Adverse influence of diazepam upon resistance to Klebsiella pneumoniae infection in mice

doi:10.1016/0378-4274(83)90188-1

Toxicology Letters

Volume 16, Issues 3–4, May 1983, Pages 281-284

https://doi.org/10.1016/0378-4274(83)90188-1 Get rights and content

Abstract

Male and female mice, IOPS OF1 strain, received an i.p. injection of diazepam 1, 2, 4 or 8 mg/kg daily for 3 days prior to i.p. challenge with Klebsiella pneumoniae.

Diazepam pretreatment increased mortality due to Klebsiella pneumoniae indicating that diazepam alters natural resistance to infection. The mechanism has not been elucidated but would appear to involve T cells and/or macrophages.

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Similarly benzodiazepines have been associated with an increased incidence of pneumonia and mortality from pneumonia in patients (Obiora et al., 2013; Amarasuriya et al., 2012). In animals diazepam is known to increase susceptibility to infection in vivo with Klebsiella pneumonia (Laschi et al., 1983), Salmonella typhimurium (Galdiero et al., 1995), and Mycobacterium bovis (Righi et al., 1999) and Vaccinia and cowpox viral infection (Huemer et al., 2010). We have recently shown that diazepam treatment also increased mortality in mice with Streptococcus pneumoniae infection (Sanders et al., 2013).
Benzodiazepines increase vulnerability to infection through α1 subunit dependent Υ-amino-butyric-type-A (GABA_A) signalling. Immune cell expression of GABA_A receptors and the effect of diazepam on influenza infection was investigated. In patients with pneumonia, α1 GABA_A subunits were expressed on alveolar macrophages and blood monocytes. In mice, influenza induced dynamic changes in immune cell GABA_A subunit expression: α1 subunits decreased on alveolar macrophage, but increased on monocytes, CD4 + and CD8 + T cells. Following influenza viral infection, diazepam delayed weight loss on day 3 but later increased weight loss. Viral load was unaffected but increased bacterial superinfection was noted on day 10.
Influence of dexmedetomidine therapy on the management of severe alcohol withdrawal syndrome in critically ill patients
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The interindividual and intraindividual variability of benzodiazepine pharmacokinetics and their unpredictable duration of action in cases of prolonged use or end-organ dysfunction heighten the risk associated with this class of medications for AWS [19,20]. Furthermore, benzodiazepines have been associated with ICU delirium, a reduction in restorative sleep, respiratory depression, anion gap metabolic acidoses, pneumonia, and immunosuppression [21–27]. In this study, we observed a 33% incident need for invasive mechanical ventilation, particularly for airway protection, and an 18% incidence of new-onset pneumonia during ICU admission.
Although benzodiazepines are first-line drugs for alcohol withdrawal syndrome (AWS), rapidly escalating doses may offer little additional benefit and increase complications. The purpose of this study was to evaluate dexmedetomidine's impact on benzodiazepine requirements and hemodynamics in AWS.
This retrospective case series evaluated 33 critically ill adults with a primary diagnosis of AWS from 2006 to 2012 at an academic medical center.
Dexmedetomidine began a median (interquartile range) of 11 (2, 32) hours into intensive care unit admission and was titrated to an infusion rate of 0.7 (0.4, 0.7) μg kg^− 1 h^− 1 to achieve the desired depth of sedation. In the 12 hours after dexmedetomidine began, patients experienced a 20-mg reduction in median cumulative benzodiazepine dose used (P < .001), a 14-mm Hg lower mean arterial pressure (P = .03), and a 17-beats/min reduction in median heart rate (P < .001). Four (12%) patients experienced hypotension (systolic blood pressure < 80 mm Hg) during therapy, and there were no cases of bradycardia (heart rate < 40 beats/min).
Dexmedetomidine decreased benzodiazepine requirements and improved the overall hemodynamic profile of patients with severe AWS. These results provide promising evidence about the potential benefit of dexmedetomidine for AWS.
Point: Should benzodiazepines be avoided in mechanically ventilated patients? Yes
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Effects of different doses and schedules of diazepam treatment on lymphocyte parameters in rats
2010, International Immunopharmacology
Citation Excerpt :
In this line of evidence, it was suggested that prenatal diazepam (1.5 mg/kg) treatment decreased the resistance of the adult litters to Mycobacterium bovis [19] and also that adult hamsters treated with high doses of diazepam (2.0 and 3.0 mg/kg) and inoculated with M. bovis exhibited increased granuloma areas in the liver and lungs and increased scores of M. bovis colony-forming units isolated from the liver, lung and spleen [20]. Another study, involving adaptive immune response, established that during an adult life exposure, it was necessary to employ high doses of diazepam (8 mg/kg) to impair mice's resistance to a bacterial infection [21]. TSPO is an important component of the mitochondrial permeability transition pore (MPTP).
Benzodiazepines (BZD) are widely used for the treatment of anxiety. They enhance GABA-ergic neurotransmission through the binding on specific BDZ recognition sites, within the GABA_A receptor-ion channel complex. However, recent studies showed that BZD also act on peripheral benzodiazepine receptor sites (PBR) or translocator protein 18 kDa (TSPO). Evidence for a direct immunomodulatory action for BZD emerged from studies that demonstrated the presence of TSPO on immune/inflammatory cells. The present study was designed to analyze the effects of diazepam on rat lymphocyte parameters, specifically on phenotype, cell proliferation and cell death. The effects of both acute and long-term (21 days) diazepam (1 and 10 mg/kg/day) administrations were evaluated. Results showed that diazepam (1 mg/kg) treatment did not change the immune parameters analyzed. However, both diazepam (10 mg/kg) acute and long-term treatments decreased the number of apoptotic cells; they also increased the percentage of T cytotoxic cells; decreased the percentage of B cells and increased the corticosterone serum levels. The induction of functional tolerance was suggested for the highest dose of diazepam (10 mg/kg), but not for the smaller dose (1 mg/kg) used, at least for diazepam effects on corticosterone serum levels. Diazepam effects were discussed as being related to the number of TSPO sites present on immune cells and/or to the increased levels of serum corticosterone observed after the treatments used.
Diazepam leads to enhanced severity of orthopoxvirus infection and immune suppression
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Citation Excerpt :
Midazolam and propofol have been reported to alter secretion of interleukin 8, a chemotactic agent in human neutrophils [34], and on human peripheral blood monocytes midazolam showed inhibition of the LPS-induced production of IL1-beta and TNF [9]. Midazolam was also reported to improve the outcome of septic rats most recently [35] contradicting old reports of an adverse effect of diazepam on Klebsiella infection [36]. These discrepancies highlight the difficulties in many animal studies which arise from the problem of dissecting direct drug effects on immune cells from the psychotropic effect indirectly influencing immune mechanisms.
Benzodiazepines are drugs widely used as tranquilizers and in various other indications. We treated Balb/c mice with diazepam and infected them with cowpox (CPXV) and vaccinia virus (VACV). Disease index, weight loss and the antibody response were determined. Additionally the influence of different benzodiazepines on the mitogen response of human peripheral blood lymphocytes and spleen cells was tested. Diazepam led to earlier disease onset, prolonged duration of symptoms, higher weight loss and overall disease index in VACV infected mice. CPXV infected mice developed poxviral skin lesions only after drug administration and a significant decrease in the specific antibody response was also observed. Diazepam and alprazolam also inhibited the proliferative response of human lymphocytes/spleen cells in vitro but did not show noteworthy apoptotic effects. It is surprising that even a single dose of diazepam has a profound influence on the immune system, sufficient to facilitate symptomatic infectious disease. These data provide first evidence that commonly used drugs like Valium^® may augment severity of rare poxvirus infections such as CPXV or monkeypox. As VACV is still used as life vaccine against smallpox there is also a risk of enhanced side effects or possible interference with the success of vaccination.

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Adverse influence of diazepam upon resistance to Klebsiella pneumoniae infection in mice

Abstract

Prolongation of survival in mouse tail skin allografts by valium (diazepam)

Transplantation

Suppression of humoral and cellular immunity in normal mice by diazepam

Immunol. Lett.

Inhibition de la blastogénèse lymphocytaire par le diazépam, le méprobamate et d'autres drogues psychotropes

C.R. Acad. Sci. Paris

The national toxicology program and immunological toxicology

Pharmacol. Rev.