Treatment of pneumonia in mechanically ventilated trauma patients. Results of a prospective trial.

OBJECTIVES: To determine the efficacy and magnitude of associated adverse effects of 2 different antibiotic regimens for the treatment of pneumonia in intubated surgical patients and to assay and compare blood samples and bronchoalveolar lavage fluid with respect to some host-defense parameters, especially in patients with unilateral pneumonia. DESIGN: Randomized, prospective, unblinded clinical comparison of 2 treatment arms with respect to intent to treat and clinical and microbiologically evaluable patients. SETTING: Six university surgical services in teaching hospitals with modern and well-staffed intensive care units. INTERVENTIONS: The consistency and objectively of the diagnosis of pneumonia was improved by the use of a grid of diagnostic parameters. Aggressive mechanical approaches to pneumonia in intubated surgical patients were supplemented by therapeutic use of aztreonam and vancomycin hydrochloride or combined imipenem and cilastatin sodium. RESULTS: Patients randomized to the aztreonam-vancomycin group were somewhat more ill, fared slightly better, and had fewer serious drug-related side effects than did those treated with imipenem-cilastatin (all P > .05). Immunologic parameters assessed by evaluation of bronchoalveolar lavage fluid showed differences between infected pulmonary lobes and noninfected ones; some changes were also noted in patients who recovered compared with those whose pneumonia persisted or recurred. CONCLUSIONS: Clinical studies of pneumonia in surgical patients need to be stratified to assure comparability, to identify patients in whom treatment is likely to fail, and to display differences between more and less effective therapies. Studies of blood and bronchoalveolar lavage samples showed that certain local and systemic immunologic parameters correlate with clinical status and outcome.

Second place winner of the Conrad Jobst Award in the gold medal paper competition. Increased antibiotic effectiveness in a model of surgical infection through continuous infusion.

As long as infection remains the most common cause of morbidity and mortality in severely ill patients, there exists the need for more effective anti-infective therapy. The current study was undertaken to determine whether continuous infusion (CONT) is superior to intermittent administration (INT) of an equal amount of cefazolin (CEF) in a model of surgical infection. The thigh suture model consists of the surgical placement of 1 cm of cotton suture with absorbed K. pneumoniae into the thigh muscle of mice. The experimental groups were: 1) controls (n = 20) with thigh suture inoculation and treatment with intraperitoneal (IP) sterile saline; 2) CONT infusion group that received CEF at 60 mg/kg IP 30 minutes before inoculation followed by CONT IP infusion at 180 mg/kg/day (n = 22) for 3 days; and 3) INT injection group that received CEF at 60 mg/kg IP 30 minutes before inoculation followed by INT IP injections every 8 hours at 180 mg/kg/day (n = 20) for 3 days. All CEF treated animals received identical quantities of total CEF, and all groups were followed for 10 days. The control and INT CEF groups had 20% survival, whereas the CONT CEF group had 81% survival, (P < 0.001). Continuous CEF yielded constant serum levels of 19 +/- 1 micrograms/mL, whereas INT injections resulted in peak serum level of 74 +/- 12 micrograms/mL at one minute but declined to 3.9 +/- 0.9 micrograms/mL in 2 hours. Although there was statistically significant tissue bacterial growth in the INT injection group, there was extensive tissue bacterial clearance in the CONT infusion group.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of copovithane as a nonspecific immunomodulator in surgically simulated sepsis.

Copovithane (CPV), a synthetic polymer, has been shown to have antitumor activity and also to reduce mortality in experimental murine peritonitis. The purpose of this study was to compare CPV with muramyl dipeptide (MDP), an immunomodulator of proven efficacy in simulated surgical infection. Six groups of CBA/J mice were compared; they received intramuscular injections of normal saline (controls), MDP (100 micrograms), or CPV (100, 200, and 400 mg/kg) 24 h prior to bacterial challenge. The challenge consisted of a Klebsiella-impregnated thigh suture. The first experiment assessed survival after bacterial challenge. The MDP and the CPV groups both had median survival times of 3 days, significantly longer than the control group (1 day, p less than .05). In the second experiment, animals were sacrificed at 6, 24, and 48 h following bacterial challenge, and blood and infected muscle were taken for quantitative bacteriology. At 6 h, there was no difference between groups. Both the MDP and CPV groups had significantly (p less than .05) lower blood bacterial counts than the control group at 24 and 48 h. Both the MDP and CVP groups had significantly lower local bacterial recovery than controls at 48 h (p less than .05), and local bacterial recovery of the MDP group was significantly lower than the control group at 24 h (p less than .05). CPV improved survival and reduced local and systemic bacterial recovery compared with controls. Although the effect of CPV was similar to MDP in this model, it consistently was of lower magnitude and had a narrow dose range.

Effects of interferon-gamma treatment on surgically simulated wound infection in mice.

Interferon-gamma (IFN-gamma) has been shown to have immunoregulatory properties and is able to modulate resistance to several microbial infections. This study was designed to determine the efficacy of IFN-gamma treatment in a mouse model of infection that simulates many clinical conditions associated with surgical wound infection: viz, a bacteria laden suture and tissue injury. The test bacteria were Klebsiella pneumoniae. Groups of CBA/J mice received either IFN-gamma or RPMI-1640 medium (controls) subcutaneously. IFN-gamma was administered daily at a dose of 7500 units for 5 days prior to bacterial challenge. Mice treated with IFN-gamma survived significantly longer than controls. Systemic bacterial recovery was significantly reduced in the IFN-gamma treated group but local bacterial recovery was unaffected.

Effects of muramyl dipeptide and lead acetate on carbon clearance and endotoxin-induced mortality in mice.

Muramyl dipeptide (MDP) is a nonspecific immune adjuvant thought to affect the macrophage. MDP had been used safely without immunosuppressive or toxic side effects in our laboratory and others. Endotoxin, or lipopolysaccharide (LPS), is thought to be responsible for many of the systemic toxic effects of gram-negative infection. Lead acetate potentiates the lethal effects of endotoxin, an effect attributed to increased hepatotoxicity involving both hepatocytes and Kupffer macrophages. This study was undertaken to examine putative mechanism of action of MDP relating to the reticuloendothelial system. Endotoxin was given intraperitoneally to susceptible mice that were pretreated with MDP, lead acetate, or both, and to unmodified controls. Lead acetate significantly enhanced lethality due to LPS, but pretreatment with MDP did not alter mortality. Carbon clearance was measured in mice treated with MDP, lead, or both. There was no difference in the phagocytic index of control mice and those mice treated with lead acetate at various times prior to the injection. Carbon clearance increased significantly in mice pretreated with MDP but was unaltered by the addition of lead acetate. We conclude that if hyperphagocytosis of endotoxin occurs in MDP-pretreated mice, it does not cause additional mortality. Muramyl dipeptide appeared to be a safe reticuloendothelial stimulant that did not enhance the toxicity of lead or LPS in this experimental model.

Effects of muramyl dipeptide and clindamycin in a murine abdominal abscess model.

Peritonitis and subsequent local and remote complications are an important source of morbidity and mortality, which persist despite the best available treatment. Reasonable therapeutic efforts, therefore, have included stimulation of host defenses with immune adjuvants, recently typified by muramyl dipeptide (MDP). Murine abdominal abscesses were created by intraperitoneal injection of Bacteroides fragilis and autoclaved fecal suspensions, and the effects of MDP and clindamycin on these abscesses were evaluated. At 10(4) colony-forming units (CFU) per milliliter of Bacteroides fragilis, intraperitoneal clindamycin was effective in reducing both the incidence of abscess formation as well as the number of abscesses per mouse as compared with controls at doses of 5 mg/kg and 2 mg/kg (P less than 0.01). The effect was more significant when the drug was given 30 min prior than when given after injection of organisms (P less than 0.02). At 10(7) and 10(8) CFU/ml, pretreatment with MDP increased abscess formation (P less than 0.05, P less than 0.01), an effect that was obscured by clindamycin administration, which decreased number of abscesses from controls irrespective of pretreatment with MDP. Abscesses were present on the third day after injection, and MDP, paradoxically, had increased the number of abscesses by the fifth day. Clindamycin reduced abscess formation at all concentrations of bacteria and had a dose and time-dependent response. MDP increased abscess formation only at high concentrations of Bacteroides fragilis, but clindamycin abolished this effect and reduced the number of abscesses to similar levels in both the clindamycin alone and clindamycin + MDP groups.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro characteristics of tobramycin-PMMA beads: compressive strength and leaching.

Antibiotic-impregnated polymethylmethacrylate (PMMA) bone cement beads have been used as a local drug delivery system for the treatment of bone and soft tissue infections. The beads deliver a high local level of antibiotic with a decreased risk of toxic systemic levels. This study was undertaken to determine the antibiotic release characteristics of tobramycin-impregnated beads over time and to determine the compressive strength of these beads. Acrylic resin (PMMA) bone cement beads were prepared with three different concentrations of tobramycin. The beads were tested for compressive strength, and their antibiotic release characteristics were determined over a 21 day period by radioimmunoassay and by biological testing against a variety of bacteria. The compressive strength of the beads was found to be adequate to avoid fragmentation during their clinical use. There was gradual release of tobramycin from the beads over the entire 21 days, but the release was most marked during the first 48 hours. There was antibiotic activity against both gram-negative and gram-positive organisms, except Enterococcus, for the entire 21 day period. The release of tobramycin followed a curvilinear relationship and was directly related to the initial antibiotic concentration of the bead. Tobramycin-impregnated polymethylmethacrylate beads may represent a reliable method of local antibiotic delivery with sustained activity against a broad spectrum of organisms.

The role of muramyl dipeptide in the therapy of established experimental bacterial infection.

Muramyl dipeptide (MDP) actively potentiates host defences and confers protection when given before a bacterial challenge. Experiments were undertaken to characterize its actions when used alone or in combination with cephaloridine in a manner analogous to clinical therapy, i.e. after initiation of bacterial infection. MDP, alone or in combination, significantly decreased the systemic manifestations of infection compared with placebo when administered up to 6 h following bacterial contamination. Its effect on the primary lesion was less marked, but it may potentiate host defences sufficiently to have an impact on the decisive period. Benefits observed in this study were of lesser magnitude than those observed following administration of the dipeptide before bacterial inoculation.

Non-specific host defence stimulation and antibiotic-resistant infection.

The impact of a subinhibitory dose of clindamycin combined with stimulation of host defences by muramyl dipeptide (MDP) in an animal model of surgical infection with Escherichia coli was studied. Both the percentage of bacteria recovered from the implantation site and the degree of bacteraemia were quantitated at timed intervals following the bacterial challenge. Neither of these parameters was significantly different in animals treated with clindamycin alone compared to placebo animals. A significant reduction in bacteraemia was observed in animals treated with a combination of MDP and clindamycin when compared to animals receiving either agent alone. Local bacterial recovery was paradoxically greater in this combined treatment group. The presence of subinhibitory concentrations of clindamycin in vivo appears to render E. coli more susceptible to the systemic effects of host defence stimulation by MDP.

A reassessment of the influence of steroids on neutrophil phagocytosis.

The impact of corticosteroids on host defense processes has been studied frequently because of its obvious clinical significance in many surgical patients. A technique that quantifies intraleukocyte iodination was used to measure polymorphonuclear leukocyte phagocytosis in heat inactivated and nonheat inactivated sera in the presence of two different corticosteroids: hydrocortisone sodium phosphate (HSP) and methylprednisolone sodium succinate (MSS). HSP produced a significant reduction in phagocytosis in the cells of healthy subjects when both heat inactivated autologous and isologous serum samples were used. MSS showed no such effect. Conversely, MSS produced a significant reduction in phagocytosis in the cells of healthy subjects when nonheat inactivated autologous serum was used but not when isologous serum was used. These data generally tend to confirm previous studies suggesting that MSS is less deleterious to some host defense processes than HSP and may be the steroid of choice when infection threatens the recipient.

Effects of pure or combined inocula of Escherichia coli and Bacteroides fragilis on the liver and related metabolism.

To test for synergy between a facultative and anaerobic bacterium and the role hepatic hypoxia may have in its development, rats were subjected to intravascular infusion of 10(8) Escherichia coli, 10(9) Bacteroides fragilis, or a combination of both. Acute effects were evaluated by selected 6-hour measurements, including hepatic pO2, and longer range effects by liver cultures and histology in rats surviving 7 days. During the acute period, systemic arterial pressure and pO2 in bacteremic groups did not differ from saline-infused controls. However, hepatic oxygen supply was significantly reduced in E. coli rats and those given the combined bacteria (mean hepatic pO2 less than 10 mm. Hg versus 20.8 mm. Hg in controls). Significant increases of plasma lactate and pulse rate were also recorded. By comparison, hepatic pO2 was not reduced significantly in the B. fragilis rats, and pulse rate was similar to controls. Plasma lactate, however, increases more rapidly than in other groups. Survival rates were 100 per cent in the B. fragilis group, 88 per cent in the E. coli group, and 65 per cent in the combined group. The difference between the latter groups was not significant. Hepatic histology was normal in rats of the B. fragilis group at 7 days postchallenge. In survivors of the E. coli and combined inoculum groups, there was evidence of anoxic damage and occasional foci of neutrophilic infiltration. Liver cultures were more often positive in rats of the combined inoculum group (p less than 0.05), most often for E. coli, than in the other groups. In summary, although the acute effects of E. coli were not changed appreciably by combination with B. fragilis, the higher rate of E. coli liver infection in survivors suggests that its viability was enhanced. The role of hepatic hypoxia in this remains unclear. It is feasible that hypoxic foci provided temporary protection for B. fragilis, enabling the organisms to affect favorably the survival of E. coli.

Nonspecific enhancement of resistance to local bacterial infection in starved mice.

We studied the effect of muramyl dipeptide (MDP) on enhancing resistance to local bacterial challenge in starved mice. The challenge consisted of the intramuscular insertion of a suture laden with Klebsiella pneumoniae. Mice that had been pretreated with MDP had a statistically lower rate of bacterial recovery at the site of the challenge, had consistently fewer bacteria in the blood, and had improved short-term survival. By enhancing local bacterial containment, MDP pretreatment of immunocompromised animals reduces the level of bacteremia and subsequent mortality.

Simulated surgical wound infection in mice: effect of stimulation on nonspecific host defense mechanisms.

Experiments were conducted to ascertain whether nonspecific host defenses could be enhanced in a reliable animal model simulating the local bacterial infection that frequently complicates surgical wounds. The test lesion was studied in detail and exemplifies the concept that the ultimate expression of the host-pathogen interaction is the capacity of that pathogen to persist or grow in a given host. Mice were challenged by intramuscular insertion of cotton suture impregnated with 10(7) to 10(8) Escherichia coli K-12. The mice were subsequently killed at intervals, and the suture and muscle mass were retrieved, homogenized, and quantitatively cultured. Numbers of viable organisms in tissue from control animals were compared with those from experimental animals that received BCG (Bacillus Calmette-Guérin) vaccine, a nonspecific immunostimulant, prior to bacterial challenge. Improved tissue antibacterial activity appeared in animals that had received BCG vaccine 13 days prior to bacterial challenge. Differing doses and intervals were not protective. Enhancement of nonspecific host defense mechanisms may be helpful in combination with current measures for improved control of surgical wound infection.