Antimicrobial prophylaxis of gastrointestinal surgical procedures and treatment of intraabdominal infections

Antibiotic prophylaxis and treatment regimens ideally are selected on the basis of efficacy, safety, and cost. This review evaluates current, selected literature on antibiotic prophylaxis for colorectal surgery, presumptive antibiotic administration following penetrating abdominal trauma, and treatment of intraabdominal infections. Single-drug regimens with the newer, broad-spectrum agents are assessed and compared with combination regimens; specific regimens are recommended. Colorectal procedures require an antimicrobial agent with activity against both aerobes and anaerobes. Patients undergoing elective colorectal procedures can be adequately protected with an orally administered three-dose regimen of neomycin/erythromycin. Parenteral antibiotic administration is generally not necessary, but, cefoxitin is recommended for nonelective colorectal surgery. The risk of potential infectious complications following penetrating abdominal trauma without colonic perforation is less than with colonic perforation; however, antibiotic therapy that includes activity against aerobes and anaerobes is recommended for all types of penetrating abdominal trauma. Although cephalothin, cefamandole, or cefoxitin alone may be used in abdominal trauma without perforation of the colon, only cefoxitin is recommended as a single-drug alternative to the standard clindamycin/gentamicin regimen in trauma with colonic perforation. Single-drug therapy with cefoxitin or moxalactam can be used successfully as alternatives to the standard regimens of clindamycin/gentamicin or metronidazole/gentamicin in many patients with intraabdominal sepsis. Single-drug regimens reduce the risk of developing adverse effects and are cost-effective. However, if resistant organisms are suspected, or if the patient has been hospitalized for a prolonged period or has multiple organ failure, it may be necessary to supplement cefoxitin therapy with an antibiotic that will enhance coverage against gram-negative aerobes.     

Prevention and management of enterococcal infection: cost implications

Enterococcal infections are becoming increasingly prevalent, in part because of the widespread use of cephalosporins and a greater number of immunosuppressed patients. Most infections where enterococci are isolated are pelvic or intraabdominal. The actual pathogenic role of the enterococcus remains controversial, since many types of organisms are usually cultured as well. Although specific therapy directed at the enterococcus may not always be necessary, reasonable indications for specific therapy include the presence of shock, immunosuppression, or persistent or recurrent infection. Enterococcal bacteremia is associated with a mortality rate in excess of 40 percent. This entity, as well as enterococcal endocarditis and meningitis, should be treated with bactericidal, combination antibiotic therapy, which includes a penicillin and an aminoglycoside. Mixed infections probably can be treated with a penicillin alone. Penicillin-allergic patients should be treated with vancomycin. The costs of nosocomial infection or superinfection are very high; costs incurred as a result of enterococcal infection or superinfection may be prevented by avoiding prolonged prophylactic or broad-spectrum therapeutic regimens (such as cephalosporins) that lack antienterococcal activity. Extended-spectrum penicillins may be effective prophylactic regimens for intraabdominal or pelvic procedures and should serve as adequate therapy for mixed infections in these sites.     

Use of cephalosporins with enhanced anti-anaerobic activity for treatment and prevention of anaerobic and mixed infections

The microbiology, adverse-effect profiles, pharmacokinetics, published results of comparative clinical trials, and costs of cephalosporins with enhanced antianaerobic activity are reviewed. Cefoxitin, ceftizoxime, cefotetan, and moxalactam have been used as single agents in the treatment or prophylaxis of anaerobic or mixed aerobic and anaerobic infections, including intra-abdominal, female genital tract, and soft-tissue infections. None of these agents is as active against Bacteroides species as is clindamycin or metronidazole, but differences among the four cephalosporins do not appear to be clinically important. These agents differ somewhat in their activity against gram-positive and gram-negative bacteria. The majority of adverse reactions to these agents are immunological; disulfiram-like reactions and alterations in normal hemostasis have also been observed with cefotetan and moxalactam. All of these agents are well absorbed after intramuscular injection and produce serum concentrations adequate to treat most infections. Only ceftizoxime and moxalactam produce cerebrospinal fluid concentrations adequate for treatment of gram-negative meningitis. The primary route of elimination is renal, and each agent requires dosage adjustments in patients with renal impairment. Major differences exist among the elimination half-lives of the agents in patients with normal renal function. The decision to use a cephalosporin for treatment of anaerobic infections should be based on the results of clinical trials that have demonstrated the efficacy of the agent. Data are available to support the use of cefoxitin, ceftizoxime, and moxalactam in the treatment of intra-abdominal infections; cefoxitin and moxalactam to prevent infection of traumatic injury to the abdomen; all four agents in the treatment of female genital tract infections; and all four agents for prophylactic use in surgical procedures that may involve enteric anaerobes, especially B. fragilis. Cephalosporins with enhanced antianaerobic activity appear to have similar in vitro microbiological activity and have efficacy similar to that of combination regimens for the treatment and prophylaxis of intra-abdominal infections, abdominal contamination, obstetric and gynecological infections, and soft-tissue infections.     

Identification, management, and prevention of adverse effects associated with highly active antiretroviral therapy.

PURPOSE: The adverse effects associated with highly active antiretroviral therapy (HAART), as well as potential options available for management of these complications, are summarized. SUMMARY: Effective treatment of human immunodeficiency virus (HIV) infection requires three or four drug regimens that are complicated and commonly associated with adverse effects. This makes compliance difficult and can result in treatment failures, development of resistance, and loss of future treatment options. In addition, some adverse effects may lead to an increase in morbidity and represent additional risk factors for future complications. Serious adverse events after the initiation of HAART are related to both patient and treatment characteristics. Most organ systems can be affected, depending on the drug or class of drugs being used; therefore, proper identification of adverse effects can be difficult. The most common adverse effects are gastrointestinal, neurologic, metabolic, and cardiovascular, although renal, dermatological, and hematologic events may also be encountered. Adverse-effect management has included treatment interruptions and therapeutic drug monitoring but most commonly involves switching to another drug or class of drugs. This requires a complete understanding of HAART regimens and their associated complications. HIV clinics that have employed clinical pharmacists have been able to successfully prevent or identify adverse effects through suggestions for effective treatment alternatives, medication counseling, and compliance education. CONCLUSION: The identification, management, and prevention of adverse events associated with HAART can be difficult but are integral components of effective treatment. Proper interventions are cost-effective and have resulted in improved quality of life for patients infected with HIV.     

The change of immunosuppressive regimen from calcineurin inhibitors to mammalian target of rapamycin (mTOR) inhibitors and its effect on malignancy following heart transplantation

Malignancy is a significant cause of mortality after organ transplantation. There is an increased rate of malignancy following heart transplantation (HTx) compared to the general population and other organ transplant recipients. Post-HTx patients with a history of malignancy are also at a higher risk of developing new malignancies or exacerbation of their existing malignancies. Mammalian target of Rapamycin inhibitors (mTORIs) are newly introduced immunosuppressive drugs with a unique mechanism of action. By changing the immunosuppressive regimen from classic drugs, especially calcineurin inhibitors (CNIs) to mTORIs, the rate of developing de novo malignancies and the relapse of former malignancies is significantly reduced. However, issues like allograft function, total surveillance of patients, and post-transplantation complications should be considered during the conversion of drug regimens utilizing CNIs to drug regimens employing mTORIs. We reviewed different post-heart transplant maintenance immunosuppressive regimens and their effect on post-HTx malignancies with a focus on mTORIs, compared safety against effectiveness, and gathered conclusions based on our review of the literature, which may lead clinicians to make a better evidence-based decision regarding post-HTx maintenance immunosuppressive drug regimens. Overall, CNI to mTORI conversion in post-HTx maintenance immunosuppressive drug regimens was associated with a reduced rate of developing malignancy in post-HTx patients. Furthermore, nephrotoxicity decreased significantly while using mTORIs in combination with lower doses of CNIs and the rejection rate was equivalent to CNI-only regimens. In conclusion, mTORI-based maintenance immunosuppressive drug regimens seem to be safe and beneficial when considering efficacy vs. adverse effects, and all-cause mortality rates are significantly lower in patients switched to mTORIs when compared to CNI recipients.     

World Health Organization 2018 treatment guidelines for rifampicin-resistant tuberculosis: uncertainty,potential risks and the way forward

The 2018 World Health Organization (WHO) treatment guidelines for multidrug-/rifampicin-resistant tuberculosis (MDR/RR-TB) give preference to all-oral long regimens lasting for 18–20 months. The guidelines strongly recommend combining bedaquiline, levofloxacin (or moxifloxacin) and linezolid, supplemented by cycloserine and/or clofazimine. The effectiveness of this combination in a long regimen has not been tested in any study to date, with corresponding uncertainty. The guidelines indicate that, ideally, all MDR-TB patients should have – as a minimum – the isolate tested for fluoroquinolones, bedaquiline and linezolid susceptibility before the start of treatment. Unfortunately, the capacity for drug susceptibility testing is insufficient in resource-limited settings. The risk of acquired bedaquiline resistance cannot be ignored, especially in patients with undetected resistance to fluoroquinolones. Both linezolid and cycloserine are known for their high frequency of serious adverse events. The combination of bedaquiline, moxifloxacin and clofazimine in the same regimen may excessively increase the QT interval. These expected adverse effects are difficult to monitor and manage in resource-limited settings, and may result in frequent modifications and a less effective regimen. The final STREAM results have confirmed the non-inferiority of the short regimen compared with the long regimen. Before evidence on the all-oral long and modified all-oral short treatment regimens is available, the WHO-recommended short MDR-TB regimens, with monitoring for ototoxicity, remain a better treatment option for the management of MDR/RR-TB patients who are eligible for short regimens in low- and middle-income countries. National tuberculosis programmes should also strengthen their capacity in the detection and management of fluoroquinolone-resistant MDR-TB following the WHO guidelines.     

Options for induction immunosuppression in liver transplant recipients

Immunosuppression administered in the early postoperative period following liver transplantation plays a crucial role in the survival of the graft and the patient. The introduction of cyclosporin was an important landmark in transplantation, and to this day, calcineurin inhibitors form the basis of most induction immunosuppression regimens. New drugs are being developed which are more specifically targeted to prevention of rejection, and multiple drug combinations have been proposed as a means of reducing the adverse effects of individual drugs. Azathioprine and the newer antimetabolite mycophenolate mofetil have been added to calcineurin inhibitor-based regimens with varying amounts of success. Antibody induction has evolved as a potent form of immunosuppression as well as a means of avoiding certain adverse effects, particularly nephrotoxicity. The numerous adverse effects encountered with polyclonal preparations have been reduced with the development of more specific monoclonal antibodies such as muromonab CD3 (OKT3) or interleukin (IL)-2 receptor (IL-2R) antagonists. The anti-IL-2R antibody preparations basiliximab and daclizumab have shown excellent early results due to their potent yet highly targeted immunosuppressive effect and minimal adverse effects. Further study is needed to determine the most appropriate dosage, timing and patient population for these new drugs in the setting of liver transplantation. Although a number of different induction regimens have been described, no single protocol is suitable for all liver transplant recipients. Rather, certain regimens have advantages that could favour their use in a specific subgroup of patients. A number of clinical trials are underway to identify new, more specific drugs and combinations which could be useful in induction immunosuppression.     

Ceftriaxone. A pharmacoeconomic evaluation of its use in the treatment of serious infections

Ceftriaxone possesses a broad spectrum of antimicrobial activity that includes the Gram-positive and Gram-negative aerobes commonly associated with serious infections. Its therapeutic efficacy is comparable to that of other third-generation cephalosporins and aminoglycoside-combination regimens. The most commonly reported adverse events with ceftriaxone are similar in incidence and severity to those reported with other third-generation cephalosporins. Notably, the drug has a favourable pharmacokinetic profile which allows once-daily administration. In comparative studies with other parenteral regimens requiring 3 to 6 daily doses, treatment with once-daily ceftriaxone reduced total antimicrobial drug costs (i.e. acquisition, preparation and administration costs) by 17 to 52%. Ceftriaxone was also more cost effective than ceftazidime and a variety of other antimicrobial treatment regimens (penicillins, cephalosporins, combination regimens) in the treatment of patients with community-acquired pneumonia or bronchopneumonia. This reflected lower drug and hospitalisation costs associated with a reduced length of hospital stay in ceftriaxone recipients. In noncomparative studies, ceftriaxone achieved considerable hospitalisation cost savings in patients with serious infections (mostly bone, joint, skin/skin structure infections), who were able to receive all or part of their antimicrobial therapy as outpatients. In one analysis which evaluated all direct and indirect costs (such as training programmes, transportation, time for visits and supplies) and benefits (such as hospitalisation cost savings, return to work or school, increased productivity) of outpatient ceftriaxone therapy, the overall benefit-cost ratio was approximately 5:1. The studies to date confirm that ceftriaxone is effective, well tolerated, convenient to administer and, when utilised appropriately, offers the potential for cost avoidance in patients with serious infections. Although additional well designed pharmacoeconomic analyses are needed to further evaluate its cost effectiveness, ceftriaxone should be considered an essential third-generation cephalosporin formulatory representative in most clinical settings.     

Drug-induced taste disorders.

Numerous drugs have the potential to adversely influence a patient's sense of taste, either by decreasing function or producing perceptual distortions or phantom tastes. In some cases, such adverse effects are long lasting and cannot be quickly reversed by drug cessation. In a number of cases, taste-related adverse effects significantly alter the patient's quality of life, dietary choices, emotional state and compliance with medication regimens. In this review, we describe common drug-related taste disturbances and review the major classes of medications associated with them, including antihypertensives, antimicrobials and antidepressants. We point out that there is a dearth of scientific information related to this problem, limiting our understanding of the true nature, incidence and prevalence of drug-related chemosensory disturbances. The limited data available suggest that large differences exist among individuals in terms of their susceptibility to taste-related adverse effects, and that sex, age, body mass and genetic variations in taste sensitivity are likely involved. Aside from altering drug usage, management strategies for patients with taste-related adverse effects are sorely needed. Unfortunately, stopping a medication is not always an easy option, particularly when one is dealing with life-threatening conditions such as seizures, cancer, infection, diabetes mellitus and uncontrolled hypertension. Hopefully, the information contained in this review will sensitize physicians, researchers and drug manufacturers to this problem and will result in much more research on this pressing topic.     

Atazanavir for the treatment of human immunodeficiency virus infection

Atazanavir is the first once-daily protease inhibitor for the treatment of human immunodeficiency virus type 1 infection and should be used only in combination therapy, as part of a highly active antiretroviral therapy (HAART) regimen. In addition to being the most potent protease inhibitor in vitro, atazanavir has a distinct cross-resistance profile that does not confer resistance to other protease inhibitors. However, resistance to other protease inhibitors often confers clinically relevant resistance to atazanavir. Currently, atazanavir is not a preferred protease inhibitor for initial HAART regimens. In treatment-naive patients, atazanavir can be given as 400 mg/day. However, atazanavir should be pharmacologically boosted with ritonavir in treatment-experienced patients or when coadministered with either tenofovir or efavirenz. Patients who receive atazanavir experience similar rates of adverse events compared with patients receiving comparator regimens. An exception is an increased risk of asymptomatic hyperbilirubinemia, which is due to competitive inhibition of uridine diphosphate-glucuronosyltransferase 1A1. Although hyperbilirubinemia is a common adverse drug reaction of atazanavir therapy (22-47%), fewer than 2% of patients discontinue atazanavir therapy because of this adverse effect. Common adverse effects reported with atazanavir include infection, nausea, vomiting, diarrhea, abdominal pain, headache, peripheral neuropathy, and rash. Of significance, fewer abnormalities have been observed in plasma lipid profiles in patients treated with atazanavir compared with other protease inhibitor-containing regimens. As with other protease inhibitors, atazanavir is also a substrate and moderate inhibitor of the cytochrome P450 (CYP) system, in particular CYP3A4 and CYP2C9. Clinically significant drug interactions include (but are not limited to) antacids, proton pump inhibitors, histamine type 2 receptor antagonists, tenofovir, diltiazem, irinotecan, simvastatin, lovastatin, St. John's wort, and warfarin. We conclude that atazanavir is a distinctively characteristic protease inhibitor owing to its in vitro potency, once-daily dosing, distinct initial resistance pattern, and infrequent association with metabolic abnormalities.     

Treatment of tuberculous infection and disease in children: the North American perspective

The standard preventive therapy for paediatric patients with tuberculous infection centres on isoniazid therapy. The chosen regimen of isoniazid therapy is based on individual patient factors. In the case of known or suspected resistance, combination therapy [e.g. isoniazid and rifampicin (rifampin)] or alternative therapies (e.g. pyrazinamide, a fluoroquinolone and/or ethambutol) should be employed. The goal of treatment of tuberculous disease is to achieve sterilisation in the shortest possible time. More intensive multiple drug combination regimens (e.g. isoniazid, rifampicin and pyrazinamide) have resulted in successful 6- and 9-month treatment regimens in children. If drug resistance is suspected then a fourth drug is added to the initial treatment regimen and the length of therapy may be extended to 18 months. The paediatric information available on the commonly used antituberculous agents (e.g. isoniazid, rifampicin, pyrazinamide and ethambutol) is reviewed in this article. Agents are described with an emphasis on their formulation availability, mechanism of action, pharmacokinetic properties (e.g. absorption, distribution, metabolism and elimination), adverse effects, and interactions (e.g. drug-drug, drug-food and drug-disease).     

Sulbactam/ampicillin, a new beta-lactamase inhibitor/beta-lactam antibiotic combination

Sulbactam/ampicillin is a combination of a beta-lactamase inhibitor with minimal intrinsic antibacterial activity (sulbactam sodium), and an aminopenicillin (ampicillin sodium). The addition of sulbactam to ampicillin has no effect on the chemical stability of ampicillin in aqueous solution, and the administration guidelines of the combination are the same as for ampicillin alone. Sulbactam acts primarily by irreversible inactivation of beta-lactamases from most beta-lactamase-producing organisms. The pharmacokinetics of sulbactam are similar to those of ampicillin with an elimination half-life of about one hour in most patients. One difference is that serum and tissue concentrations of sulbactam are usually twice those of ampicillin, at equivalent doses. The sulbactam/ampicillin combination has been approved for the treatment of adults with intraabdominal, skin and skin structure, and gynecological infections due to beta-lactamase-producing bacteria such as Staphylococcus aureus, Escherichia coli, and species of Klebsiella and Bacteroides. Clinical studies to date have also shown the combination to be effective for the treatment of meningitis, pneumonia, gonorrhea, epiglottis, urinary tract infections, cervical adenitis, and as prophylaxis for abdominal and gynecological surgeries. Many of these studies, however, have included small numbers of patients and/or had design flaws. Adverse effects have been minor with most being attributed to the ampicillin component. Sulbactam/ampicillin compares favorably with other antibiotic regimens in terms of acquisition costs and ease of administration.     

Treatment of adolescent obsessive-compulsive disorder with a clomipramine-fluoxetine combination

Clomipramine has been reported to be effective in the treatment of obsessive-compulsive disorder (OCD). Children and adolescents, however, tolerate poorly the adverse effects of tricyclics. Fluoxetine and other serotonin re-uptake inhibitors also appear useful in OCD, and are safer than clomipramine. To maximize the therapeutic effects and minimize adverse effects, 6 adolescents with OCD were treated in single trials with a clomipramine-fluoxetine combination. Duration of combined drug therapy ranged from 4 weeks to more than 28 weeks. Patients were first treated with clomipramine alone; if improvement or adverse effects were unsatisfactory, they received the drug combination. Clinical global improvement with clomipramine alone was moderate in 3 patients and minimal in 3. With a combined clomipramine-fluoxetine therapy, improvements were marked in 5 patients, and moderate in 1. These improvements were obtained with relatively low daily doses: clomipramine at 25 to 50 mg, and fluoxetine at 20 to 40 mg. Adverse effects appeared greater and much less tolerable with clomipramine alone than with the clomipramine-fluoxetine combination. This drug combination was well tolerated. These preliminary data suggest that relatively low doses of a clomipramine-fluoxetine combination may potentiate therapeutic effects and minimize adverse effects in OCD patients. Larger controlled trials are suggested.     

三例达格列净致糖尿病酮症酸中毒的药学监护及文献分析

目的:探讨临床药师在达格列净致糖尿病酮症酸中毒的药物治疗方案制订和药学监护中的作用.方法:临床药师参与3例达格列净致糖尿病酮症酸中毒患者的治疗,结合相关文献,协助医师完善治疗方案,提供用药建议并实施药学服务.结果和结论:达格列净致糖尿病酮症酸中毒的发生与患者胰岛功能差、胰岛素停用或减量等因素相关.临床药师参与临床治疗,...     

Pioglitazone, rosiglitazone, and rosiglitazone + metformin: new drugs. Glitazone + oral antidiabetic combination: inadequately evaluated

(1) When single-agent therapy provides inadequate glycaemic control for patients with type 2 diabetes, most guidelines recommend metformin in combination with a glucose-lowering sulphonylurea as standard treatment, despite the lack of any proven impact on morbidity or mortality. Other options include switching to insulin or abandoning the target of strict glycaemic control. (2) Pioglitazone and rosiglitazone are approved for use in combination with a glucose-lowering sulphonylurea when metformin is poorly tolerated or contraindicated, and in combination with metformin in overweight patients. (3) A fixed-dose combination containing 1 or 2 mg of rosiglitazone plus 500 mg of metformin (hydrochloride) was launched onto the French market in October 2004. (4) The indication for rosiglitazone was extended to include its use as triple-agent therapy in combination with metformin and a glucose-lowering sulphonylurea. (5) No clinical trials assessing effects on mortality or morbidity have evaluated rosiglitazone or pioglitazone in combination with other oral antidiabetic drugs. (6) Several trials have compared the glucose-lowering effects of dual-agent therapy using rosiglitazone or pioglitazone plus a glucose-lowering sulphonylurea or metformin versus dual-agent therapy with metformin and a glucose-lowering sulphonylurea. (7) These clinical trials indicate that in terms of HbA1c level, dual-agent therapy based on rosiglitazone or pioglitazone is about as effective as combination therapy with metformin plus a glucose-lowering sulphonylurea. (8) The main known adverse effect of pioglitazone and rosiglitazone is water-sodium retention, which can provoke oedema and haemodilution anaemia, and can aggravate or reveal heart failure. (9) Pioglitazone has a positive effect on the lipid profile, whereas rosiglitazone increases the LDL-cholesterol level. (10) Dual-agent therapy with pioglitazone and a sulphonylurea causes more weight gain than metformin plus a sulphonylurea. (11) Several trials have assessed triple-agent regimens containing a glitazone. Three placebo-controlled double-blind trials have tested pioglitazone (one trial, nearly 300 patients) or rosiglitazone (two trials, about 1200 patients) for 12 to 26 weeks in patients whose glycaemia was poorly controlled by dual-agent therapy with a sulphonylurea plus metformin. The glycated haemoglobin level fell by 0.3% to 1.1% (in absolute values), depending on the trial and the dosage, but at a cost of the usual adverse effects such as weight gain, anaemia and oedema. Three unblinded trials have compared oral triple-agent regimens containing glitazone versus insulin plus metformin, alone or in combination with a glucose-lowering sulphonylurea; the treatment including glitazone was no more effective in terms of the glycated haemoglobin level, but was associated with an increase in adverse effects and dropouts. (12) Given the limited clinical data available in early 2005, pioglitazone and rosiglitazone have no place in the management of type 2 diabetes.