Streptococcus pyogenes meningitis and endocarditis in a patient with prosthetic mitral valve.

Streptococcus pyogenes is commonly found in cutaneous and pharyngeal infections, but rarely causes meningitis and endocarditis. We report a 77-year-old male with history of prosthetic mitral valve, presenting with meningitis and endocarditis secondary to S. pyogenes. We aim to raise awareness among clinicians of rare infectious etiology as the cause of endocarditis and meningitis, and importance of prompt diagnosis in ensuring success of medical treatment and long-term survival. .

Effects of anidulafungin and voriconazole, singly and in combination, on cytokine/chemokine production by human monocyte-derived macrophages infected with Candida glabrata or activated by lipopolysaccharide.

BACKGROUND: Candida glabrata causes infections associated with severe sepsis, production of high concentrations of cytokines/chemokines, and high mortality. This study describes the effects of anidulafungin (ANF) and voriconazole (VRC), singly and in combination, on the production of eight cytokines/chemokines by human monocyte-derived macrophages (MDM) infected with C. glabrata or activated by lipopolysaccharide (LPS). METHODS: MDM monolayers were established, infected with C. glabrata or activated with LPS, and then treated with high or low concentrations of ANF, VRC, or both. Cytokine/chemokine levels in MDM supernatants were determined. RESULTS: Levels of cytokines/chemokines were significantly elevated in supernatants of infected or LPS-activated MDM. Except for interleukin-10, all significant decreases in cytokine/chemokine concentrations (p < 0.01) occurred in supernatants of infected MDM treated with high concentrations of ANF or ANF + VRC. CONCLUSIONS: Decreases in cytokine/chemokine levels in supernatants of infected MDM treated with high concentrations of ANF or ANF + VRC suggest that similar treatment could improve survival in patients with severe, invasive C. glabrata infections and markedly elevated levels of serum cytokines/chemokines.

Effects of echinocandins on cytokine/chemokine production by human monocytes activated by infection with Candida glabrata or by lipopolysaccharide.

Serious Candida glabrata infections, which can be difficult to treat, are often treated with echinocandins. We compared in vitro the effects of high and low concentrations of 3 echinocandins (micafungin [MCF], caspofungin [CAS], and anidulafungin [ANF]), voriconazole (VRC), and amphotericin B (AmB), singly and VRC in combination with MCF, CAS, and ANF, on the production of cytokines/chemokines by human monocyte-derived macrophages (MDM). MDM were activated by infection with C. glabrata or lipopolysaccharide (LPS). Luminex multi-analyte microsphere technology was used for cytokine/chemokine analysis. Concentrations of cytokines/chemokines were significantly elevated following activation by infection or LPS. Treatment with high concentrations of echinocandins, singly or in combination with VRC, was most effective in lowering the elevated cytokine/chemokine levels. This effect occurred only with MDM activated by infection with C. glabrata and not with LPS. Treatment with VRC or AmB alone had little or no effect on cytokine/chemokine levels. In severe C. glabrata infection associated with very high concentrations of dysregulated cytokines/chemokines, echinocandins, singly or in combination with VRC, may decrease cytokine/chemokine concentrations and thus may improve host survival.

Comparison of CLSI broth macrodilution and microdilution methods for echinocandin susceptibility testing of 5 Candida species.

In order to compare the Clinical and Laboratory Standards Institute (CLSI) broth macrodilution and microdilution methods of susceptibility testing for echinocandins and yeast, 55 strains of Candida representing 5 species were tested using the CLSI-recommended broth macro- and microdilution methods. Small (1-3 log(2)) but potentially important method-, species-, and drug-dependent differences in MICs were observed.

Post-antifungal effects and time-kill studies of anidulafungin, caspofungin, and micafungin against Candida glabrata and Candida parapsilosis.

Candida glabrata (Cgl) and Candida parapsilosis (Cpa) can cause serious infections and can be resistant to some antifungal drugs. In treating infections caused by these organisms, killing rates and post-antifungal effects (PAFE) are important factors in both dose interval choice and outcome. Two strains each of Cgl and Cpa were studied. For PAFE studies, each organism was exposed to micafungin (MCF), anidulafungin (ANF), or caspofungin (CAS) for 1 h at concentrations ranging from 0.25 to 16×MIC. Cell suspensions were then washed 3 times and resuspended in fresh broth. Time 0 was immediately after resuspension of the yeast. Time-kill experiments were done using similar drug concentrations. Samples were removed at each time point (0-120 h) and viable counts determined. PAFE of ANF and CAS were generally very long, were markedly longer than those of MCF, and increased with increased drug concentration. For ANF and CAS, PAFE for Cgl were greater than those for Cpa only at 0.5 to 2 × MIC. Time-kill experiments showed that ANF, CAS, and MCF were fungicidal at 8 to 16 × MIC up to 120 h. CAS had the greatest activity against Cgl, while ANF and MCF were more active than CAS against Cpa. Because of the prolonged PAFE of these echinocandins, especially ANF and CAS, less frequent dosing during therapy of Cpa and Cgl infections could be considered. Further studies are needed to determine the clinical efficacy of longer dosing intervals.

Time-kill studies with micafungin and voriconazole against Candida glabrata intracellularly in human monocyte-derived macrophages and extracellularly in broth.

The purpose of this study was to determine by time-kill methodology the anticandidal effectiveness and durability of micafungin (MCF) and voriconazole (VRC), singly and in combination, against Candida glabrata (Cgl), intracellularly in human monocyte-derived macrophages and extracellularly in RPMI-MOPS broth with and without fetal calf serum (FCS) or pooled human serum (PHS). The anticandidal activity of MCF was concentration-dependent and durable. Combinations of MCF + VRC both intra- and extracellularly were more effective than single drugs. However, in extracellular experiments, FCS, and even more PHS, significantly decreased the anticandidal activity of MCF and VRC. Our in vitro studies suggest that MCF alone may be adequate where protein concentration is low (intracellular or extravascular sites), while MCF + VRC combinations may be preferred where protein concentration is high such as in the intravascular space.

Activities of tigecycline and comparators against Legionella pneumophila and Legionella micdadei extracellularly and in human monocyte-derived macrophages.

The activity of tigecycline against Legionellae, which are intracellular pathogens, was evaluated intracellularly in human phagocytes and extracellularly, and compared to the activities of erythromycin and levofloxacin. Clinical isolates of L. pneumophila serogroups 1, 5, and 6 and L. micdadei were tested in time-kill experiments. Extracellular experiments were done using buffered yeast extract broth. For intracellular assays, monolayers of human monocyte-derived macrophages (MDM) were infected with L. pneumophila or L. micdadei. Antibiotics (0.05-2.5 × MIC) were then added. MDM were lysed at 0, 24, 48, and 72 h and viable bacteria in the lysates were enumerated. Based on multiples of the MICs, tigecycline was less active extracellularly than levofloxacin or erythromycin. However, intracellular killing of both L. pneumophila and L. micdadei by tigecycline at 72 h was greater than for erythromycin or levofloxacin. Currently, evidence does not support the use of tigecycline as a first-line drug for treatment of Legionella infections. However, since Legionellae are intracellular pathogens, these results suggest that tigecycline should be effective for treatment of infections caused by these bacteria.

IFN-gamma enhances killing of methicillin-resistant Staphylococcus aureus by human monocytes more effectively than GM-CSF in the presence of daptomycin and other antibiotics.

Because cytokines have been utilized in treatment of sepsis in neonates, we studied the effects of interferon-gamma (IFN-gamma) and GM-CSF on killing of intracellular methicilin-resistant Staphylococcus aureus (MRSA) by human monocyte derived macrophages (MDM) in the presence of daptomycin (Dap), rifampin (Rif), gentamicin (Gen), and combinations of these drugs. MDM infected with MRSA were treated with Dap (1 x MIC), Gen (0.5 x MIC), or Rif (1 x MIC), singly or in combination, with or without cytokines. MDM were lysed and viable bacteria counted. With antibiotics, MDM activated by IFN-gamma had a more rapid and prolonged bacterial killing effect than MDM activated by GM-CSF. This effect was most obvious with the triple-drug combination. In contrast, GM-CSF reduced intracellular killing under most experimental conditions compared to the effect of antibiotics alone. Dap alone and two- and three-drug combinations demonstrated significant killing effect for the 48 h of the assay. IFN-gamma enhanced rapid intracellular killing of MRSA in the presence of triple-drug treatment or Dap alone. GM-CSF in combination with the antibiotics reduced killing under most conditions studied. Further studies to confirm these observations with IFN-gamma-activated MDM and other MRSA strains are needed to support clinical trials for difficult-to-treat MRSA infections.

Anticandidal effects of voriconazole and caspofungin, singly and in combination, against Candida glabrata, extracellularly and intracellularly in granulocyte-macrophage colony stimulating factor (GM-CSF)-activated human monocytes.

OBJECTIVES: The antifungal effects of voriconazole and caspofungin, singly and in combination, were determined against Candida glabrata in time-kill curves in broth, in human monocyte-derived macrophages (MDMs) and in MDMs activated by granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: Three strains of fluconazole-resistant C. glabrata were evaluated. For intracellular studies, MDM monolayers, with or without GM-CSF activation, were infected with C. glabrata and treated with voriconazole and caspofungin at 2.5x and 5x MIC, respectively, or at 1x MIC. Extracellular studies in broth were performed using drug concentrations from 0.1 to 10x MIC. Viable yeast were enumerated at 0, 24 and 48 h. RESULTS: Significantly greater killing of C. glabrata occurred with the drug combination than with either single drug, both intracellularly and extracellularly (P < 0.01). For voriconazole, the antifungal activity in MDM activated by GM-CSF was greater than that in unactivated MDM, regardless of antibiotic concentration or time of exposure. However, for caspofungin and for the two-drug combination, enhanced activity in GM-CSF-activated MDM depended on the drug concentration and time of exposure. CONCLUSIONS: Our data suggest that combinations of voriconazole and caspofungin may be efficacious for the treatment of serious C. glabrata infections. With single-drug therapy, especially voriconazole, GM-CSF activation of monocytes could be considered.

Activities of daptomycin and comparative antimicrobials, singly and in combination, against extracellular and intracellular Staphylococcus aureus and its stable small-colony variant in human monocyte-derived macrophages and in broth.

We investigated the antistaphylococcal activities of daptomycin, gentamicin, and rifampin against two Staphylococcus aureus strains and their stable small-colony variants, singly and in combination, in human monocyte-derived macrophages and in broth. Intracellularly, the three-drug combination and two-drug combinations with rifampin were most effective. Extracellularly, daptomycin, daptomycin plus gentamicin, gentamicin plus rifampin, and the three-drug combination had similar activities.

Effects of gatifloxacin and levofloxacin on rates of hypoglycemia and hyperglycemia among elderly hospitalized patients.

STUDY OBJECTIVES: To compare rates of hypoglycemia and hyperglycemia among elderly hospitalized patients with normal blood glucose concentrations at baseline who were receiving either gatifloxacin or levofloxacin, and to determine if appropriateness of their doses, according to their package inserts, was associated with hypoglycemia or hyperglycemia. DESIGN: Retrospective cohort study. SETTING: Integrated Veterans Administration (VA) health care system. PATIENTS: Nine hundred thirty-seven elderly (>or= 65 yrs) patients with documented blood glucose levels of 65-140 mg/dl before receiving a fluoroquinolone. MEASUREMENTS AND MAIN RESULTS: Between January 2003 and April 2004, 405 patients receiving levofloxacin met study criteria. In April 2004, gatifloxacin was substituted for levofloxacin on the formulary of this VA system. Thus, between April 2004 and December 2004, 532 patients received gatifloxacin. All blood glucose concentrations during hospitalization that were measured during fluoroquinolone therapy or within 72 hours of completion of therapy were reviewed. Demographic characteristics, comorbidities, insulin and oral hypoglycemic therapies, disease severity, blood glucose levels, and outcomes were recorded and compared between groups. The two groups were similar at baseline for all characteristics examined except previous hospitalization. In the logistic regression, gatifloxacin was independently associated with both hypoglycemia (adjusted odds ratio [AOR] 2.5, 95% confidence interval [CI] 1.2-5.7, p=0.04) and hyperglycemia (AOR 2.4, 95% CI 1.5-3.6, p<0.001). Improper dosage adjustment based on renal function was not associated with higher rates of hypoglycemia and hyperglycemia for either drug. Of the 532 patients receiving gatifloxacin, 465 (87.4%) received appropriate doses, yet gatifloxacin was associated with higher rates of hypoglycemia and hyperglycemia compared with patients receiving levofloxacin. CONCLUSIONS: Higher rates of both hypoglycemia and hyperglycemia were noted among elderly hospitalized patients who received gatifloxacin compared with those receiving levofloxacin, irrespective of dosing.

Comparison of beta-lactam and macrolide combination therapy versus fluoroquinolone monotherapy in hospitalized Veterans Affairs patients with community-acquired pneumonia.

Data comparing the treatment outcomes of the two most frequently recommended empirical antibiotic regimens for community-acquired pneumonia (CAP)--combination therapy with an extended-spectrum beta-lactam and a macrolide (BL+M) or fluoroquinolone (F) monotherapy--for patients with severe CAP are sparse. The purpose of this study was to compare empirical BL+M combination therapy with F monotherapy for Veterans Affairs (VA) patients with severe CAP. This retrospective study included patients with CAP who received empirical therapy with BL+M or F between October 1999 and May 2003 in the Upstate New York VA Network. Outcome measures were 14-day mortality, 30-day mortality, and length of hospital stay (LOS). Severe CAP was defined as a class V pneumonia severity index (PSI). During the study period, 261 patients received BL+M and 254 received F. Disease severity was similar for the two treatment groups at admission, and the presence of tachycardia was the only difference noted. For PSI class V patients, there were lower 14-day and 30-day mortality rates with BL+M than with F (14-day rates, 8.2% versus 26.8% [P = 0.02]; 30-day rates, 18.4% versus 36.6% [P = 0.05]). No differences in mortality between treatment groups were noted for the lower PSI classes. The overall median LOS was significantly longer for the BL+M combination group than for the F monotherapy group (6.0 days versus 5.0 days, respectively [P = 0.01]), but no difference in LOS was noted among PSI class V patients. Our study showed that improved outcomes may be realized with BL+M in cases of severe CAP. A randomized clinical study is warranted based on these results.

Effect of recombinant human activated protein C on the bactericidal activity of human monocytes and modulation of pro-inflammatory cytokines in the presence of antimicrobial agents.

OBJECTIVES: To determine the effects of recombinant human activated protein C (rhAPC) on the antimicrobial activity and cytokine production of normal human monocyte-derived macrophages (MDMs) in the presence and absence of Escherichia coli infection, with and without treatment with levofloxacin or ampicillin. METHODS: MDM monolayers were infected with E. coli ATCC 25922 and treated with levofloxacin or ampicillin in the presence or absence of rhAPC. Antimicrobial activity and cytokine (TNF-alpha, IL-1beta, IL-6 and IL-8) concentrations in the supernatants were measured. RESULTS: When low concentrations of levofloxacin were used, a therapeutic concentration of rhAPC enhanced intracellular antibacterial activity at all time points. With ampicillin, antibacterial activity increased, was unaffected or diminished depending upon the drug concentration and assay time. Without antibiotics, rhAPC had no antibacterial effect. E. coli caused cytokine production to increase many fold. This increase was significantly greater with antibiotics (P < 0.01). Without antibiotics, rhAPC decreased production of TNF-alpha, IL-1beta and IL-6, but not IL-8. At high levofloxacin concentrations, rhAPC was associated with further increases in the concentrations of these cytokines. Cytokine concentrations at 24 h were unaffected by rhAPC in the presence of ampicillin and E. coli. CONCLUSIONS: rhAPC can affect the bactericidal activity and cytokine production of human MDM in the presence of infection and antibiotic therapy. Importantly, factors such as type and concentration of antibiotics, presence of bacteria and timing must be taken into consideration when evaluating cytokine data from septic patients.

Antimicrobial activities of daptomycin, vancomycin, and oxacillin in human monocytes and of daptomycin in combination with gentamicin and/or rifampin in human monocytes and in broth against Staphylococcus aureus.

We investigated the antistaphylococcal activity of daptomycin, vancomycin, oxacillin, gentamicin, and rifampin in human monocyte-derived macrophages. Compared with vancomycin and oxacillin, daptomycin had the most rapid and greatest antibacterial activity, but that of oxacillin was most sustained. The combination of daptomycin, gentamicin, and rifampin was most effective intracellularly, while daptomycin plus gentamicin and the three-drug combination were most effective extracellularly, completely eliminating viable Staphylococcus aureus.

Antifungal effect of voriconazole on intracellular Candida glabrata, Candida krusei and Candida parapsilosis in human monocyte-derived macrophages.

Infections caused by Candida species other than Candida albicans are increasingly common, and decreased susceptibility to azoles has made them more difficult to treat. Since phagocytic killing is important in elimination of Candida infections, intracellular killing of fluconazole-resistant Candida glabrata, Candida krusei and Candida parapsilosis (four strains each) by voriconazole was investigated in human monocyte-derived macrophages (MDMs). MDMs were infected with Candida, and voriconazole was then added. MDMs were lysed at 0, 24 or 48 h after infection, and viable Candida in the lysates enumerated. Compared to the starting inoculum, the number of viable intracellular C. parapsilosis and C. glabrata in untreated MDMs increased to 28,121 and 351 %, respectively, in 48 h. In contrast, the number of C. krusei decreased to 42 %. In MDMs treated with voriconazole, the decrease in viable count was dependent upon drug concentration. At 48 h, C. glabrata was killed only at 5x MIC (P < 0.05), C. krusei was killed at all voriconazole concentrations, while C. parapsilosis was inhibited at 0.5 and 1x MIC and killed at > or = 2.5x MIC (P < 0.05). The data show that intracellular growth and survival of these Candida species in the absence or presence of voriconazole vary markedly. The activity of voriconazole depends on the concentration of the drug and the time of exposure. For the 12 Candida strains studied, regression curves show that the maximum intracellular anticandidal activity of voriconazole was reached at 3.5-5x MIC.

Antibacterial activities of gemifloxacin, levofloxacin, gatifloxacin, moxifloxacin and erythromycin against intracellular Legionella pneumophila and Legionella micdadei in human monocytes.

OBJECTIVES: The antibacterial activity of a new fluoroquinolone, gemifloxacin, was tested against intracellular Legionella pneumophila and Legionella micdadei and was compared with the activities of levofloxacin, gatifloxacin, moxifloxacin and erythromycin. METHODS: For intracellular assays, bacteria were used to infect human monocyte-derived macrophages prepared from heparinized blood of healthy volunteers. Antibiotics were added following phagocytosis. Numbers of viable bacteria were determined at 0, 24, 48, 72 and 96 h. RESULTS: The intracellular antibacterial activity of gemifloxacin was concentration- and time-dependent. All of the quinolones had similar activities against L. pneumophila and L. micdadei at 10 x MIC, but there were minor differences: at 24 h moxifloxacin was significantly more active than the other quinolones against L. pneumophila, while gemifloxacin was more active against L. micdadei (P < 0.01). All of the quinolones were markedly more active than erythromycin (P < 0.01). The antibacterial effect of gemifloxacin against L. pneumophila following drug removal at 24 h persisted for 72 h at 20 x MIC but not at 10 x MIC, while for L. micdadei the antibacterial effect persisted for 24 h at 10 x MIC. CONCLUSIONS: All of the quinolones had similar activities against intracellular L. pneumophila and L. micdadei and were markedly more effective than erythromycin.

Effects of voriconazole, granulocyte-macrophage colony-stimulating factor, and interferon gamma on intracellular fluconazole-resistant Candida glabrata and Candida krusei in human monocyte-derived macrophages.

Infections caused by fluconazole-resistant Candida glabrata and Candida krusei are increasingly common causes of morbidity and mortality. We investigated the intracellular killing of fluconazole-resistant C. glabrata and C. krusei by cytokine-activated human monocyte-derived macrophages (MDM) in the presence and absence of voriconazole. For C. glabrata, MDM were activated with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interferon gamma (IFN-gamma) before infection, after infection, or both before and after infection, whereas for C. krusei MDM were activated with cytokines both before and after infection. Activated MDM were infected, treated with voriconazole, and then lysed, and viable yeast in the lysates enumerated at 0, 24, or 48 h after infection. In the presence of voriconazole (2.5 x MIC), the best activity against C. glabrata occurred when MDM were activated with GM-CSF for 24 h before infection as well as after infection or when they were activated for 24 h before infection alone. A lesser effect was observed when MDM were activated for at least 1 h before infection or when they were treated with cytokines only after infection. IFN-gamma activation had a significant but lesser effect than GM-CSF. Activity against C. krusei in the presence of voriconazole was greatest when MDM were activated with IFN-gamma rather than GM-CSF. Our results suggest that cytokines increase the intracellular anticandidal effect of voriconazole and may be useful as therapeutic adjuvants to voriconazole for treatment of infections caused by fluconazole-resistant C. glabrata and C. krusei.

Mass mailing and telephone contact were effective in recruiting veterans into an antibiotic treatment randomized clinical trial.

OBJECTIVE: Achieving enrollment goals of randomized clinical trials (RCT) within budgets depends on the timely recruitment of sufficient numbers of participants. We report a comparison of recruitment methods and yields of previously deployed veterans into a large RCT. STUDY DESIGN AND SETTING: A retrospective survey concerning recruitment was administered to staff at 28 sites participating in the VA Cooperative Study #475, "Antibiotic Treatment of Gulf War Veterans' Illnesses" (GWVI). RESULTS: Twenty-one sites reported identifying 31,407 Gulf War Veterans (GWV). Of these, 13.7% were successfully contacted, 3.5% were enrolled, and 1.2% were randomized. Mass mailings and direct telephone calls to GWV identified from a GWV database accounted for 78% of the GWV contacted. The other 22% were contacted by using referrals from medical staff, veterans' groups, media advertisements, and other methods. Data collected prospectively at the Albany Stratton VAMC were similar to data collected retrospectively from other sites. CONCLUSION: These findings demonstrate that in previously deployed GWV with GWVI, 1.2% could be randomized. Although the use of all recruitment methods combined achieved the study recruitment goal, these data demonstrate that mass mailing and direct telephone contacts were effective recruitment methods.

Effect of levofloxacin on the viability of intracellular Chlamydia pneumoniae and modulation of proinflammatory cytokine production by human monocytes.

Although antibiotics are known to affect the intracellular growth of Chlamydia pneumoniae in acute infections, their efficacy in therapy for chronic infections, including atherosclerosis, remains debatable. Human monocyte-derived macrophages (MDM) obtained from monocytes of healthy donors were infected with C. pneumoniae AR-39 and treated with levofloxacin (8 microg/mL) immediately after infection (0 hours) or 24 hours after infection. Levofloxacin treatment at 24 hours, but not at 0 hours, resulted in a significant decrease in the number of C. pneumoniae inclusions within the MDM (p < 0.05). Also decreased were concentrations of proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-8 in the extracellular medium (p < 0.01). Viable counts in titrations remained similar to those in untreated controls. In summary, levofloxacin administered to MDM at serum-attainable levels 24 hours after C. pneumoniae infection significantly decreased inclusion counts and proinflammatory cytokine production, but did not eliminate the C. pneumoniae infection.

Benefits and harms of doxycycline treatment for Gulf War veterans' illnesses: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: It has been hypothesized that certain Mycoplasma species may cause Gulf War veterans' illnesses (GWVIs), chronic diseases characterized by pain, fatigue, and cognitive symptoms, and that affected patients may benefit from doxycycline treatment. OBJECTIVE: To determine whether a 12-month course of doxycycline improves functional status in Gulf War veterans with GWVIs. DESIGN: A randomized, double-blind, placebo-controlled clinical trial with 12 months of treatment and 6 additional months of follow-up. SETTING: 26 U.S. Department of Veterans Affairs and 2 U.S. Department of Defense medical centers. PARTICIPANTS: 491 deployed Gulf War veterans with GWVIs and detectable Mycoplasma DNA in the blood. INTERVENTION: Doxycycline, 200 mg, or matching placebo daily for 12 months. MEASUREMENTS: The primary outcome was the proportion of participants who improved more than 7 units on the Physical Component Summary score of the Veterans Short Form-36 General Health Survey 12 months after randomization. Secondary outcomes were measures of pain, fatigue, and cognitive function and change in positivity for Mycoplasma species at 6, 12, and 18 months after randomization. RESULTS: No statistically significant differences were found between the doxycycline and placebo groups for the primary outcome measure (43 of 238 participants [18.1%] vs. 42 of 243 participants [17.3%]; difference, 0.8 percentage point [95% CI, -6.5 to 8.0 percentage points]; P > 0.2) or for secondary outcome measures at 1 year. In addition, possible differences in outcomes at 3 and 6 months were not apparent at 9 or 18 months. Participants in the doxycycline group had a higher incidence of nausea and photosensitivity. LIMITATIONS: Adherence to treatment after 6 months was poor. CONCLUSION: Long-term treatment with doxycycline did not improve outcomes of GWVIs at 1 year.