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Query: UMLS:C0032285 (pneumonia)
 54,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We demonstrated previously that human cytomegalovirus (CMV) infections could enhance the expression of cellular topoisomerase II and this enzyme activity is essential for CMV to replicate in vitro (Benson and Huang, 1988; Benson and Huang, 1990). In this study, we further show that in addition to m-AMSA and VM26 which we had previously reported, a widely used and clinically available drug, etoposide (VP-16 or VePesid) can irreversibly inhibit CMV replication at the drug concentration (2.5 micrograms/ml) greatly below toxic levels to stationary phase cells. Growing cells were more sensitive to etoposide than stationary phase cells and slight growth inhibition occurred at 2.5 micrograms/ml level. This inhibitor does not prevent the expression of CMV immediate-early and early genes, but can inhibit viral DNA and late viral-proteins synthesis. Because of their irreversible inhibitory effects and approval usage in clinical oncology, it is suggested that this group of compounds, particularly etoposide (VP-16), can be used to control life-threatening CMV infections, such as CMV pneumonitis and CMV retinitis, in cancer and immunocompromised patients or patients with AIDS.
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PMID:Irreversible inhibition of human cytomegalovirus replication by topoisomerase II inhibitor, etoposide: a new strategy for the treatment of human cytomegalovirus infection. 131 May 81

Type I and II topoisomerase activities were partially purified from Pneumocystis carinii. The catalytic (strand-passing) activities of both enzymes were selectively inhibited by members of a series of dicationic-substituted bis-benzimidazoles compared with those of topoisomerases of mammalian (calf thymus) origin. The most active inhibitors of the parasite enzymes were also highly effective in an in vivo animal model of P. carinii pneumonia. Selected dicationic-substituted bis-benzimidazoles also strongly inhibited the induction of the topoisomerase I- and II-mediated cleavable complex, suggesting that the biologically active DNA minor groove-binding molecules inhibit the enzyme-DNA binding step of the topoisomerase reaction sequence. The apparent selectivities for the parasite enzymes and the low levels of toxicity to mammalian cells for the biologically active bis-benzimidazoles suggest that these compounds hold promise as effective therapeutic agents in the treatment of a life-threatening AIDS-related disease, P. carinii pneumonia.
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PMID:Selective inhibition of topoisomerases from Pneumocystis carinii compared with that of topoisomerases from mammalian cells. 781 Sep 95

Five topoisomerase II inhibitors (amsacrine [m-AMSA], two epipodophyllotoxins, and two quinolones) and the alkaloid camptothecin (a topoisomerase I inhibitor) were evaluated to assess their activities against Pneumocystis carinii. In vitro, both etoposide (VP-16) and teniposide (VM-26) at 1 microgram/ml suppressed P. carinii growth. Amsacrine was toxic to P. carinii and to the feeder cells in vitro. Camptothecin suppressed the growth of P. carinii in vitro only at 100 micrograms/ml. Studies in immunosuppressed mice demonstrated the efficacy of teniposide against P. carinii pneumonia, but successful administration of teniposide was schedule dependent with significant toxicity at therapeutic dosages.
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PMID:Activity of topoisomerase inhibitors against Pneumocystis carinii in vitro and in an inoculated mouse model. 839 91

A series of over 60 agents representing several different classes of compounds were evaluated for their effects on the ATP pools of Pneumocystis carinii populations derived from immunosuppressed rats. A cytotoxicity assay based on an ATP-driven bioluminescent reaction was used to determine the concentration of agent which decreased the P. carinii ATP pools by 50% versus untreated controls (IC50). A ranking system based on the IC50 value was devised for comparison of relative responses among the compounds evaluated in the cytotoxic assay and for comparison to in vivo efficacy. With few exceptions, there was a strong correlation between results from the ATP assay and the performance of the compound in vivo. Antibiotics, with the exception of trimethoprim-sulfamethoxazole (TMP-SMX), were ineffective at reducing the ATP pools and were not active clinically or in the rat model of P. carinii pneumonia. Likewise, other agents not expected to be effective, e.g., antiviral compounds, did not show activity. Standard anti-P. carinii compounds, e.g., TMP-SMX, pentamidine, and dapsone, dramatically reduced ATP levels. Analogs of the quinone and topoisomerase inhibitor groups were shown to reduce ATP concentrations and hold promise for further in vivo investigation. The cytotoxicity assay provides a rapid assessment of response, does not rely on replicating organisms, and should be useful for assessment of structure-function relationships.
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PMID:A cytotoxicity assay for evaluation of candidate anti-Pneumocystis carinii agents. 902 Nov 95

Trovafloxacin had greater in-vitro activity than comparative fluoroquinolone agents against penicillin-sensitive pneumococci in studies from the USA, UK, Slovakia, Czech Republic, Sweden and South Africa. This activity was maintained against penicillin-resistant strains, with MIC90 values of < or = 0.25 mg/L observed for both groups. Bactericidal activity appeared to occur within one or two dilutions of the MIC and, in the limited number of strains studied, the MIC was independent of the medium tested and pH over the range pH 5-8. Mutation to decreased susceptibility to trovafloxacin occurred in vitro at a low frequency in the pneumococcus (< or = 8.9 x 10(-9)). Mutants with changes in the topoisomerase IV A subunit (GrlA) were still inhibited by 0.5 mg/L of trovafloxacin. Trovafloxacin was more efficacious than ciprofloxacin, temafloxacin or ofloxacin in mouse pneumonia models for both penicillin-susceptible and penicillin-resistant pneumococci. Trovafloxacin was also highly efficacious in a rabbit pneumococcal meningitis model. These data suggest that the clinical efficacy of trovafloxacin against pneumococci should be evaluated further.
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PMID:In-vitro and in-vivo activity of trovafloxacin against Streptococcus pneumoniae. 922 70

We report on a sixty-seven year old miner with pemphigus vulgaris characterised clinically by a three month history of relapsing oral lesions and blisters/erosions on the trunk, axillae and extremities, histologically by suprabasal cleavage due to acantholysis, immunologically by the epidermal intercellular net-like pattern due to deposits of IgG- and IgM-antibodies and complement C3 in the direct immunofluorescence as well as by serum antibodies to desmoglein 3 (130 KD) and plakoglobin (85 KD) by immunoblotting analysis. Silicosis has already been known for 6 years. In addition, antinuclear antibodies, anti-ssDNA-antibodies and anti-topoisomerase antibodies were found. Clinical improvement and clearing of skin symptoms could be achieved by systemic steroids in combination with cyclophosphamide. However, the patient died of sepsis deriving from recalcitrant pneumonia. Although the association of silicosis with various autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and dermatomyositis has been reported many times, our patient is, to the best of our knowledge, the second case with features of the two diseases: pemphigus vulgaris and silicosis.
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PMID:Pemphigus vulgaris in association with silicosis. 1112 24

New quinolone compounds have been recommended for use in the treatment of respiratory tract infections, particularly pneumonia caused by multi drug-resistant Streptococcus pneumoniae. Of concern, however, is the recent emergence of pneumococcal isolates with reduced susceptibilities to both old and new quinolone compounds. This necessitates the employment of quinolone-use strategies aimed at restricting the emergence of resistance, to extend the effectiveness of this very important class of antibacterial agents. This article provides a comprehensive review of the recent discoveries in type II topoisomerase/quinolone structure-function relationships. It also addresses new insights into the mechanisms of quinolone resistance, the predicted trends in quinolone resistance, and possible strategies for quinolone use against S. pneumoniae.
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PMID:Quinolone Resistance: Older Concepts and Newer Developments. 1117 27

Fluoroquinolone-resistant cultures of Streptococcus pneumoniae were isolated from 2 patients who were treated for pneumonia with levofloxacin. Nucleotide sequence analysis of bacterial DNA showed that the isolates contained mutations in both parC (DNA topoisomerase IV) and gyrA (DNA gyrase), which were shown previously to confer fluoroquinolone resistance. With the resistant isolates, the MICs for ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, and trovafloxacin were above the maximal serum drug concentrations reported for standard dosage regimens. In contrast, the MICs for gemifloxacin and moxifloxacin were below the maximal serum concentrations. Increased effectiveness at blocking the growth of resistant mutants should make gemifloxacin and moxifloxacin less likely to allow the enrichment of mutants within susceptible populations. Additional resistance mutations in the isolates were readily obtained by plating on gemifloxacin- or moxifloxacin-containing agar. Thus, neither compound is expected to halt further accumulation of resistance mutations once mutant enrichment has been initiated by less potent derivatives.
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PMID:Fluoroquinolone-resistant Streptococcus pneumoniae associated with levofloxacin therapy. 1151 44

The frequency of fluoroquinolone-resistant Streptococcus pneumoniae has increased as fluoroquinolone administration for treatment of respiratory tract infections has increased. Levofloxacin treatment failed in a patient who had pneumococcal pneumonia and had received three previous courses of levofloxacin therapy. Susceptibility testing revealed high-level resistance to levofloxacin (minimum inhibitory concentration [MIC] > 32 microg/ml), and cross-resistance to moxifloxacin (MIC 4 microg/ml), trovafloxacin (6 microg/ml), and gatifloxacin (12 microg/ml). Sequencing of the quinolone-resistance determining region revealed a mutation of serine-81 to phenylalanine (Ser81-->Phe) in the gyrA region of DNA gyrase and a Ser79-->Phe mutation in the parC region of topoisomerase IV The patient was treated successfully with intravenous ceftriaxone followed by oral cefprozil. Clinicians must be aware of local resistance patterns and the potential for fluoroquinolone treatment failures in patients with infections caused by S. pneumoniae.
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PMID:Levofloxacin treatment failure in a patient with fluoroquinolone-resistant Streptococcus pneumoniae pneumonia. 1189 97

The emergence of resistance to antimicrobial drugs in a range of bacterial pathogens of the respiratory tract creates a challenge for the clinical diagnostic laboratory. Resistance to macrolides among strains of Streptococcus pneumoniae has reached high levels in many countries. There are two main types of resistance mechanisms, one (MLSB phenotype) leading to high-level resistance and the other (M phenotype) resulting in a lower level of resistance. As there are indications that high-level resistance may have clinical relevance, it is important to be able to detect such strains. This is now possible with the erythromycin/clindamycin double disc diffusion test. Although resistance to beta-lactams has also increased, there is now evidence that some beta-lactams are still effective against isolates that have low-level resistance. In response to these observations, new breakpoints have now been introduced by the National Committee for Clinical Laboratory Standards (NCCLS) for amoxicillin, cefotaxime and ceftriaxone, which increase the percentage of pneumococcal isolates that can still be treated effectively with these agents. As a consequence of the increasing use of fluoroquinolones, resistance has now emerged to this group of compounds and this has been associated with clinical failures. Although standard minimum inhibitory concentration tests can detect strains with high levels of resistance (double step mutants) they are not reliable in detecting strains with a single mutation. This is important as there is increasing evidence that strains with a single mutation in the target topoisomerase are even more likely to develop a second mutation, leading to higher levels of resistance and thus probably, therapeutic failure. Because resistance to fluoroquinolones is currently low in the US, the NCCLS does not recommend that susceptibility testing with the newer respiratory fluoroquinolones be carried out routinely. However, since the respiratory fluoroquinolones have in fact become the first line of therapy for the treatment of community-acquired pneumonia, it may now be time to institute routine testing of clinical isolates of pneumococci to these agents. Simple techniques for the clinical diagnostic laboratory to enable these first-step mutants to be detected are urgently required.
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PMID:The era of antimicrobial resistance-implications for the clinical laboratory. 1251 45


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