Effectiveness of oral chlorhexidine on nosocomial pneumonia, causative micro-organisms and mortality in critically ill patients: a systematic review and meta-analysis.

We carried out a systematic review and meta-analysis of randomized trials to explore the effectiveness of oral chlorhexidine on nosocomial pneumonia, causative bacteria, and mortality. PubMed, Embase, and the Cochrane Register of Controlled Trials were searched for randomized trials in critically ill patients receiving oral chlorhexidine. Odds ratios (OR) were pooled with the random effects model. Twenty-two randomized trials including 4277 patients were identified. Chlorhexidine significantly reduced the incidence of nosocomial pneumonia (OR 0.66; 95% confidence interval [CI] 0.51-0.85) and ventilator-associated pneumonia (OR 0.68, 95% CI 0.53-0.87). There was a significant reduction of nosocomial pneumonia due to both Gram-positive (OR 0.41; 95% CI 0.19-0.85) and Gram-negative (OR 0.68; 95% CI 0.51-0.90) bacteria, but only pneumonia due to "normal" flora (OR 0.51; 95% CI 0.33-0.80). The subgroup analysis revealed a significant benefit of chlorhexidine on nosocomial pneumonia in surgical patients only (OR 0.52; 95% CI 0.33-0.82). Mortality was not affected. This review indicates that in critically ill, mainly surgical, patients, oral chlorhexidine reduces nosocomial pneumonia, ventilator-associated pneumonia, nosocomial pneumonia due to Gram-positive and Gram-negative bacteria, and due to "normal" flora, without affecting mortality. Further studies should explore the efficacy of oral chlorhexidine in non-surgical critically ill population.

Oral endotoxin in healthy adults.

This article presents a study that measured oral endotoxin levels in healthy persons with the Limulus amoebocyte lysate microassay. Only young nonsmoking adults with a healthy dentition measured with the plaque index and a good level of oral hygiene based on a twice-daily (morning and evening) tooth-brushing regimen were admitted to this open study. Each person was required to provide two oral washings of 10 ml sterile saline solution 1 week apart. Only those volunteers without oral carriage of aerobic gram-negative bacilli were enrolled in the baseline study. A total of 15 healthy adults with a median age of 29 years (range, 25 to 43 years) were included in the trial. The mean plaque score of the group was 1.2 +/- 0.1. They all maintained a twice-daily tooth-brushing regimen unaltered throughout the sampling period. A total of 30 mouth rinses were studied. None of the samples yielded potential pathogens including aerobic gram-negative bacilli, Staphylococcus aureus and yeasts; a culturing technique based on preenrichment in nutrient medium was used. Data showed mean oral endotoxin levels of 20 ng per ml of mouth rinse; the aerobic E. coli endotoxin was used as the classical standard. This is equivalent to 1 mg of anaerobic endotoxin per ml of undiluted saliva after correcting for the 10 to 10(2) dilution factor of the mouth rinse itself and for the 10(3) times less sensitivity of anaerobic endotoxin in the Limulus amoebocyte lysate-assay. The discussion includes the physiologic and clinical benefit of the low endotoxicity of anaerobic gram-negative flora apart from the technical aspects of both culture and endotoxin assays used in the study.

Effects of sarafloxacin hydrochloride on human enteric bacteria under simulated human gut conditions.

The effects of sarafloxacin, a newly developed veterinary fluoroquinolone antimicrobial, on 15 strains of aerobic and anaerobic bacteria of human origin were assessed under simulated human gut conditions. An in vitro gut simulation model was designed to mimic the situation of sarafloxacin (free and bound to meat) passing through the human gastrointestinal tract. The survival of bacteria in the simulation model and any subsequent change in the sensitivity of isolates to sarafloxacin were measured. The inhibitory level of sarafloxacin for the tested bacteria was strain dependent. It appeared that in broth culture Escherichia coli isolates were sensitive to sarafloxacin concentrations 5-fold lower than the concentrations present in the simulated gut model, suggesting that sarafloxacin may be partially unavailable due to absorption to organic matter in the model. There was no significant observed change in the sarafloxacin sensitivity of the bacterial strains exposed to the compound in the model.

Selective decontamination of the digestive tract contributes to the control of disseminated intravascular coagulation in severe liver impairment.

A premature neonate with severe Coxsackie B1 hepatitis acquired in utero developed disseminated intravascular coagulation a few days after birth. The neonate did not respond to conventional treatment. Eradication of aerobic gram-negative bacilli (Enterobacteriaceae) from the gut with oral nonabsorbable polymyxin E and tobramycin (selective decontamination of the digestive tract) was followed by clinical improvement; disseminated intravascular coagulation was controlled. After an unstable convalescence, the neonate recovered and was discharged in good general condition. A correlation between oral feeding, gut carriage of Enterobacteriaceae, fecal endotoxin pool, and platelet counts was observed. The eradication of gut carriage of aerobic gram-negative bacilli was associated with a significant decrease of the intestinal endotoxin pool and paralleled the recovery from thrombocytopenia. Selective decontamination is discussed as a method of possible value for controlling systemic endotoxin-induced symptoms in the critically ill with intestinal endotoxemia.

Effect of selective elimination of the oral flora on mucositis in irradiated head and neck cancer patients.

Recently it has been reported that chlorhexidine 0.1% rinsing was not successful in eradication of gram-negative bacilli in patients who have head and neck cancer. These bacilli could play a role in irradiation mucositis. This study reports the effect of lozenges containing 2 mg polymyxin E, 1.8 mg tobramycin, and 10 mg amphotericin B qid on the oropharyngeal flora in 15 irradiated head and neck cancer patients. The results were compared with those of a previous study in two groups of 15 patients comparing chlorhexidine rinsing with placebo. In all patients using lozenges, eradication of gram-negative bacilli and yeasts was achieved within 3 weeks. A significant increase of enterococci was found. Mucositis was significantly reduced compared with the previous two groups. All patients showed erythema only, whereas 80% of both the placebo and chlorhexidine rinsing patients suffered from severe mucositis, with signs of pseudomembranes developing from the third week of conventional irradiation protocol. The effect of selective elimination of gram-negative bacilli from the oropharynx and the prevention of severe mucositis may be explained by the eradication of these bacteria and/or neutralization of salivary endotoxin, released by gram-negative bacilli, mediating the inflammatory processes.

Mucositis prevention by selective elimination of oral flora in irradiated head and neck cancer patients.

Mucositis induced by irradiation is the reactive inflammatory-like process of the oropharyngeal mucous membranes following irradiation. Bacteria colonizing the oral tissues are thought to contribute to this inflammatory process. The eradication of Gram-negative bacilli (selective elimination of oral flora) in fifteen comparably irradiated head and neck cancer patients was found to be associated with a significant reduction in mucositis compared with two groups of 15 patients receiving either placebo or chlorhexidine rinsing. Criteria used were the extent of local mucositis signs (mucositis score), as well as generalized side-effects such as the need of nasogastric tube feedings following severe feeding problems. Mucositis signs were confined to erythema only in all selectively decontaminated patients. No pseudomembranes were observed and artificial feeding was completely prevented. These promising results need further confirmation in larger (multicenter) studies.

Chlorhexidine inactivation by saliva.

Chlorhexidine mouth rinsing is commonly used for oral flora reduction. Indigenous microorganisms (viridans streptococci) are significantly suppressed, while "hospital-acquired" gram-negative bacilli are not affected in vivo. To explain the discrepancies between good in vitro and poor in vivo activity of chlorhexidine, minimum bactericidal concentration values for 120 isolates were studied by means of a standard dilution method in fresh whole saliva, broth, and glucose 5%. Both saliva and broth significantly reduced the bactericidal activity of chlorhexidine against all microorganisms tested as compared to glucose 5% (p less than 0.01). Minimum bactericidal concentrations for indigenous flora were significantly lower than the values obtained for the "hospital-acquired" microorganisms (p less than 0.05). These observations of chlorhexidine inactivation by saliva may explain why chlorhexidine mouth rinsing is of limited value in decontaminating the oral cavity.

Sink flora in a long-stay hospital is determined by the patients' oral and rectal flora.

Sinks in a new long-stay hospital (LSH) were cultured weekly during 4 consecutive months to evaluate the microbial profile before and after occupancy of the hospital. From the elderly patients admitted to the patient care rooms oral and rectal specimens were collected to examine the contribution of the patients' flora to the sink contamination. Isolates were typed biochemically, serologically and by susceptibility pattern. Before occupancy Gram-negative bacilli were not isolated. Once the elderly patients, who were highly colonized on admission, occupied their rooms identical strains gradually contaminated the sinks. Escherichia coli, Klebsiella, Pseudomonas and Acinetobacter species were the major correlating strains. The mean concentration of the correlating isolates was higher in throat and intestines compared to the mean concentration of the non-correlating strains. These strains seem to have a greater chance to be shed and then transferred via the hands of personnel to sinks. This report shows that the major route of environmental contamination is from patient carriers to sinks, and not the reverse way.

Effect of chlorhexidine rinsing on the oropharyngeal ecology in patients with head and neck cancer who have irradiation mucositis.

Oral flora is thought to contribute to irradiation mucositis in patients with head and neck cancer. Neglect of oral hygienic care may also contribute to mucositis. The purpose of this prospective, randomized, placebo-controlled, double-blind study was to evaluate the effect of chlorhexidine 0.1% mouthrinses on oral flora and irradiation mucositis. This study included 30 patients with head and neck cancer who had comparable irradiation portals. One group (N = 15) rinsed four times daily with chlorhexidine 0.1%, the other group (N = 15) with a placebo. The oral flora was cultured (oral washing technique) twice before and three times per week during the period of radiotherapy. On the same days, the severity of mucositis was determined. The colonization index of viridans streptococci was significantly reduced only after 5 weeks of chlorhexidine 0.1% treatment. The colonization patterns of Candida species, Streptococcus faecalis, staphylococci, and Enterobacteriaceae, Pseudomonadaceae, and Acinetobacter species were not influenced by 5 weeks of use of chlorhexidine rinses when compared with the placebo. No differences were seen between the two study groups in the development and severity of mucositis. In conclusion, suppression of oral flora and a lowering of the severity of mucositis by means of disinfecting mouthrinses were not successful.

Gut decontamination by oral ofloxacin and ciprofloxacin in healthy volunteers.

The selectivity of enterobacterial decontamination during oral ofloxacin and ciprofloxacin was studied in 15 volunteers. Dilution studies of 294 faecal samples were made to monitor concentrations of enterobacteria, yeasts and enterococci. Detection of beta-aspartylglycine content was used for evaluation of interaction with the indigenous (mostly anaerobic) flora. Inactivation of ofloxacin and ciprofloxacin by faeces was studied to explain the effects of gut decontamination. Escherichia coli was successfully eliminated from the gut in all volunteers during treatment. Decontamination was found to be more or less selective with both quinolones, although yeast overgrowth and decrease of enterococci was significantly higher with ciprofloxacin. This may be explained by the higher intrinsic activity of ciprofloxacin against anaerobic flora, the inactivation by faeces being low for both agents. Ofloxacin and ciprofloxacin are two new quinolones of value in the therapy of infections between 'waist and knee' (e.g. cystitis, enteritis, prostatitis) because of the elimination of the infection focus combined with the eradication of the source.

Enterobacteriaceae suppression by three different oral doses of polymyxin E in human volunteers.

Polymyxin E is frequently used as an oral drug for flora suppression of the gastrointestinal canal. The suppression effect is dose dependent because polymyxin E is moderately inactivated by faecal and food compounds. Three oral polymyxin E doses (150, 300, 600 mg daily) were given to six volunteers for 6 days. The Enterobacteriaceae suppression effect was compared by means of the suppression index i.e. ratio of total number of faecal samples free of Enterobacteriaceae to the total number of faecal samples. The impact on the indigenous (mostly anaerobic) flora was measured in four ways: (i) beta-aspartylglycine content; (ii) volatile fatty acid pattern; (iii) yeast overgrowth and (iv) Streptococcus faecalis decrease. Enterobacteriaceae suppression was most successful during 600 mg oral polymyxin E (suppression indices during 150, 300 and 600 mg were 0.32, 0.55 and 0.89 respectively). None of the four markers of indigenous flora alterations were positive. However, using this dosage half of the volunteers suffered rather severe gastrointestinal side-effects. Oral polymyxin E in a dosage of minimum 600 mg daily seems to possess the ideal properties of a flora suppression agent, if the gastrointestinal side-effects could be mitigated.

Patterns of porphyrin excretion in feces as determined by liquid chromatography; reference values and the effect of flora suppression.

While determining reference values for porphyrins in feces as measured by liquid chromatography, we observed strong fluctuations in fecal porphyrin contents. To explain these fluctuations, we selectively suppressed the intestinal flora of healthy persons. Suppression of aerobic flora had no effect on fecal porphyrin excretions, whereas suppression of anaerobic flora completely inhibited the transformation of protoporphyrin to pempto- and deuteroporphyrin for as long as five days after stopping medication. During this latter, the conversion to mesoporphyrin was clearly increased in one person and in others partly affected or decreased. During complete suppression of flora for prolonged periods, the production of proto- and coproporphyrins was decreased and deutero-, pempto-, and mesoporphyrins were absent. We conclude that the nature of fecal porphyrins is mostly affected by action of anaerobic bacteria, different kinds of bacteria having different effects. Some, like aerobic Gram-negative bacteria, have little or no effect on porphyrins; some cause production of mesoporphyrin; some promote a conversion to pempto- and deuteroporphyrin; and some mainly cause production of copro- and protoporphyrin. We give examples in which normal to slightly increased excretions of fecal porphyrin do not exclude a diagnosis of porphyria, and relatively high concentrations do not confirm one.

Release and antimicrobial activity of silver sulphadiazine from different creams.

The release and antimicrobial activity of silver sulphadiazine from five different creams were studied: unguentum emulsificans aquosum, unguentum hydrophylicum non ionogenicum, paraffin cream (15 per cent), a homemade preparation and a commercially available preparation (Flamazine). A diffusion cell was used to measure the release and the agar well diffusion technique to determine the antibacterial activity of the silver sulphadiazine released. The paraffin cream (15 per cent) preparation had the highest release rate, followed by the homemade cream and the commercially available cream. The antibacterial activity ran parallel with the release results. This study shows the silver sulphadiazine paraffin cream to be superior to the other four preparations, including the commercially available silver sulphadiazine cream, using release and antibacterial activity as criteria.

Oropharynx decontamination preventing Candida vegetation on voice prostheses.

Candida vegetations found in silicone voice prostheses used in postlaryngectomy voice rehabilitation are associated with prosthesis dysfunction. Selective oropharyngeal decontamination with amphotericin B lozenges resulted in sharp decrease of oropharyngeal Candida concentrations with a subsequent reduction of yeast colonization on voice prostheses and in tracheoesophageal fistula in ten patients. A case report suggests that this selective oropharyngeal decontamination can prolong the device's lifetime.

Quinolones and colonization resistance in human volunteers.

The suppression of alimentary canal flora by the three quinolones nalidixic acid, ciprofloxacin and pefloxacin was investigated in fifteen volunteers. They received the three quinolone compounds in tablet form both uncoated and colon-coated. Escherichia coli suppression was poor under nalidixic acid, but complete under ciprofloxacin and pefloxacin for both administration forms. The indigenous anaerobic flora contributing to the control of aerobic Streptococcus faecalis and Candida albicans in the intestines ('colonization resistance') was not affected by nalidixic acid and pefloxacin, and only slightly by ciprofloxacin. Out of the three quinolone compounds, only colon-coated pefloxacin was associated with a considerable absorption rate at colonic level. Using these criteria of successful Escherichia coli clearing from the intestinal canal--left the indigenous flora more or less intact (in a 'selective' way)--and a good absorption rate, pefloxacin is found to be superior to ciprofloxacin and nalidixic acid. These results suggest that a colon-coated tablet with a low dose of pefloxacin is a promising administration form in the therapy of recurrent urinary tract infections and diarrhoeal diseases and in the prevention of gut colonization in immunocompromised hosts.

Effect of chlorhexidine and acetic acid on phagocytosis by polymorphonuclear leucocytes.

The effect of two disinfectants, chlorhexidine and acetic acid, on host leucocytes and bacteria was studied. At a concentration of 50 mg/l, chlorhexidine was found to be bactericidal without interfering with leucocyte function. A concentration of 500 mg/l of acetic acid was neither leucotoxic nor bactericidal. Effects equivalent to the aforementioned were achieved in serum by increasing the chlorhexidine concentration by a factor of 20 and the acetic acid concentration by a factor of 5. Acetic acid reduced leucocyte function more rapidly than it killed bacteria. On the basis of these findings, chlorhexidine is to be preferred for local application in burn wounds to prevent colonisation and infection.

Influence of faeces on the activity of antimicrobial agents used for decontamination of the alimentary canal.

The influence of faeces on the activity of 9 antibiotics currently used for selective decontamination of the digestive tract was studied. These in vitro findings showed that the antimicrobial activity is differently affected by the presence and concentration of faeces. Great differences in loss of activity were observed on different microorganisms. Decontaminating drugs which were found to be minimally inactivated in vitro by the presence of faeces are proven to be superior in clinical studies too.

Remarks on the structure-activity relationship of silver sulfanilamides.

The biological activity of a series of 10 silver sulfanilamides is studied in relation to the physical parameters pK alpha, log K, and the aqueous solubility. None of the parameters demonstrate a simple relationship with the activity. A discussion of the significance of log K and the solubility in relation to the activity is given.