Objective To investigate whether symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is non-inferior to antibiotics in the treatment of uncomplicated lower urinary tract infection (UTI) in women, thus offering an opportunity to reduce antibiotic use in ambulatory care. Design Randomised, double blind, non-inferiority trial. Setting 17 general practices in Switzerland. Participants 253 women with uncomplicated lower UTI were randomly assigned 1:1 to symptomatic treatment with the NSAID diclofenac (n=133) or antibiotic treatment with norfloxacin (n=120). The randomisation sequence was computer generated, stratified by practice, blocked, and concealed using sealed, sequentially numbered drug containers. Main outcome measures The primary outcome was resolution of symptoms at day 3 (72 hours after randomisation and 12 hours after intake of the last study drug). The prespecified principal secondary outcome was the use of any antibiotic (including norfloxacin and fosfomycin as trial drugs) up to day 30. Analysis was by intention to treat. Results 72/133 (54%) women assigned to diclofenac and 96/120 (80%) assigned to norfloxacin experienced symptom resolution at day 3 (risk difference 27%, 95% confidence interval 15% to 38%, P=0.98 for non-inferiority, P<0.001 for superiority). The median time until resolution of symptoms was four days in the diclofenac group and two days in the norfloxacin group. A total of 82 (62%) women in the diclofenac group and 118 (98%) in the norfloxacin group used antibiotics up to day 30 (risk difference 37%, 28% to 46%, P<0.001 for superiority). Six women in the diclofenac group (5%) but none in the norfloxacin group received a clinical diagnosis of pyelonephritis (P=0.03). Conclusion Diclofenac is inferior to norfloxacin for symptom relief of UTI and is likely to be associated with an increased risk of pyelonephritis, even though it reduces antibiotic use in women with uncomplicated lower UTI. Trial registration ClinicalTrials.gov NCT01039545.

Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 M in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats. Pneumococcal meningitis has a high level of mortality (up to 30%), and brain and/or cochlear damage occurs in up to 50% of the survivors (2). Inflammatory mediators, such as tumor necrosis factor alpha (TNF-␣) and matrix metalloproteinases (MMPs), are produced during the host response to bacteria and contribute to the pathophysiology that can ultimately lead to death, brain damage, and hearing impairment (23,26,29,36). The role of cytokines and MMPs in the pathophysiology of the cochlear damage associated with pneumococcal meningitis is still unknown. However, it has been demonstrated that MMPs are constitutively expressed at high levels in the cochlea (8) and that in meningitis pneumococci and polymorphonuclear leukocytes (PMNs) extend from the cerebrospinal fluid (CSF) to the perilymph via the cochlear aqueduct (5).Tetracyclines are bacteriostatic agents with broad-spectrum antimicrobial activity (3). Doxycycline is a semisynthetic, longacting, second-generation tetracycline which is absorbed rapidly and penetrates well into the brain and CSF (48). Doxycycline has been shown to have anti-inflammatory effects that are separate and distinct from its antimicrobial action (13,16,35,43). These effects include the reduction of cytokine release and the inhibition of MMPs (7, 38). Experimental and clinical studies have indicated that treatment with doxycycline may be beneficial in inflammatory diseases associated with excessive MMP activity (7,13,35).In pneumococcal meningitis massive subarachnoid and ventricular space inflammation is triggered by the presence of bacteria in the CSF space (7,1...

Perinatal brain damage is associated not only with hypoxicischemic insults but also with intrauterine inflammation. A combination of antenatal inflammation and asphyxia increases the risk of cerebral palsy Ͼ70 times. The aim of the present study was to determine the effect of intracisternal (i.c.) administration of endotoxin [lipopolysaccharides (LPS)] on subsequent hypoxic-ischemic brain damage in neonatal rats. Seven-day-old Wistar rats were subjected to i.c. application of NaCl or LPS (5 g/pup). One hour later, the left common carotid artery was exposed through a midline neck incision and ligated with 6-0 surgical silk. After another hour of recovery, the pups were subjected to a hypoxic gas mixture (8% oxygen/92% nitrogen) for 60 min. The animals were randomized to four experimental groups: 1) sham control group, left common carotid artery exposed but not ligated (n ϭ 5); 2) LPS group, subjected to i.c. application of LPS (n ϭ 7); 3) hypoxic-ischemic study group, i.c. injection of NaCl and exposure to hypoxia after ligation of the left carotid artery (n ϭ 17); or 4) hypoxic-ischemic/LPS study group, i.c. injection of LPS and exposure to hypoxia after ligation of the left carotid artery (n ϭ 19). Seven days later, neonatal brains were assessed for neuronal cell damage. In a second set of experiments, rat pups received an i.c. injection of LPS (5 g/pup) and were evaluated for tumor necrosis factor-␣ expression by immunohistochemistry. Neuronal cell damage could not be observed in the sham control or in the LPS group. In the hypoxicischemic/LPS group, neuronal injury in the cerebral cortex was significantly higher than in animals that were subjected to hypoxia/ischemia after i.c. application of NaCl. Injecting LPS intracisternally caused a marked expression of tumor necrosis factor-␣ in the leptomeninges. Applying LPS intracisternally sensitizes the immature rat brain to a subsequent hypoxicischemic insult. (Pediatr Res 53: 770-775, 2003) Abbreviations LPS, lipopolysaccharides TNF-␣, tumor necrosis factor-␣ i.c., intracisternal TLR, toll-like receptor

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In experimental bacterial meningitis, matrix metalloproteinases (MMPs) and reactive oxygen species (ROS) contribute to brain damage. MMP-9 increases in cerebrospinal fluid (CSF) during bacterial meningitis and is associated with the brain damage that is a consequence of the disease. This study assesses the origin of MMP-9 in bacterial meningitis and how ROS modulate its activity. Rat brain-slice cultures and rat polymorphonuclear cells (PMNs) that had been challenged with capsule-deficient heat-inactivated Streptococcus pneumoniae R6 (hiR6) released MMP-9. Coincubation with either catalase, with the myeloperoxidase inhibitor azide, or with the hypochlorous acid scavenger methionine almost completely prevented activation, but not the release, of MMP-9, in supernatants of human PMNs stimulated with hiR6. Thus, in bacterial meningitis, both brain-resident cells and invading PMNs may act as sources of MMP-9, and stimulated PMNs may activate MMP-9 via an ROS-dependent pathway. MMP-9 activation by ROS may represent a target for therapeutic intervention in bacterial meningitis.