Adjuvant non-bacteriolytic and anti-inflammatory combination therapy in pneumococcal meningitis: an investigation in a mouse model.

OBJECTIVES: Therapy with antibiotics, dexamethasone, and supportive intensive care has improved the prognosis of pneumococcal meningitis, but mortality remains high. Here, we investigated an adjunctive combination therapy of the non-bacteriolytic antibiotic daptomycin plus several anti-inflammatory agents to identify the currently most promising adjunctive combination therapy for pneumococcal meningitis. METHODS: C57BL/6 mice were infected by injection of pneumococci into the cisterna magna. Treatment was begun 21 h after infection, and consisted of ceftriaxone plus (a) dexamethasone, (b) dexamethasone plus daptomycin, (c) daptomycin, (d) daptomycin plus an anti-IL1 antibody, (e) daptomycin plus roscovitine, or (f) daptomycin plus an anti-C5 antibody. Animals were followed until 45 h after infection. Furthermore, adjunctive daptomycin plus anti-C5 antibodies were assessed in a long-term follow-up. RESULTS: Adjunctive treatment with daptomycin and an anti-C5 antibody was superior to adjunctive dexamethasone and reduced disease symptoms (clinical score 1.1 ± 1.1 versus 5.0 ± 2.7, p < 0.0083), improved explorative activity (open field test 17.8 ± 8.2 versus 7.4 ± 4.3 crossed fields/2 minutes, p < 0.0083), and reduced hearing impairment (thresholds for click stimulus 96.1 ± 14.7 versus 114.8 ± 9.3 dB SPL, p < 0.0083) in the acute stage. Furthermore, explorative activity (14.4 ± 7.3 crossed fields/2 minutes versus 6.3 ± 7.2, p < 0.05) and cognitive function (t-maze test, exploration time previously unknown alley 72.4 ± 14.3 versus 48.7 ± 25.6%, p < 0.05) was improved at 2 weeks after infection. Treatment with daptomycin plus an anti-IL-1ß antibody or roscovitine was not of significant benefit in comparison to adjunctive therapy with dexamethasone. CONCLUSIONS: An adjunctive combination of the non-lytic antibiotic daptomycin plus an anti-C5 antibody was superior to standard therapy with adjunctive dexamethasone in the treatment of pneumococcal meningitis.

The changes of T-PAH levels and health status of mussels in Izmit bay (Turkey) after Marmara earthquake and subsequent refinery fire.

As is well known, a powerful earthquake along the North Anatolian Fault struck the eastern part of the Marmara region on August 17, 1999. Izmit Bay, which is known as one of the most polluted sites of Turkey, was also affected by the quake and the subsequent refinery fire. The measurements performed just before and after the earthquake showed that T-PAH levels increased significantly after the event [Okay OS, Tolun L, Telli-Karakoç F, Tüfekçi V, Tüfekçi H, Morkoç E. Izmit Bay (Turkey) ecosystem after Marmara earthquake and subsequent refinery fire: the long-term data. Marine Pollution Bulletin 2001;42:361-9]. In the framework of ecotoxicological studies, the Bay ecosystem was continuously monitored for T-PAH levels in seawater, sediments and mussels (Mytilus galloprovincialis) to find out whether change occurred during the 2-year period following the earthquake. For that purpose, after the earthquake, the samples were collected six times between the period of September 1999 and March 2001 at coastal stations of the Bay situated away from the mouth of main discharges. The responses of the mussels were also measured by means of the lysosomal stability of the blood cells and feeding rate biomarker techniques at two different sites of the bay. Although the T-PAH levels in all matrices generally showed a decreasing trend, they were found to be still high especially at stations near the refinery. Both biomarker results showed that the health status of the mussels is very poor in the Bay ecosystem, based on the results obtained from the two sites monitored.

Izmit Bay (Turkey) ecosystem after Marmara earthquake and subsequent refinery fire: the long-term data.

As a part of Marmara Sea, Izmit Bay (Turkey) has been one of the most polluted sites in the region for the last 25 years. On 17 August 1999, a powerful earthquake along the North Anatolian Fault struck the eastern part of the Marmara region including Izmit Bay. The earthquake destroyed many coastal cities. The Bay was also affected by the quake and subsequent fire in the refinery situated on the north-eastern coast of the Bay. Oceanographic characteristics and polycyclic aromatic hydrocarbon (PAH) levels of Izmit Bay (Marmara Sea) have been investigated to find out the degree of contamination. Seawater samples were collected at nine stations of the Bay in April and September 1999 and the results were compared with those obtained in the previous years (1984 and 1994). Monitoring data are presented for plant nutrients (nitrate + nitrate, ortho-phosphate and silicate), dissolved oxygen and chlorophyll a. Surface sediments and mussels, Mytilus galloprovincialis, have been analysed for total PAH (T-PAH) contents in April and September 1999 (before and after the Marmara Earthquake) for the samples collected from eight coastal stations of the Bay. Biomarker (Lysosomal stability and feeding rate) studies at three different sites of the Bay have also been performed to investigate the effect of pollution on mussels. Nitrate + nitrite levels in the upper layer of the eastern part of the Bay increased significantly compared to those measured before the earthquake. Of the samples analysed, the highest o-phosphate concentrations were found in September 1999 in the bottom waters of the Bay. The concentration of chlorophyll a reached its minimum value of the last 15 years. Dissolved oxygen decreased dramatically from 1984 to 1999. Total PAH concentrations measured in April 1999 at both offshore and coastal sites of the Bay were more or less the same (2 micrograms l-1). The subsequent fire after the earthquake caused an increase in the total PAH levels in water column, in sediment and in mussels. Seawater total PAH concentrations ranged between 3.5 and 11 micrograms l-1 at open coast stations and 5-17.5 micrograms l-1 at coastal stations in September 1999. A 2- to 3-fold increase in sediment PAH concentrations (200-5220 mg kg-1 dry weight) was detected after the earthquake. This increase was much more significant in the sediments located around the refinery. More contaminated mussels were detected around the refinery area (110-170 mg kg-1 dry weight). Overall, sediment and mussel PAH concentrations in Izmit Bay are much higher than those found in the other marine systems. In general, the feeding rate and the neutral red retention times of the mussels decreased in some sites of the Bay after the earthquake, but no direct correlation could be detected between the body burden of mussels and biomarkers or between the two biomarker techniques.

Towards a clean Izmit Bay.

The elongated semi-enclosed Bay of Izmit, which receives both domestic and industrial wastes, has been monitored by measuring its physical and biochemical parameters for 2 years, 1994-1995. It is clear that there are two distinct water masses. The upper layer has been occupied by the less saline (22-26 ppt) waters of the Black Sea origin; whereas the lower layer contains saline (38.5 ppt) Mediterranean waters. The seasonal variations in the biochemical characteristics were dependent on the bay's two-layer flow system. If one considers the distribution of transparency in the upper bay waters, it has been observed that the Secchi disk depth (SDD) decreases from west to east. Furthermore, these depths are limited by the high primary productivity associated with the low concentrations of nutrients observed during the spring. Discharges of wastes into the surface waters significantly affect the biological production and oxygen consumption in the lower layer. Within the last 10 years, 80% of organic matter has been removed from industrial wastewater. However, organic loads from the domestic wastewaters have doubled because of the growth in the surrounding population. Fortunately, as a result, the total organic loads in the bay have not changed significantly within the last 10 years.

The pollution status and the toxicity of surface sediments in Izmit Bay (Marmara Sea), Turkey.

Izmit Bay is one of the most polluted and populated enclosed sea in Turkey. It has been the centre of industrial activities for the last 30 years. Seven major sources enter the bay waters along the north coastline of the bay. This investigation forms part of continuing ecotoxicology studies in the Izmit Bay designed to constrain and minimise the pollution caused by flourishing industry and a growing population. Sediments sampled from the mouths of the major discharges of Izmit Bay were analysed for their organic carbon, total polycyclic aromatic hydrocarbon (t-PAH) and trace inorganic element (Cd, Al, As, Pb, Hg and Cu) contents and compared with those found in the sediments from the reference station in the outer bay (in the Marmara Sea). The toxicity of sediments was determined in the bulk and elutriate samples by using algal (Phaeodactylum tricornutum) batch bioassays. Chemical data showed that the sediments collected from the inner sites of the bay have been contaminated with Cd, Hg, As and PAHs. Organic carbon contents were also found higher. All the major industrial discharges into the bay are now biologically treated but bioassays performed with bulk sediments revealed that the recent sediments are toxic to the microalgae throughout the bay. The results are consistent with the previous toxicity studies performed with the industrial discharges.