Combined Antibiotic Therapy

The indications for combined antibiotic therapy are reviewed, and two major indications are discussed at length: the prevention of development of antibiotic resistance and the possibility of achieving antibiotic synergism.Since micro-organisms vary in their behaviour in the presence of different antibiotic combinations, careful evaluation of clinical response and close laboratory control are necessary.Antibiotics are divided into four groups and their possible combinations are described. It is emphasized that bactericidal antibiotics, e.g. penicillin and streptomycin, which act only on multiplying bacteria, may be antagonized by some bacteriostatic antibiotics, e.g. tetracycline. Clinical observations appear to confirm the usefulness of this division of the antibiotics.     

Antibiotic Therapy in Current Surgical Practice

The clinical surgeon is required to assume important responsibilities in the management of microbial infections. To be effective, antibiotics should be used against sensitive organisms, the lesion should be infused adequately, and, ideally, the antibiotic should be bactericidal and compatible with other antibiotic agents in combination. A survey of commonly used antibiotics disclosed that penicillin in its synthetic and natural forms is still the drug of choice in most cases, particularly since, in its different forms, it may be used in combination with other agents to give a wide antibacterial spectrum. As a major surgical problem, Gram-positive septicemia has been superseded by Gram-negative septicemia and attendant endotoxin shock. Most authorities advocate a combination of bactericidal and bacteriostatic antibiotics in the treatment of endotoxin shock. However, while antibiotic therapy is considered crucial in the treatment of this condition, the mortality rate is still high and no uniform regimen of antibiotic therapy has been accepted.     

Antibiotic Therapy of Staphylococcal Infections

The antibiotic treatment of staphylococcal infections remains a problem. Isolation of the organism and sensitivity testing are necessary in the choice of antibiotic. Penicillin G is the most effective penicillin against non-penicillinase-producing staphy-lococci; for the penicillinase producers there is very little to choose between the semisynthetic penicillins, methicillin, cloxacillin, nafcillin and oxacillin. For patients who are hypersensitive to penicillin, the bacteriostatic drugs (erythromycin, novobiocin, tetracycline, chloramphenicol, oleandomycin) are useful for mild infections, while for more severe illness the bactericidal drugs (vancomycin, ristocetin, kanamycin, bacitracin, neomycin) have been used successfully. Acute staphylococcal enterocolitis is probably best treated by a semisynthetic penicillin. Other antibiotics which have been found useful, with clinical trials, for staphylococcal infections are cephalosporin, fucidin, cephaloridine and lincomycin. The latter drug has been reported of value in the treatment of osteomyelitis. There is little justification for the prophylactic use of antibiotics to prevent staphylococcal infection. Surgical drainage is still an important adjunct in the treatment of many staphylococcal infections.     

Cycling Empirical Antibiotic Therapy in Hospitals: Meta-Analysis and Models

The rise of resistance together with the shortage of new broad-spectrum antibiotics underlines the urgency of optimizing the use of available drugs to minimize disease burden. Theoretical studies suggest that coordinating empirical usage of antibiotics in a hospital ward can contain the spread of resistance. However, theoretical and clinical studies came to different conclusions regarding the usefulness of rotating first-line therapy (cycling). Here, we performed a quantitative pathogen-specific meta-analysis of clinical studies comparing cycling to standard practice. We searched PubMed and Google Scholar and identified 46 clinical studies addressing the effect of cycling on nosocomial infections, of which 11 met our selection criteria. We employed a method for multivariate meta-analysis using incidence rates as endpoints and find that cycling reduced the incidence rate/1000 patient days of both total infections by 4.95 [9.43–0.48] and resistant infections by 7.2 [14.00–0.44]. This positive effect was observed in most pathogens despite a large variance between individual species. Our findings remain robust in uni- and multivariate metaregressions. We used theoretical models that reflect various infections and hospital settings to compare cycling to random assignment to different drugs (mixing). We make the realistic assumption that therapy is changed when first line treatment is ineffective, which we call “adjustable cycling/mixing”. In concordance with earlier theoretical studies, we find that in strict regimens, cycling is detrimental. However, in adjustable regimens single resistance is suppressed and cycling is successful in most settings. Both a meta-regression and our theoretical model indicate that “adjustable cycling” is especially useful to suppress emergence of multiple resistance. While our model predicts that cycling periods of one month perform well, we expect that too long cycling periods are detrimental. Our results suggest that “adjustable cycling” suppresses multiple resistance and warrants further investigations that allow comparing various diseases and hospital settings.     

Compromised Chemical Toxicity in Year-Weathered Soils: Implications for Compromised Toxicity Factors

With contaminated terrestrial sites always being multiple decades old before they first submit to health risk assessments for humans and ecological receptors, there is great opportunity for soils to elicit markedly lesser chemical toxicity than would be expected. Soil aging and weathering foster various physico-chemical processes that reduce the toxic potency or bioavailability of sequestered chemicals. Because only brand new and unadulterated chemicals with seemingly maximum potencies are used in animal dosing that supports toxicity factor derivation, measured chemical concentrations in soil can be misleading, producing exaggerated risk and hazard outcomes. We sought to determine the extent to which toxicity reduction occurs in experimentally amended soils, working with large soil volumes exposed to the unimpeded ambient condition for a calendar year. A broad toxicity testing matrix for two chemicals (i.e., multiple test species, endpoints, effect level concentrations, and soil types), found species’ responses in contaminated soils to be indistinguishable from those in control soil 80% and 98% of the time for the inorganic and organic compounds used, respectively; a case in point was lead with a soil concentration of 11,000 mg/kg. The results suggest that incorporating a toxicity reduction term is an indispensable task when deriving toxicity factors.     

Local and Systemic Antibiotic Therapy of Wounds and Burns

Postoperative wound infection rates range between 3% for clean wounds to 28% for dirty wounds. Indiscriminate antibiotic prophylaxis is ineffective. Requisites for effectiveness are specificity of the antibiotic for wound pathogens, the achievement of therapeutic tissue levels within four to six hours of wounding, and use only for high-risk situations. Topical neomycin is recommended in special-risk clean cases. In addition, in contaminated cases, a combination of penicillin G, a biosynthetic penicillin, and broad-spectrum penicillin parenterally is used, preoperatively, intra-operatively, and immediately postoperatively. Intravenous penicillin G and a biosynthetic penicillin are used for patients with major trauma and burns.     

Pseudomembranous Enterocolitis: Resurgence Related to Newer Antibiotic Therapy

Six patients with pseudomembranous entercolitis were seen at one institution over a six-month period. Clindamycin therapy preceded the diagnosis in all six patients and possibly caused the disease in five cases. Common clinical features included diarrhea, abdominal pain, fever, leukocytosis, radiographic findings of large bowel dilatation with mucosal thickening and a characteristic sigmoidoscopic or gross pathologic demonstration of discrete yellow-white plaques on an otherwise normal mucosa. Complications included toxic megacolon and sigmoid colon perforation. Two of the six patients died. The literature since 1970 is tabulated to clarify the clinical and pathological features of pseudomembranous enterocolitis associated with newer antibiotic therapy. Lincomycin and clindamycin are strongly implicated in the recent resurgence of this formerly rare variety of colitis.     

Therapy of Anorectal Gonorrhea in Men: Efficacy of Oral Antibiotic Regimens

The results of therapy in 916 men with anorectal gonorrhea treated with orally given antibiotic drugs were reviewed retrospectively. There was a 17.8 percent failure rate for tetracycline (total dose, 10 grams) and a 10.7 percent failure for 3.5 grams of ampicillin plus 1 gram of probenicid. Repeating the ampicillin plus probenicid dose once in 8 to 14 hours reduced the failure rate to 1.6 percent, an efficacy comparable to the regimen of 4.8 million units of aqueous procaine penicillin G given intramuscularly plus 1 gram of probenicid given orally for treatment of anorectal gonorrhea.     

Compromised calnexin function in calreticulin-deficient cells

Calnexin and calreticulin are molecular chaperones, which are involved in the protein folding, assembly, and retention/retrieval. We know that calreticulin-deficiency is lethal in utero, but do not understand the contribution of chaperone function to this phenotype. Here we studied protein folding and chaperone function of calnexin in the absence of calreticulin. We show that protein folding is accelerated and quality control is compromised in calreticulin-deficient cells. Calnexin-substrate association is severely reduced, leading to accumulation of unfolded proteins and a triggering of the unfolded protein response (UPR). PERK and Ire1alpha and eIF2alpha are also activated in calreticulin-deficient cells. We show that the absence of calreticulin can have devastating effects on the function of the others, compromising overall quality control of the secretory pathway and activating UPR-dependent pathways.