discoloration of teeth	N	N	Y	S
	33	18 y, M	Transplantation (lung)	Mycobacterium abscessus	SSTI	Y	Findings of the antibiogram (in vitro data)	600mg bid po	30 d	Pancytopenia	N	N	Y	S
	16	7 m, M	Prematurity	VRE	CNS infection (ventriculitis)	N	In vitro data	10mg/kg/d tid iv	21 d	None	N	VP shunt removal	N	S
	30	17 y, F	No underlying disease	Mycobacterium tuberculosis	Bilateral pulmonary lesions	Y	Intractable multidrug-resistant tuberculosis	600mg bid po	8 m	None	N	N	Y	F

Abs, antibiotics; LNZ, linezolid; HIV, human immunodeficiency virus; MRSA, methicillin-resistant Staphylococcus aureus; MRSE, methicillin-resistant Staphylococcus epidermidis; VRE, vancomycin-resistant enterococci; PHH, post-hemorrhagic hydrocephalus; RDS, respiratory distress syndrome; SSTI, skin and soft tissue infection; HgbSS, homozygous sickle cell anemia; NICU, neonatal intensive care unit; CVC, central venous catheter; CNS, central nervous system; VP, ventriculoperitoneal; CT, computed tomography; y, years; m, months; w, weeks; d, days; M, male; F, female; po, per os; iv, intravenous; bid, twice daily; tid, three times daily; NR, not reported; Y, yes; N, no; S, survival; F, failure.

CNS and other type bacterial infections 

The most common type of infection in which linezolid has been used is CNS infection. Specifically, three cases have been ventriculoperitoneal (VP)-shunt infections, two meningitis (one with ventriculitis), two brain abscesses, and one ventriculitis.16, 17, 18, 19, 20, 21, 22, 23 Other less common types of infections have been bacteremia (± endocarditis), pneumonia, and skin/soft tissue as well as bone infections.24, 25, 26, 27, 28, 29, 30, 31, 32, 33 The most common isolates against which linezolid has been used are Staphylococcus spp, either MRSA or MRSE, followed by Enterococcus spp, either VRE or E. faecalis.

Unusual pathogens 

While the use of linezolid against Staphylococcus and Enterococcus strains is well established, of interest are case reports about infections due to rare pathogens that linezolid has been able to eradicate. A very interesting and rare case of brain abscesses caused by Nocardia spp in a male kidney transplant recipient aged 12.7 years has been presented.20 The patient suffered from chronic renal failure and developed multiple brain abscesses due to Nocardia farcinica early after kidney transplantation and immunosuppression. The patient was treated with linezolid and his condition rapidly improved with complete regression of the cerebral lesion after a few months.

Another rare case was a 17-month-old boy who suffered from complex congenital heart disease.21 He developed meningitis due to Gemella haemolysans belonging to the family of Streptococcaceae. The isolate was resistant to penicillin, ceftazidime, ceftriaxone, clindamycin, levofloxacin and vancomycin and susceptible to linezolid and chloramphenicol. Intravenous administration of linezolid and chloramphenicol was started and the patient's clinical status progressively improved. A couple of days after initiation of linezolid and chloramphenicol treatment, the patient became afebrile and subsequent CSF cultures were negative. After 10 days of antibiotic treatment, the patient's clinical status was excellent and the inflammation markers returned to normal.

Infections due to mycobacteria 

There are three published case reports on infections caused by Mycobacterium spp in which linezolid was effective. The first case occurred in a 17-year-old female with no apparent underlying disease.30 In the past she had developed bilateral pulmonary lesions due to multidrug-resistant (MDR) Mycobacterium tuberculosis and had been treated five times for a total of 10 years, having received over 14 drugs for MDR M. tuberculosis. Susceptibility testing of the Mycobacterium isolate had shown resistance in eight out of 14 drugs. She received combination therapy with linezolid, and although the patient died after 8 months from severe respiratory failure, cultures were negative after 5 months of linezolid combined treatment.

The second case occurred in a 13-year-old African American female with sickle cell anemia.31 She had a central venous catheter (CVC) and frequent admissions for vaso-occlusive painful episodes. Diagnosis of infection due to Mycobacterium fortuitum was confirmed by cultures from blood and the CVC tip at the time of removal. However, a second blood culture obtained 1 week after catheter removal was also positive. Initial therapy included clarithromycin, linezolid, and doxycycline. Due to resistance to doxycycline and intermediate susceptibility to clarithromycin, antimicrobial therapy was changed to linezolid, ciprofloxacin, and trimethoprim–sulfamethoxazole (TMP/SMX). The last positive culture was obtained 1 week after the catheter removal and initiation of treatment. Afterwards, subsequent cultures were negative, but linezolid was discontinued 2 months later because of the development of lactic acidosis.

A third case occurred in an 18-year-old boy diagnosed with cystic fibrosis with pancreatic, liver, and lung involvement and requiring double lung transplantation.33 One year after transplantation he developed a subcutaneous nodule produced by Mycobacterium abscessus with subsequent hematogenous spread, as well as bronchial and bone marrow involvement. Treatment with ciprofloxacin and linezolid was started on the basis of the susceptibility results. Linezolid was replaced by clarithromycin after 1 month of treatment due to pancytopenia. Two years later, the patient remained asymptomatic with respiratory function parameters in the normal range.

Discussion 

In this study we reviewed the data on linezolid use in neonatal and pediatric patients and we found that it is safe and effective for approved indications, i.e., pneumonia and skin/soft tissue infections, and off-label indications, such as endocarditis and CNS and osteoarticular infections, caused by antibiotic-resistant Gram-positive organisms. In parallel, it offers potentially significant advantages for treating such patients due to its excellent, both intravenous and oral, bio-availability. Additionally, in pediatric patients who are unable to tolerate conventional agents or after treatment failure, linezolid shows great promise for the treatment of multi-resistant Gram-positive organisms. Concurrently with the increase in serious infections in children due to resistant Gram-positive bacteria, linezolid use in pediatrics has expanded and will probably result in a widening of the current linezolid indications.

Linezolid exhibits several characteristics that promote CNS penetration, including low plasma protein binding, neutral charge, low molecular weight, and amphiphilicity. Linezolid penetrates well into the CSF even in the absence of inflammation and this suggests a potential role for linezolid in the management of CNS infections due to resistant Gram-positive organisms in pediatric patients.34 In individuals with non-inflamed meninges, linezolid concentrations in CSF were found to be 70% of plasma concentrations.34 In a pediatric patient with a VP-shunt infection, linezolid reached therapeutic levels in the CSF with a CSF/serum ratio of 1/1.23 In other reports that correlated outcome with CSF linezolid trough levels the findings were: range 1.5–7.0mg/l and CSF/serum ratio 0.8–17.35, 36 The typical minimum inhibitory concentration (MIC) of linezolid for S. aureus is 2mg/l.37 Thus, standard doses of linezolid are usually able to achieve sufficient concentrations in the CSF to yield adequate antibacterial activity. In addition, high CSF penetration may be more clinically significant than its theoretical limitation of bacteriostatic activity. Numerous reports of adult and pediatric patients have documented successful linezolid therapy for CNS infections caused by Gram-positive bacteria.18, 19, 23, 35, 38, 39 Even in preterm neonates, linezolid as a single agent or in combination with other antibiotics has successfully treated ventriculostomy-related CSF infections.13

Besides its high penetration in the CSF, linezolid rapidly penetrates osteoarticular tissues as well as synovial fluid and achieves high levels in these sites, supporting its use for the treatment of osteomyelitis and septic arthritis caused by antibiotic-resistant Gram-positive organisms.40 A study of a single-dose linezolid penetration into bone, fat, and muscle in adult patients, demonstrated rapid penetration into all sites. The mean concentrations achieved at 10 and 30min after infusion were 9.1 and 6.3mg/l in bone, 4.5 and 4.1mg/l in fat, and 10.4 and 12mg/l in muscle, exceeding the MIC for susceptible organisms (≤4mg/l).41 In a pediatric case series with osteoarticular infections due to MRSA, MSSA, E. faecium, and CoNS, linezolid achieved a cure rate of 84.6%.9 Additionally, linezolid appeared to be useful and well tolerated in step-down therapy or compassionate use for pediatric Gram-positive orthopedic infections. In an osteomyelitis series of adults, the compassionate use of linezolid led to clinical cure rates of 70% and 82% in cases with MRSA infections and all-cause infections, respectively, results similar to those of the previous pediatric study.42 In children with bone and/or joint infections, oral therapy with linezolid is a potential alternative to home-based intravenous therapy with a glycopeptide for the completion of antibiotic treatment and it avoids the need for and risks associated with prolonged vascular access.9

Several reports have described patients, mainly adults, suffering from endocarditis, successfully treated with linezolid.8, 24, 43, 44 The most important reason for administering linezolid was previous failure of a more conventional antimicrobial regimen. In addition, it has been suggested that higher doses of linezolid may be necessary to achieve cure in some refractory endocarditis cases. In a review of case reports that enrolled 42 patients with endocarditis treated with linezolid, the outcome was considered to be successful in 79% of patients, including the only child that was enrolled in this review, a preterm infant who had a favorable outcome.44 The use of oral linezolid avoids the need for ongoing intravenous access and can be particularly beneficial in patients with endocarditis in whom an additional therapy for 3 to 4 weeks is required after hospital discharge. Although at present linezolid is not a standard therapy for endocarditis, it can be a reasonable alternative for cases of endocarditis caused by MRSA or multi-resistant enterococci. Further studies are needed to confirm the efficacy of linezolid, to determine treatment duration, and to exclude possible under-reporting of side effects due to prolonged treatment.

Linezolid is bactericidal against streptococci and bacteriostatic against enterococci and staphylococci. It is commonly used against E. faecium or Enterococcus faecalis including VRE strains, S. aureus including MRSA strains, CoNS including MRCoNS strains, and streptococci including PRSP strains.1, 2 However, the clinical efficacy of linezolid has also been demonstrated for less common susceptible isolates such as Nocardia spp and Gemella spp, M. tuberculosis and non-tuberculous mycobacteria.

The principal reason for initiating linezolid therapy in nocardiosis was most commonly a history of, or development of intolerance to TMP–SMX, which is considered as the treatment of choice for infections due to Nocardia spp.11 Until the development of linezolid, the major limitation in the treatment of nocardiosis had been the absence of a second oral antimicrobial agent with activity against all Nocardia spp. Linezolid has an excellent in vitro activity profile against a range of Nocardia spp, but the in vivo data are very limited. However, linezolid has been successfully used for the treatment of infections due to Nocardia asteroides, Nocardia otitidiscaviarum, Nocardia brasiliensis and Nocardia farcinica, in studies including adult patients.11, 20 The MIC50 and the MIC90 for all species other than N. farcinica are 2 and 4mg/l, respectively, and for N. farcinica are both 4mg/l.45 N. farcinica is most often associated with antibiotic resistance and >50% of cases involve disseminated infection. Linezolid would appear to be a valid alternative for the treatment of Nocardia spp infections in cases in which TMP–SMX has failed, where its use is contraindicated, or where a second agent is indicated.11, 20

Linezolid has also been used against Gemella spp infections. Gemella belongs to the family of Streptococcaceae and includes five species, G. haemolysans, Gemella morbillorum, Gemella bergeriae, Gemella sanguinis and Gemella palaticanis.46 Linezolid in vitro data, available only for G. haemolysans and G. morbillorum, have shown an excellent in vitro susceptibility profile with MIC50 of 1mg/l and MIC90 of 2mg/l, for both species.47 There is only one reported case in which linezolid was used for the treatment of Gemella infection; this was a CNS infection due to G. haemolysans in a child, with an excellent outcome.21 Although G. haemolysans isolated from clinical specimens in the past have usually been sensitive to penicillin G and ampicillin, recent data suggest an emerging resistance.21, 48 Prompt appropriate treatment of infections due to Gemella spp can usually lead to a favorable outcome, but due to their increasing resistance, the use of linezolid should be considered.

In recent years, the epidemiology of tuberculosis (TB) has altered due to the emergence of HIV infection and the spread of MDR-TB. Treatment failure of MDR-TB can lead to the generation of intractable or extensively antibiotic-resistant (XDR)-TB strains, which are resistant to isoniazid, rifampin and at least three of the six main classes of second-line drugs.49 In addition, many patients have shown cross-resistance against newer fluoroquinolones, suggesting that previous administration of older fluoroquinolones may have a negative impact on the effectiveness of new compounds.50 This has increased concerns regarding future epidemics of virtually untreatable TB. Linezolid has shown good activity against M. tuberculosis, including resistant strains, and has a MIC90 in the 0.5–1mg/l range, high maximal concentration in serum, and an excellent ability to penetrate into bronchial mucosa and bronchoalveolar lavage fluid. A key pharmacodynamic parameter for M. tuberculosis has been reported to be the area under the curve over a 24-h dosing interval (AUC)24/MIC. This fact along with the slow growth of M. tuberculosis and the high concentration achievable in serum and tissues, can allow daily-half dosage of linezolid to be effective.51 In a case series, all eight patients included showed a durable culture conversion in response to linezolid, suggesting that patients with intractable or XDR-TB may benefit from treatment with daily-half doses of linezolid. A half-dose regimen may reduce the risk of myelosuppression but does not reduce the risk of neurotoxicity.30 In conclusion, although daily-half doses of linezolid have been found effective in patients with intractable or extensive MDR-TB, this dosage regimen has not been found to reduce long-term use-related side effects, such as peripheral and optic neuropathy. In addition, although the limited evidence suggests that linezolid may be considered as a second-line agent for TB, any treatment with linezolid should be weighed against the risks associated with its long-term use.52

Disseminated disease due to non-tuberculous mycobacteria is a growing problem occurring infrequently and almost exclusively in immunocompromised patients. Non-tuberculous mycobacteria, such as M. fortuitum and M. abscessus, are called ‘rapid growers’ because sufficient growth and identification can typically be achieved in the laboratory in 3 to 7 days.53 Linezolid has shown promising results when used as combined treatment with other drugs against antibiotic-resistant non-tuberculous mycobacteria. However, in a sickle cell anemia patient suffering from M. fortuitum infection and in a lung transplant recipient with cystic fibrosis suffering from M. abscessus infection, linezolid treatment was discontinued due to adverse effects.31, 33 Although linezolid is effective in the eradication of non-tuberculous mycobacteria in children suffering from intractable or antibiotic-resistant strains, linezolid therapy should be closely monitored for adverse effects.

Although resistance to linezolid remains rare with rates lower than 0.1%, mutations conferring resistance have been found on the 23S rRNA genes.37, 54 Resistance has typically been associated with prolonged linezolid courses, undrained abscesses, and indwelling devices and has occurred most frequently in enterococci. However, as hospital- and community-acquired MRSA continues to increase, there will likely be increased linezolid use with associated linezolid resistance.15 In addition to staphylococci and enterococci, resistance to linezolid has also developed in other Gram-positive bacteria.54, 55 Linezolid use in children should be limited and this agent should not be considered as a first-line antibiotic, in order to avoid unnecessary expansion of resistance. Any therapy with linezolid should be weighed against the risks of prolonged duration of treatment.

The most common adverse effects of linezolid are diarrhea, loose stools, nausea, vomiting, headache, rash, itching, and fever.56 However, post-marketing surveillance has noted some rare but serious adverse events. Given these rare potentially serious adverse events, the safety profile of linezolid must be well monitored during treatment.56 Physicians must be aware of the symptoms and signs of toxicity so that linezolid can be immediately discontinued if these occur. Although there are no official guidelines for monitoring, regular monitoring of linezolid should include: (1) symptoms and signs of lactic acidosis, which are non-specific, but include nausea, vomiting, mental status changes, tachycardia and hypotension, and possibly regular monitoring of the serum bicarbonate levels; (2) development of cytopenias through blood count monitoring; (3) development of peripheral and optic neuropathy symptoms.

For peripheral neuropathy, regular checks for symptoms such as numbness or tingling and examination for changes in reflex, sensation, and strength can be performed. Baseline ophthalmological assessment for color vision and visual acuity can also be assessed, especially if a long course of treatment is planned. Adverse events of linezolid may be more common when the drug is used for longer than 28 days, which is the treatment length currently approved by the US Food and Drug Administration.3, 56, 57 Although of uncertain significance, linezolid's MAOI activity presents a potential risk of drug interactions with adrenergic and serotonergic agents. Knowledge of its MAOI activity and proper precautions may prevent adverse effects such as serotonin syndrome.14

The emergence of resistant Gram-positive bacteria, such as MRSA, MRCoNS, VRE, and PRSP, as major pediatric pathogens of serious infections, has highlighted limitations in treatment options. Newer agents including linezolid, daptomycin, and quinupristin–dalfopristin are alternatives to vancomycin for the treatment of resistant Gram-positive organisms. Although daptomycin and quinupristin–dalfopristin are approved by the US Food and Drug Administration for the treatment of adults, very few data are available in pediatric patients.

Taking into account that this is a retrospective, multi-source case review study, the possibility of a reporting bias cannot be excluded. This is based on the fact that after the licensing of linezolid, articles on linezolid use in children changed from clinical trials and cases with more favorable outcomes to off-label indication use, adverse effects, and development of resistance studies. The result is an underestimate of the total number of children that have taken linezolid. In addition, our review includes a limited number of case series and reports to clarify the role of linezolid use for off-label indications or against less common organisms in pediatric patients for which additional research is necessary.

In conclusion, linezolid appears to be effective and safe in the treatment of pediatric patients with serious infections for its approved and off-label indications, including pneumonia and endocarditis, as well as skin/soft tissue, CNS and osteoarticular infections caused by antibiotic-resistant Gram-positive organisms. In addition, it has clinical efficacy for less common susceptible isolates such as Nocardia spp, Gemella spp, M. tuberculosis, and non-tuberculous mycobacteria. However, novel indications for linezolid use need to be established in newer studies with an emphasis on adverse effects and the development of resistance.