Table 5.

Studies With Outcome Data of Fluoroquinolone-Associated Musculoskeletal Events in Children (Excluding Neonates)

First Author and Reference	Study Design	No. Treated With FLQ/Total	Age	Indication	FLQ	Duration of FLQ Exposure	Duration of Follow-Up	Incidence of FLQ-Associated MSK Event	Description of Events
Schaad 198775	Retrospective observational study	11	0.3–9.6 years	Urinary tract infections (UTI)	Nalidixic acid	9–600 days	3–12 years	No difference with comparator group	Episodes of arthralgia were judged to have no relation to the drugs.
Rumler 198774	Retrospective study	207/408	1–7.2 years, mean 6.5 years	Chronic UTI	Nalidixic acid	27–1689 days, mean 168 days	10 years	0%	No adverse effects to hip or knee joints.
Adam 198972	Retrospective study	50/100	0.1–11 years, mean 4.8 years	Unknown	Nalidixic acid	10–815 days, mean 118 days	2 years	0%	Neither group showed evidence of joint damage confirmed by radiographic imaging.
Kuhn 1990108	Retrospective study	396	<18 years	Cystic fibrosis (CF)	Ciprofloxacin	5–48 days, mean 9.2 days	Unknown	2.5%	Reversible arthralgia, all tolerated subsequent courses with FLQ.
Schaad 199278	Prospective review	18	6–24 years	CF exacerbation	Ciprofloxacin	90 days	22 months	0%	No evidence of arthropathies or joint abnormalities confirmed by radiological and MRI studies.
Danisovicova 1994109	Prospective observational study	14/29	4–18 years	CF-related infections	Ciprofloxacin Ofloxacin	4–28 days 1	week–16 months	43%	Transient arthralgia. Changes on MRI were seen in both groups at high rates.
Nuutinen 199473	Controlled follow-up	78	<15 years	Recurrent UTI	Nalidixic acid	6–570 days, mean 86 days	14.8–24.7 years, mean 19.6 years	No difference with comparator group	No growth disturbances were found.
Pradhan 199566	Case series	58	8 months–13 years	Fever ≥7 days, Salmonella typhi infection	Ciprofloxacin	9–16 days	10–15 days to 37 months	0%	No evidence of joint swellings, arthralgia or restriction of movements.
Bethell 1996110	Prospective cohort study	326/549	1–14 years	Typhoid fever	Ciprofloxacin Ofloxacin	3–7 days	2 years	0%	No evidence of acute joint toxicity. Height velocity was similar to control group at end of follow-up.
Richard 199777	Randomized, controlled trial	55/108	5–17 years	Bronchopulmonary infections, CF	Ciprofloxacin	14 days	20–30 days	No difference with comparator group	Arthralgia and extremity pain.
Church 1997111	Prospective, randomized trial	41/84	5–17 years	CF exacerbation	Ciprofloxacin	Median 13 days	14–28 days	No difference with comparator group	Arthralgia of mild to moderate severity, majority resolved without intervention.
Jick 1997112	Retrospective study	1733	<17 years	Variety of infections	Ciprofloxacin	Unknown	45 days	0%	No new cases of acute arthritis or joint toxicity.
Hampel 199739	Safety report	1795	<17 years	Compassionate use	Ciprofloxacin	1–303 days	Unknown	1.50%	Mild to moderate arthralgia, typically self-resolving.
Salam 1998113	Randomized, controlled trial	71/143	2–15 years	Shigellosis	Ciprofloxacin	5 days	180 days	18%, no difference with comparator group	Arthralgia, no patients had signs of arthritis.
Leibovitz 200027	Randomized, controlled trial	95/201	6 months–10 years	Acute invasive diarrhea	Ciprofloxacin	3 days	21 ± 5 days	1%	One patient developed bilateral knee arthralgia within hours of treatment, but subsided without intervention after a few hours. Therapy was not discontinued.
Saez-Llorens 200236	Randomized trial	108/203	3–12 years	Bacterial meningitis	Trovafloxacin	5–14 days	6–12 months	No difference with comparator group	Transient arthralgia and joint abnormalities. MRI in patient with joint inflammation negative for arthropathy, later resolved.
Yee 2002114	Observational	7897	<19 years	Variety of infections	Ofloxacin, Levofloxacin, Ciprofloxacin	Unknown	60 days	50 verified cases (<1%)	Most frequently involved the joint, tendon, cartilage and gait disorder.
Zimbabwe BSADSG 2002115	Randomized, controlled trial	253	1–12 years	Shigella	Ciprofloxacin	3–5 days	14 days	3.5%	Mild arthralgia with normal joint function at follow-up.
Chalumeau 200340	Prospective, comparative cohort study	264/525	<19 years	Variety of infections	Ciprofloxacin Ofloxacin Pefloxacin	1–327 days	15 days	3.8% vs 0.4% (greater than comparator group)	Transient arthralgia of large joints or myalgia; no tendinopathy was observed.
Ciprofloxacin Package Insert 200523	Prospective, comparative study	335/684	1–17 years	Complicated UTIs and pyelonephrtitis	Ciprofloxacin	10–21 days	1 year	13.7% vs 9.5% (statistically greater than comparator group)	Mild to moderate arthralgia, typically self-resolving within 30 days of end of treatment.
Sher 2005116	Randomized, comparative study	176/354	6 months–7 years	Otitis media (AOM)	Gatifloxacin	10 days	12 months	0%	No evidence of abnormal joint or gait findings.
Pichichero 200588	Review of data from clinical trials	867	6 months–7 ears	AOM	Gatifloxacin	10 days	12 months (n = 671)	No difference with comparator group	Transient arthralgia, self-resolving. No evidenceof arthropathy.
Bradley 200728	Open-label, active-comparator, non-inferiority trial	405/539	6 months–16 years	Community acquired pneumonia (CAP)	Levofloxacin	10 days	25–35 days	No difference with comparator group	Arthralgia and myalgia.
Noel 200782	Database review of three clinical trials	2233	6 months–16 years	CAP or AOM	Levofloxacin	7–14 days	1 year	3.4% vs 1.8% (statistically greater than comparator group)	Myalgia, arthralgia, pathologic fracture, arthropathy, and pain in extremity. Incidence appeared to increase over time.
Pinon 201084	Case series	2	11,23 months	Multidrug-resistant tuberculosis (TB)	Moxifloxacin	Unknown	18 months	0%	No evidence of adverse effects.
Chauny 201285	Case series	6	9 months–14 years	TB	Moxifloxacin, Levofloxacin	1–16 months	Unknown	2 patients	Patient 1 had polyarthritis 1 month after starting therapy, which resolved after stopping. Patient 2 had arthralgia after 4 days, but symptoms spontaneously resolved while on treatment.
Garazzino 201486	Case series	9	6 months–13 years	Pulmonary TB	Moxifloxacin	3–13.4 months	0–36 months	1 patient	One case of ankle arthritis after 3 months of therapy that spontaneously resolved after discontinuation.
Bradley 201483	Follow-up safety study	124/207	6 months–16 years	CAP or AOM	Levofloxacin	7–14 days	5 years	<1%	Transient arthralgia of knee and elbow, synovitis of hip.

^aFLQ, fluoroquinolone; MSK, musculoskeletal.