Does Chlamydia trachomatis MoPn enter a microbiologically-inapparent state during experimental infection of the mouse genital tract?

Microbiologically-inapparent chlamydial infection may contribute towards the immunopathogenesis of these diseases. Although morphologically and physiologically aberrant non-cultivable chlamydiae can be induced reversibly in cell culture, evidence for these forms in infections of animals and humans is indirect. A mouse model of salpingitis caused by the mouse pneumonitis biovar of Chlamydia trachomatis (MoPn) was used to determine the existence of non-cultivable organisms in vivo. Following intravaginal inoculation, mice yielded high chlamydial counts for 7-14 dyas, with a decline in culture-positivity by 21-28 days. A significant elevation of IFN gamma production in infected tissues was measured for 21 days and, from 28-70 days, all mice were culture-negative and developed characteristic hydrosalpinges. MoPn was detected by PCR in vaginal swabs of 80% and 69% respectively of culture-negative animals at 21 and 28 days. In a second study, 100%, 63% and 50% of culture-negative genital tissue homogenates were PCR-positive at 21, 28 and 42 days. Immunosuppression with either cyclophosphamide or hydrocortisone failed to regenerate cultivable chlamydiae. Tissues were disrupted by homogenization and inoculated intranasally to MF1 mice which are extremely susceptible to MoPn, but all culture-negative specimens were non-infectious. The significance of the PCR-positive culture-negative specimens requires further investigation, since these may represent a non-cultivable state in the deeper tissues of the mouse genital tract which may be beyond the reach of reactivating triggers.     

Experimental Bacteroides fragilis endocarditis in rabbits

A serum-resistant strain of Bacterioides fragilis that did not produce heparinase was used to study the characteristics of B. fragilis endocarditis in the rabbit experimental model. The infective dose required to produce endocarditis in 50% of rabbits was significantly lower for rabbits with left-sided intracardiac catheters (log10 6.3 colony-forming units +/- 0.6/ml) as compared with right-sided intracardiac catheters (log10 7.7 colony-forming units +/- 0.8/ml). After 3 days of infection, bacterial titers of the tricuspid vegetations were significantly lower than titers of aortic vegetations (P less than 0.01), although at 5 days the titers were similar (P greater than 0.05). The weights of tricuspid vegetations, although similar at 3 days (P less than 0.05). There were no spontaneous deaths during 12 days of infection. In rabbits with the catheter removed before infection, bacterial titers were similar to those titers in rabbits with the catheter continuously in place. This model will permit study of various drug regimens for treatment of this disease.     

Enhanced virus clearance by early inducible lymphocytic choriomeningitis virus-neutralizing antibodies in immunoglobulin-transgenic mice

Following infection of mice with lymphocytic choriomeningitis virus (LCMV), virus-neutralizing antibodies appear late, after 30 to 60 days. Such neutralizing antibodies play an important role in protection against reinfection. To analyze whether a neutralizing antibody response which developed earlier could contribute to LCMV clearance during the acute phase of infection, we generated transgenic mice expressing LCMV-neutralizing antibodies. Transgenic mice expressing the immunoglobulin mu heavy chain of the LCMV-neutralizing monoclonal antibody KL25 (H25 transgenic mice) mounted LCMV-neutralizing immunoglobulin M (IgM) serum titers within 8 days after infection. This early inducible LCMV-neutralizing antibody response significantly improved the host's capacity to clear the infection and did not cause an enhancement of disease after intracerebral (i.c.) LCMV infection. In contrast, mice which had been passively administered LCMV-neutralizing antibodies and transgenic mice exhibiting spontaneous LCMV-neutralizing IgM serum titers (HL25 transgenic mice expressing the immunoglobulin mu heavy and the kappa light chain) showed an enhancement of disease after i.c. LCMV infection. Thus, early-inducible LCMV-neutralizing antibodies can contribute to viral clearance in the acute phase of the infection and do not cause antibody-dependent enhancement of disease.     

In vivo activities of amoxicillin and amoxicillin-clavulanate against Streptococcus pneumoniae: application to breakpoint determinations

The in vivo activities of amoxicillin and amoxicillin-clavulanate against 17 strains of Streptococcus pneumoniae with penicillin MICs of 0.12-8.0 mg/liter were assessed in a cyclophosphamide-induced neutropenic murine thigh infection model. Renal impairment was produced by administration of uranyl nitrate to prolong the amoxicillin half-life in the mice from 21 to 65 min, simulating human pharmacokinetics. Two hours after thigh infection with 10(5) to 10(6) CFU, groups of mice were treated with 7 mg of amoxicillin per kg of body weight alone or combined with clavulanate (ratio, 4:1) every 8 h for 1 and 4 days. There was an excellent correlation between the MIC of amoxicillin (0.03 to 5.6 mg/liter) and (i) the change in log10 CFU/thigh at 24 h and (ii) survival after 4 days of therapy. Organisms for which MICs were 2 mg/liter or less were killed at 1.4 to 4.2 and 1.6 to 4.1 log10 CFU/thigh at 24 h by amoxicillin and amoxicillin-clavulanate, respectively. The four strains for which MICs were >4 mg/liter grew 0.2 to 2.6 and 0.6 to 2. 3 logs at 24 h despite therapy with amoxicillin and amoxicillin-clavulanate, respectively. Infection was uniformly fatal by 72 h in untreated mice. Amoxicillin therapy resulted in no mortality with organisms for which MICs were 1 mg/liter or less, 20 to 40% mortality with organisms for which MICs were 2 mg/liter, and 80 to 100% mortality with organisms for which MICs were 4.0-5.6 mg/liter. Lower and higher doses (0.5, 2, and 20 mg/kg) of amoxicillin were studied against organisms for which MICs were near the breakpoint. These studies demonstrate that a reduction of 1 log10 or greater in CFU/thigh at 24 h is consistently observed when amoxicillin levels exceed the MIC for 25 to 30% of the dosing interval. These studies would support amoxicillin (and amoxicillin-clavulanate) MIC breakpoints of 1 mg/liter for susceptible, 2 mg/liter for intermediate, and 4 mg/liter for resistant strains of S. pneumoniae.     

Improvement of glucose/insulin metabolism reduces hypertension in insulin-dependent diabetes mellitus recipients of kidney-pancreas transplantation

OBJECTIVE: The current guidelines recommend 1-wk triple therapy regimens for eradicating H. pylori infection. Until now, shorter regimens have scarcely been investigated. Azithromycin is a new generation macrolide antibiotic with unusual and favorable pharmacokinetics, and seems to be a very promising agent for innovative anti-H. pylori regimens. We assessed the efficacy and tolerability of a new 4-day low dose triple therapy in comparison with a well established 1-wk triple therapy in the treatment of Helicobacter pylori infection. METHODS: One hundred-sixty consecutive patients with biopsy-proven H. pylori infection were randomized to receive lansoprazole 30 mg b.i.d. on days 1-4, azithromycin 500 mg u.i.d. on days 2-4, and tinidazole 2000 mg u.i.d. on day 3 (LAT group), or 7 days of triple therapy of omeprazole 20 mg u.i.d., clarithromycin 250 mg b.i.d., and tinidazole 500 mg b.i.d. (OCT group). Patients with gastric or duodenal active ulcer received proton pump inhibitors for an additional 4 wk. H. pylori eradication was defined as negative of both rapid urease test and histology on biopsies taken from the gastric body and antrum at least 1 month after the end of treatment. RESULTS: Seven patients in the LAT group and four in the OCT group were lost to follow-up. No significant difference in either efficacy or tolerability was observed between the two regimens. Active ulcers healed in 97.8% of cases with LAT and in 100% of cases with OCT. The eradication rate was 80.8% in the LAT group and 85.5% in the OCT group, considering the per-protocol results, and 73.3% and 81.2%, respectively, considering the intention-to-treat results. Side effects occurred in one LAzT patient and in two OCT patients; they were mild and did not interfere with compliance. CONCLUSION: The new proposed ultrashort triple therapy, including lansoprazole, low dose azithromycin for 3 days, and a single dose of tinidazole, appears to be a very effective anti-H. pylori regimen, a simpler, cheaper, well-tolerated, and equally effective alternative to 1-wk triple therapy.     

Omeprazole, azithromycin and amoxicillin or amoxicillin plus clavulanic acid in eradication of Helicobacter pylori in duodenal ulcer disease

Treatment with omeprazole (OME), azithromycin (AZI) and amoxicillin (AMO) resulted in encouraging Helicobacter pylori cure rates in pilot and control studies. The aim of this study was to establish whether OME + AZI in combination with either AMO or ACA (amoxicillin plus clavulanic acid) are effective in curing H. pylori infection. A hundred patients with active duodenal ulcer and H. pylori infection were treated with OME (day 1-10: 2 x 40 mg/day, day 11-24: 40 mg/day, day 25-42: 20 mg/day) plus AZI 500 mg/day for the first 6 days. Patients were randomly assigned to either AMO 2 x 1000 mg/day (group A, n = 50) or ACA 2 x 1250 mg/day (group B, n = 50) during the first 10 days of treatment. H. pylori status was determined by urease test and histology before and 6 weeks after completion of therapy. Ninety-five patients completed the study. H. pylori infection was eradicated in 85.4% (41/48) patients from group A (intention-to-treat (ITT) analysis: 82%) versus 91.5% (43/47) patients from group B (ITT) analysis: 86%) (NS). All ulcer had healed after 42 days of omeprazole treatment. Side effects, usually minor, were recorded in 12.5% (group A) and 14.9% (group B) of patients (NS). Therapy had to be discontinued in two patients (one in group A and one group B) only. Ten-days treatment with OME and AZI (for the first 6 days) with AMO or ACA are simple and highly effective regimens to cure H. pylori infection in patients with duodenal ulcer disease.     

Stetteria hydrogenophila, gen. nov. and sp. nov., a novel mixotrophic sulfur-dependent crenarchaeote isolated from Milos, Greece

To test the therapeutic efficacy of levamisole, 5-week-old DBA/2 mice were inoculated intraperitoneally with 10 plaque-forming units of encephalo-myocarditis virus. Levamisole (2.5 mg/kg/per day) was administered intraperitoneally daily, starting simultaneously with the virus inoculation, in experiment I for 14 days, and daily on days 14 to 28 in experiment II in mice that survived to 14 days after virus inoculation. In experiment I, survival was higher, the severity of myocarditis was less, and myocardial virus titers were lower in treated than in untreated animals. In experiment II, levamisole was not effective. No significant changes in serum neutralizing antibody titers occurred in either experiment. Furthermore, levamisole prevented associated lymphoid organ atrophy induced by the virus infection. An additional in vitro study revealed the absence of anti-viral activity of the drug. Thus, levamisole may have favorable effects upon encephalomyocarditis virus myocarditis by preventing the virus-induced lymphoid organ atrophy and reducing myocardial virus replication in the acute stage.     

Once weekly azithromycin therapy for prevention of Mycobacterium avium complex infection in patients with AIDS: a randomized, double-blind, placebo-controlled multicenter trial

We conducted a randomized, double-blind, placebo-controlled multicenter trial of azithromycin (1,200 mg once weekly) for the prevention of Mycobacterium avium complex (MAC) infection in patients with AIDS and a CD4 cell count of < 100/mm3. In an intent-to-treat analysis through the end of therapy plus 30 days, nine (10.6%) of 85 azithromycin recipients and 22 (24.7%) of 89 placebo recipients developed MAC infection (hazard ratio, 0.34; P = .004). There was no difference in the ranges of minimal inhibitory concentrations of either clarithromycin or azithromycin for the five breakthrough (first) MAC isolates from the azithromycin group and the 18 breakthrough MAC isolates from the placebo group. Of the 76 patients who died during the study, four (10.5%) of 38 azithromycin recipients and 12 (31.6%) of 38 placebo recipients had a MAC infection followed by death (P = .025). For deaths due to all causes, there was no difference in time to death or number of deaths between the two groups. Episodes of non-MAC bacterial infection per 100 patient years occurred in 43 azithromycin recipients and 88 placebo recipients (relative risk, 0.49; 95% confidence interval, 0.33-0.73). The most common toxic effect noted during the study was gastrointestinal, reported by 78.9% of azithromycin recipients and 27.5% of placebo recipients. Azithromycin given once weekly is safe and effective in preventing disseminated MAC infection, death due to MAC infection, and respiratory tract infections in patients with AIDS and CD4 cell counts of < 100/mm3.     

Sendai viruses with altered P, V, and W protein expression

Wild-type Sendai virus expresses three proteins containing the N-terminal half of the P protein open reading frame due to mRNA editing; a full-length P protein (ca. 70% of the total), a V protein with the N-terminal half fused to a Cys-rich Zn(2+)-binding domain (ca. 25% of the total), and a W protein representing the N-terminal half alone (ca. 5% of the total). To examine the role of these proteins in the virus life cycle, we have prepared recombinant viruses in which the normal V mRNA expresses a W protein (V-stop; 70% P, 30% W), one which cannot edit its P gene mRNA (delta 6A; 100% P), and one which overedits its mRNA like parainfluenza virus type 3 (swap/8;20-40% P, 30% V, 30% W). All these viruses were readily recovered and grew to similar titers in eggs, and except for the P gene products, cell lines individually infected with these viruses accumulated similar amounts of viral macromolecules. The relative competitive advantage of each virus was determined by multiple cycle coinfections of eggs and found to be rSeV-Vstop = rSeV-wt > rSeV-delta 6A > rSeV-swap/8. On the other hand, rSeV-swap/8 underwent multiple cycles of replication in C57BI/6 mouse lungs and was highly virulent for these animals, whereas rSeV-delta 6A was avirulent in mice and this infection was quickly cleared. Remarkably, rSeV-Vstop appeared to be more virulent for inbred C57BI/6 mice than rSeV-wt, but was partially attenuated in infections of outbred ICR mice. Thus, the expression of either the V or the W proteins is sufficient for multiple cycles of infection and pathogenesis in C57BI/6 mice, whereas W can only partially substitute for V for pathogenesis in ICR mice.     

Antibiotic treatment of children with secretory otitis media. Amoxicillin-clavulanate is superior to penicillin V in a double-blind randomized study

OBJECTIVE: To compare the effect of 2 different antimicrobial agents in the treatment of secretory otitis media (SOM). DESIGN: Prospective, double-blind, randomized study. PATIENTS: From a pool of 1450 children (aged 1-10 years) with SOM, defined by tympanometry as having type B or C2 tympanograms, 429 with SOM of at least 3 months' duration were included in the trial. After exclusion of 69 patients, the remaining 360 were evenly distributed among 4 treatment groups: penicillin V (Primcillin) for 14 and 28 days, and amoxicillin and clavulanate potassium in combination (Spektramox) for 14 and 28 days. Criteria for improvement was a change in tympanometric findings to type C1 or type A. RESULTS: The success rates were in favor of amoxicillin-clavulanate treatment for 28 days (P < .001) (rates for respective 14- and 28-day groups: penicillin V, 23% and 19%; amoxicillin-clavulanate, 31% and 44%). Antimicrobial therapy was more efficient (P < .001) in unilateral vs bilateral disease. CONCLUSION: Antibiotic treatment improves the middle ear status in patients with SOM, and amoxicillin-clavulanate provides superior improvement to penicillin V.     

Efficacy of LY303366 against amphotericin B-susceptible and -resistant Aspergillus fumigatus in a murine model of invasive aspergillosis

LY303366 is a novel antifungal echinocandin with excellent in vitro activity against Aspergillus spp. We compared four doses (1, 2.5, 10, and 25 mg/kg of body weight) of LY303366 with amphotericin B (0.5 to 5 mg/kg) in a temporarily neutropenic murine model of invasive aspergillosis against an amphotericin B-susceptible (AF210) and an amphotericin B-resistant (AF65) Aspergillus fumigatus isolate based on in vivo response. Mice were immunosuppressed with cyclophosphamide (200 mg/kg) and infected 3 days later. Treatment started 18 h after infection and lasted for 10 days. LY303366 was given once daily intravenously for 10 days, and amphotericin B (at 0.5, 2, and 5 mg/kg) was given once daily intraperitoneally for 10 days, or only on days 1, 2, 4, and 7 (at 5 mg/kg). Kidneys and lungs from survivors were cultured on day 11. Control mice in both experiments had 90 to 100% mortality. Amphotericin B at 0.5 mg/kg and LY303366 at 1 mg/kg yielded 10 to 20% survival rates for mice infected with either AF210 or AF65. Amphotericin B at 2 and 5 (both regimens) mg/kg yielded a 70 to 100% survival rate for mice infected with AF210 but a 10 to 30% survival rate for mice infected with AF65 (P = 0.01 to 0.04 compared with AF210). Against AF210 and AF65, LY303366 at 2.5, 10, and 25 mg/kg produced a survival rate of 70 to 80%, which was as effective as amphotericin B for AF210, but superior to amphotericin B for AF65 (P < 0.03 to 0.0006). For AF65, LY303366 at 10 and 25 mg/kg/day was superior to amphotericin B at 2 and 5 mg/kg/day in reducing tissue colony counts (P = 0.01 to 0.003), and for AF210, amphotericin B at 5 mg/kg/day and at 5 mg/kg in four doses was more effective than all four regimens of LY303366 in reducing renal culture counts (P = 0.01 to 0.0001). The present study shows, for the first time, that in vivo resistance of A. fumigatus to amphotericin B exists, although this could not be detected by in vitro susceptibility assays. Furthermore, LY303366 appears to be effective against amphotericin B-susceptible and -resistant A. fumigatus infection in this model and should be further evaluated clinically.     

Depression of the N-demethylation of erythromycin, azithromycin, clarithromycin and clindamycin in murine Toxoplasma infection

The N-demethylation of macrolides was studied in a murine model of infection. Mice were infected with a cystogenic strain of Toxoplasma gondii (20 or 40 cysts/mouse) and microsomes were prepared from liver homogenates and jejunum villus tip enterocytes on day 10 post-infection. The rate of N-demethylation of the anti-Toxoplasma macrolides azithromycin, clarithromycin and clindamycin was investigated and compared to that of the macrolide erythromycin, a marker of activity of the cytochrome P-450 3A (CYP3A) mono-oxygenases. In infected mice (20 cysts/mouse), the rate of N-demethylation fell in the liver and jejunum for erythromycin (-25% and -35%, respectively), azithromycin (-12% and -10%, respectively), clarithromycin (-23% and -21%, respectively) and clindamycin (-20% and -28%, respectively). The degree of hepatic depression was more marked in mice receiving a 40-cysts burden: for erythromycin (-54%), azithromycin (-29%), clarithromycin (-49%) and clindamycin (-47%).     

Low- versus high-dose azithromycin triple therapy for Helicobacter pylori infection

BACKGROUND: We report a clinical trial which evaluated the effectiveness of triple therapy containing low- and high-dose azithromycin to treat Helicobacter pylori infection. METHODS: From March 1997 to March 1998, patients infected with H. pylori were assigned to receive either: Treatment 1: ranitidine bismuth citrate (RBC) (400 mg b.d.) and amoxycillin (1 g b.d.) for 10 days with azithromycin 500 mg o.m. for 3 days: or Treatment 2: RBC and amoxycillin for 10 days with azithromycin 1 g o.m. for 3 days. H. pylori eradication was established by a urea breath test at least 4 weeks after therapy. Side-effects and compliance were assessed using a diary. RESULTS: Sixty-eight patients were enrolled. Fifty-seven per cent of patients were treated for active peptic ulcer disease or a history of peptic ulcer disease. Treatment 1 cured H. pylori in 44% and 44% by per protocol and intention-to-treat analysis, respectively. The corresponding eradication rates for Treatment 2 were 79% and 75%. Two patients taking Treatment 2 dropped out of the study because of side-effects. CONCLUSIONS: With RBC and amoxycillin for 10 days, azithromycin at a dose of 1 g/day for 3 days was significantly better at curing H. pylori infection than azithromycin 500 mg/day for 3 days.     

Vascularized partial first metatarsal transfer for the treatment of phalangeal osteomyelitis

In this double-blind, parallel-group, multicenter study, 169 patients with symptoms of maxillary sinusitis but without radiographically confirmed empyema (pus) were randomly assigned to receive either 500 mg azithromycin once daily for 3 days (87 patients) or placebo daily for 3 days (82 patients). Nasal secretion, maxillary tenderness and pain, nasal obstruction, general malaise, and hyposmia were assessed at the start of the study and on days 4, 11, and 25 of treatment. After 11 days 58% of the patients in the azithromycin group were cured versus 31% in the placebo group; after 25 days the cure rate was 79% versus 67%, respectively. When both cure and improvement were considered, the corresponding figures after day 25 were 90% and 88%, respectively. Adverse events, predominantly gastrointestinal, occurred in 24 (27%) of the azithromycin-treated patients and in 15 (18%) of those treated with placebo, but the difference was not statistically significant. There was a difference in efficacy in favor of azithromycin in the treatment of rhinitis with symptoms of maxillary sinusitis but without radiological signs of empyema (pus). Antibiotics should only be used to alleviate symptoms in patients with moderate to severe symptoms, as the results after 25 days for both improvement and cure are equal. In the treatment of acute rhinitis with symptoms and signs of maxillary sinusitis but without empyema, treatment with azithromycin seems to result in a better cure rate after 10-12 days when compared with placebo.     

Norepinephrine efflux evoked by potassium chloride in cat sympathetic nerves: dual mechanism of action

Azithromycin prevents malaria in animal models and early clinical trials. We determined the prophylactic efficacy of three antibiotic regimens given for 10 weeks (azithromycin, 250 mg daily; azithromycin, 1,000 mg weekly; and doxycycline, 100 mg daily) relative to that of placebo for 232 adult volunteers residing in an area of intense malaria transmission. Any confirmed parasitemia during the study was considered a prophylactic failure. Two hundred thirteen volunteers (92%) completed the study. The prophylactic efficacies were as follows: daily azithromycin, 82.7% (95% confidence interval [CI], 68.5%-91.1%); weekly azithromycin, 64.2% (95% CI, 47.1%-77.1%); and daily doxycycline, 92.6% (95% CI, 79.9%-97.5%). All regimens were well tolerated. We concluded that both 100 mg of doxycycline and 250 mg of azithromycin, given daily, were effective as prophylaxis for malaria in this setting. If studies with nonimmune volunteers confirm these results for semi-immune volunteers, a daily azithromycin regimen may have special utility for individuals with contraindications to treatment with doxycycline or other antimalarial agents.     

Long-term production of rotavirus antibody and protection against reinfection following a single infection of neonatal mice with murine rotavirus

It has been found that mice infected with murine rotavirus can be protected against subsequent murine rotavirus infection for up to 2 months. It was also reported that protection against rotavirus infection in adult mice correlated with serum and stool rotavirus IgA titers. The present study was conducted to determine the duration of rotavirus antibody production and protection against rotavirus infection in this mouse model and its possible correlation with rotavirus antibody titers. It was found that protection of mice against subsequent infection following a single oral immunization with the murine rotavirus strain EDIM was 100% effective for at least 14 months, most of the lifetime of a mouse. During this period, serum and stool rotavirus antibody titers which included serum IgA, IgG, and neutralizing antibody to EDIM, as well as stool IgA, remained elevated. Of particular note, stool rotavirus IgA titers gradually decreased to levels that were approximately 10% of their peak at 1 month after infection but did not decrease further, while serum rotavirus IgG titers continuously increased during the 14 months of the study. Serum rotavirus IgA titers varied from month to month but overall remained relatively constant throughout the 14-month period. Thus, both serum and stool rotavirus antibody was retained at substantial levels long after a single rotavirus immunization in the absence of reexposure, and mice remained protected against reinfection.     

Azithromycin. A review of its use in paediatric infectious diseases

Azithromycin is an azalide antimicrobial agent active in vitro against major pathogens responsible for infections of the respiratory tract, skin and soft tissues in children. Pathogens that are generally susceptible to azithromycin include Haemophilus influenzae (including ampicillin-resistant strains), Moraxella catarrhalis, Chlamydia pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae, Legionella spp., Streptococcus pyogenes and Streptococcus agalactiae. Azithromycin is also generally active against erythromycin- and penicillin-susceptible Streptococcus pneumoniae and methicillin-susceptible Staphylococcus aureus. Azithromycin is administered once daily, achieves clinically relevant concentrations at sites of infection, is slowly eliminated from the body and has few drug interactions. In children, azithromycin is usually given as either a 3-day course of 10 mg/kg/day or a 5-day course with 10 mg/kg on the first day, followed by 5 mg/kg/day for a further 4 days. These standard regimens were as effective as amoxicillin/clavulanic acid, clarithromycin, cefaclor and amoxicillin in the treatment of children with otitis media. Azithromycin was also as effective as either phenoxymethylpenicillin (penicillin V), erythromycin, clarithromycin or cefaclor against streptococcal pharyngitis or tonsillitis in children, but appears to result in more recurrence of infection than phenoxymethylpenicillin in this indication, necessitating a dosage of 12 mg/kg/day for 5 days. Community-acquired pneumonia, bronchitis and other respiratory tract infections in children responded as well to azithromycin as to amoxicillin/clavulanic acid, cefaclor, erythromycin or josamycin. Azithromycin was similar or superior to ceftibuten in mixed general practice populations of patients. However, symptoms of lower respiratory tract infections resolved more rapidly with azithromycin than with erythromycin, josamycin or cefaclor. Skin and soft tissue infections responded as well to azithromycin as to cefaclor, dicloxacillin or flucloxacillin, and oral azithromycin was as effective as ocular tetracycline in treating trachoma. Although not as well tolerated as phenoxymethylpenicillin in the treatment of streptococcal pharyngitis, azithromycin is at least as well tolerated as most other agents used to treat respiratory tract and other infections in children and was better tolerated than amoxicillin/clavulanic acid. Adverse events that do occur are mostly gastrointestinal and tend to be mild to moderate in severity. CONCLUSIONS: Azithromycin is an effective and well tolerated alternative to first-line agents in the treatment of respiratory tract, skin and soft tissue infections in children, offerring the convenience of a short, once-daily regimen.     

Induction of reactivation of herpes simplex virus in murine sensory ganglia in vivo by cadmium

Herpes simplex viruses maintained in a latent state in sensory neurons in mice do not reactivate spontaneously, and therefore the factors or procedures which cause the virus to reactivate serve as a clue to the mechanisms by which the virus is maintained in a latent state. We report that cadmium sulfate induces latent virus to reactivate in 75 to 100% of mice tested. The following specific findings are reported. (i) The highest frequency of induction was observed after two to four daily administrations of 100 micrograms of cadmium sulfate. (ii) Zinc, copper, manganese, or nickel sulfate administered in equimolar amounts under the same regimen did not induce viral reactivation; however, zinc sulfate in molar ratios 25-fold greater than those of cadmium induced viral replication in 2 of 16 ganglia tested. (iii) Administration of zinc, nickel, or manganese prior to the cadmium sulfate reduced the incidence of ganglia containing infectious virus. (iv) Administration of cadmium daily during the first week after infection and at 2-day intervals to 13 days after infection resulted in the recovery from ganglia of infectious virus in titers 10- to 100-fold higher than those obtained from animals given saline. Moreover, infectious virus was recovered as late as 11 days after infection compared with 6 days in mice administered saline. (v) Administration of cadmium immediately after infection or repeatedly after establishment of latency did not exhaust the latent virus harbored by sensory neurons, inasmuch as the fraction of ganglia of mice administered cadmium and yielding infectious virus was similar to that observed in mice treated with saline. We conclude that induction of cadmium tolerance precludes reactivation of latent virus. If the induction of metallothionein genes was the sole factor required to cause reactivation of latent virus, it would have been expected that all metals which induce metallothioneins would also induce reactivation, which was not observed. The results therefore raise the possibility that in addition to inducing the metallothionein genes, cadmium inactivates the factors which maintain the virus in latent state.     

An open-label, noncomparative study to evaluate the efficacy, safety, and tolerability of azithromycin in the treatment of patients with acute sinusitis

The efficacy, safety, and tolerability of a 5-day, once-daily course of azithromycin were assessed in patients with acute sinusitis. Patients received two 250-mg capsules of azithromycin on day 1 and one 250-mg capsule on days 2 through 5. Of 102 clinically assessable patients, 27 (26.5%) were cured and 69 (67.6%) were improved on days 5 to 7. At days 12 to 16, 88 (86.3%) had a favorable clinical response. A total of 64 patients experienced adverse events; in all but two patients, adverse events were of mild or moderate severity. Thus azithromycin given once daily for 5 days was an effective treatment for patients with acute sinusitis.     

Permanent impairment of embryo development by hydrosalpinges

Recent reports suggest a deleterious effect of hydrosalpinges on pregnancy outcome for in-vitro fertilization (IVF) and improvement following surgical treatment. We compared the effect of hydrosalpinx on pregnancy outcome in 286 patients having 348 IVF cycles and followed the development of untransferred embryos for 7 days to determine if hydrosalpinges affect oocyte quality or embryo development. The delivery rate per retrieval was significantly lower for patients with hydrosalpinx, but was restored by surgical treatment to that of patients without hydrosalpinx. However, the implantation rate per embryo transferred and normal blastulation of untransferred embryos, which were significantly decreased in patients with hydrosalpinx, and growth arrest and degeneration of untransferred embryos, which were significantly increased compared to patients without hydrosalpinx, were not restored by surgical treatment of hydrosalpinges. We conclude that surgical treatment of hydrosalpinges decreases early pregnancy loss and improves pregnancy outcome, possibly by diminishing reversible deleterious effects exerted on the endometrium. As we have seen in our laboratory, hydrosalpinges may have a permanent negative influence on ovarian function, follicular development and oocyte quality since implantation of transferred embryos and normal blastulation of untransferred embryos remain low, and in-vitro growth arrest and degeneration remain high despite surgical treatment of hydrosalpinges.