Interactions of clindamycin with antibacterial defenses of the lung

Clindamycin is speculated to have select advantages in the treatment of certain infections because biologically active antibiotic is internalized by macrophages and PMNs in vitro. By challenging pulmonary host defenses with various bacterial species as probes, we were able to evaluate clindamycin-phagocyte interaction in vivo. A murine model was developed using an implanted mini-osmotic pump to maintain constant clindamycin blood levels at 1/4 MIC (1 microgram/ml). Mice pretreated for 24 h with clindamycin killed a significantly greater percentage of intratracheally inoculated Bacteroides thetaiotaomicron in 4 h than did control animals (37 +/- 2% versus 7 +/- 5%). The enhancing effects of clindamycin on pulmonary defenses could not be duplicated by a 1-h preincubation of B. theta in 1/4 MIC of clindamycin before inoculation into untreated mice. Clindamycin blood levels of 1 microgram/ml did not alter the rate at which Pseudomonas aeruginosa (clindamycin-resistant) was killed by pulmonary defenses, suggesting that clindamycin did not cause nonspecific activation of phagocytic defenses. Both PMNs and alveolar macrophages lavaged from the lungs of clindamycin-treated mice contained bioassayable concentrated intracellular antibiotic. The presence of intracellular antibiotic was further supported by experiments in which the intrapulmonary killing of large numbers of Staphylococcus aureus (sensitive, but not resistant organisms) was significantly enhanced (89 +/- 5 versus 70 +/- 5%) by clindamycin pretreatment. In contrast, phagocytes lavaged from mice with constant 1/4 MIC (4 micrograms/ml) blood levels of penicillin G had no detectable intracellular antibiotic activity and did not augment the intrapulmonary killing of B. theta.(ABSTRACT TRUNCATED AT 250 WORDS)     

Suboptimal clinical response to ciprofloxacin in patients with enteric fever due to <Emphasis Type="Italic">Salmonella</Emphasis> spp. with reduced fluoroquinolone susceptibility: a case series

Background

Salmonella spp. with reduced susceptibility to fluoroquinolones have higher than usual MICs to these agents but are still considered "susceptible" by NCCLS criteria. Delayed treatment response to fluoroquinolones has been noted, especially in cases of enteric fever due to such strains. We reviewed the ciprofloxacin susceptibility and clinical outcome of our recent enteric fever cases.

Methods

Salmonella enterica Serotype Typhi (S. Typhi) and Serotype Paratyphi (S. Paratyphi) blood culture isolates (1998–2002) were tested against nalidixic acid by disk diffusion (DD) and agar dilution (AD) and to ciprofloxacin by AD using NCCLS methods and interpretive criteria. Reduced fluoroquinolone susceptibility was defined as a ciprofloxacin MIC of 0.125–1.0 mg/L. The clinical records of patients treated with ciprofloxacin for isolates with reduced fluoroquinolone susceptibility were reviewed.

Results

Seven of 21 (33%) S. Typhi and S. Paratyphi isolates had reduced susceptibility to fluoroquinolones (MIC range 0.125–0.5 mg/L). All 7 were nalidixic acid resistant by DD (no zone) and by AD (MIC 128- >512 mg/L). The other 14 isolates were nalidixic acid susceptible and fully susceptible to ciprofloxacin (MIC range 0.015–0.03 mg/L).Five of the 7 cases were treated initially with oral ciprofloxacin. One patient remained febrile on IV ciprofloxacin until cefotaxime was added, with fever recurrence when cefotaxime was discontinued. Two continued on oral or IV ciprofloxacin alone but had prolonged fevers of 9–10 days duration, one was switched to IV beta-lactam therapy after remaining febrile for 3 days on oral/IV ciprofloxacin and one was treated successfully with oral ciprofloxacin. Four of the 5 required hospitalization.

Conclusions

Our cases provide further evidence that reduced fluoroquinolone susceptibility of S. Typhi and S. Paratyphi is clinically significant. Laboratories should test extra-intestinal Salmonella spp. for reduced fluoroquinolone susceptibility.

     

Significant disparity in base and sugar damage in DNA resulting from neutron and electron irradiation

In this study, a comparison of the effects of neutron and electron irradiation of aqueous DNA solutions was investigated to characterize potential neutron signatures in DNA damage induction. Ionizing radiation generates numerous lesions in DNA, including base and sugar lesions, lesions involving base–sugar combinations (e.g. 8,5′-cyclopurine-2′-deoxynucleosides) and DNA–protein cross-links, as well as single- and double-strand breaks and clustered damage. The characteristics of damage depend on the linear energy transfer (LET) of the incident radiation. Here we investigated DNA damage using aqueous DNA solutions in 10 mmol/l phosphate buffer from 0–80 Gy by low-LET electrons (10 Gy/min) and the specific high-LET (∼0.16 Gy/h) neutrons formed by spontaneous ²⁵²Cf decay fissions. 8-hydroxy-2′-deoxyguanosine (8-OH-dG), (5′R)-8,5′-cyclo-2′-deoxyadenosine (R-cdA) and (5′S)-8,5′-cyclo-2′-deoxyadenosine (S-cdA) were quantified using liquid chromatography–isotope-dilution tandem mass spectrometry to demonstrate a linear dose dependence for induction of 8-OH-dG by both types of radiation, although neutron irradiation was ∼50% less effective at a given dose compared with electron irradiation. Electron irradiation resulted in an exponential increase in S-cdA and R-cdA with dose, whereas neutron irradiation induced substantially less damage and the amount of damage increased only gradually with dose. Addition of 30 mmol/l 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS), a free radical scavenger, to the DNA solution before irradiation reduced lesion induction to background levels for both types of radiation. These results provide insight into the mechanisms of DNA damage by high-LET ²⁵²Cf decay neutrons and low-LET electrons, leading to enhanced understanding of the potential biological effects of these types of irradiation.     

Tertiary cytoreductive surgery in recurrent ovarian cancer: selection criteria and survival outcome

OBJECTIVES: Studies of tertiary cytoreductive surgery (TCS) in recurrent epithelial ovarian cancer are limited, and appropriate patient selection remains a clinical challenge. We sought to evaluate the impact of TCS on survival and to determine predictors of optimal tertiary resection. METHODS: Between January 1997 and July 2004, 47 women with recurrent epithelial ovarian cancer underwent TCS at two institutions. All patients received initial platinum and taxane-based chemotherapy following primary cytoreductive surgery. Clinico-pathologic factors and survival were retrospectively abstracted from medical records. Optimal TCS was defined as microscopic residual disease. RESULTS: Thirty of 47 (64%) patients underwent optimal TCS. Size of tumor implants<5 cm on preoperative imaging was the only significant predictor of achieving optimal TCS. Overall survival after TCS was statistically longer in patients with microscopic versus macroscopic residual disease (24 versus 16 months, p=0.03). After controlling for age, time to progression and optimal TCS, only the presence of diffuse disease at tertiary exploration remained a significant poor predictor of survival. However, in a cohort of patients with limited disease implants, multivariate analysis indicated that optimal TCS retained prognostic significance as a positive predictor of survival. Twelve patients (26%) experienced severe postoperative complications, including six with pulmonary embolism, four with fistulae and two with postoperative myocardial infarctions. CONCLUSIONS: Size of disease implants on preoperative imaging may guide the selection of candidates for TCS. In those patients with limited disease implants at laparotomy, optimal TCS is associated with improved survival.     

Therapeutic Potential of Thymoquinone in Triple-Negative Breast Cancer Prevention and Progression through the Modulation of the Tumor Microenvironment

To date, the tumor microenvironment (TME) has gained considerable attention in various areas of cancer research due to its role in driving a loss of immune surveillance and enabling rapid advanced tumor development and progression. The TME plays an integral role in driving advanced aggressive breast cancers, including triple-negative breast cancer (TNBC), a pivotal mediator for tumor cells to communicate with the surrounding cells via lymphatic and circulatory systems. Furthermore, the TME plays a significant role in all steps and stages of carcinogenesis by promoting and stimulating uncontrolled cell proliferation and protecting tumor cells from the immune system. Various cellular components of the TME work together to drive cancer processes, some of which include tumor-associated adipocytes, fibroblasts, macrophages, and neutrophils which sustain perpetual amplification and release of pro-inflammatory molecules such as cytokines. Thymoquinone (TQ), a natural chemical component from black cumin seed, is widely used traditionally and now in clinical trials for the treatment/prevention of multiple types of cancer, showing a potential to mitigate components of TME at various stages by various pathways. In this review, we focus on the role of TME in TNBC cancer progression and the effect of TQ on the TME, emphasizing their anticipated role in the prevention and treatment of TNBC. It was concluded from this review that the multiple components of the TME serve as a critical part of TNBC tumor promotion and stimulation of uncontrolled cell proliferation. Meanwhile, TQ could be a crucial compound in the prevention and progression of TNBC therapy through the modulation of the TME.     

Hyperpigmentation after nonsurgical blepharoplasty using plasma technology

Nitrogen plasma is considered nowadays one of the efficient treatment options for nonsurgical blepharoplasty. Although it is an overall safe treatment, it has some side effects. This short paper addresses the risk of hyperpigmentation following the use of plasma and list few suggestions on how to prevent it.     

Pre-marital predictors of marital violence in the WHO World Mental Health (WMH) Surveys

Social Psychiatry and Psychiatric Epidemiology - Intimate partner violence (IPV) is a pervasive public health problem. Existing research has focused on reports from victims and few studies have...