Contemporary antimicrobial susceptibility patterns of bacterial pathogens commonly associated with febrile patients with neutropenia.

One of the most challenging problems in antimicrobial chemotherapy is the effective empirical treatment of infection in patients with neutropenia. The rates of occurrence for pathogens have significantly changed (from predominance of gram-negative to gram-positive organisms) under selective pressure of broad-spectrum antimicrobial therapy or prophylaxis, and novel resistance mechanisms have emerged. To address the need for appropriate monotherapy or combination regimens for patients with neutropenia, physicians must prescribe agents with a spectrum of antimicrobial activity to inhibit the major, prevalent pathogens encountered in bloodstream infection and pneumonia; in addition, these selected agents must be active against recently described resistant organisms. Data from the SENTRY Antimicrobial Surveillance Program indicate that several broad-spectrum agents remain highly active and can be used alone or in combinations. In most cases, the newer compounds with increased activity and spectrum against gram-positive cocci (i.e., carbapenems, cefepime, levofloxacin, and trovafloxacin) offer a greater inhibitory potential for empirical therapy among patients with neutropenia and severe infections.     

New therapeutic approaches to hospital-acquired pneumonia

Conventional therapy of hospital-acquired pneumonia includes intravenous antibiotics and supportive care. In many cases, the etiologic agent of infection is not clear; thus, empiric broad-spectrum antibiotic regimens are commonly used. Combinations of beta-lactam and aminoglycoside agents are particularly popular regimens due to the high incidence of gram-negative bacillary and Staphylococcus aureus pneumonias in the hospital setting. Several new approaches to treatment of nosocomial pneumonias are currently being evaluated, however. These include: single-agent empiric coverage using a broad-spectrum beta-lactam agent; intrabronchial aminoglycoside instillation therapy; oral quinolone agents for treatment of gram-negative bacillary pneumonia; and passive immune therapy. The current experience and potential future role of these therapeutic options are discussed in this chapter.     

Gram-negative bacterial pneumonia in the immunocompromised host

Gram-negative bacillary pneumonia is common in all groups of iatrogenically immunosuppressed patients. Mortalities are directly proportional to the degree of neutropenia. Those at particular risk for gram-negative pneumonia are neutropenic patients, patients residing in the hospital setting for prolonged periods, and patients in postoperative periods (eg, organ transplant recipients). The most frequent pathogenesis for pneumonia appears to be airway colonization with gram-negative bacilli, followed by lowe respiratory tract infection. Thus, attention to infection control measures and surveillance culture data is important. Because sputum production is scant or absent, and blood cultures positive in only 30% to 40% of patients, it is often difficult to identify specific etiologic agents. If bacterial pneumonia is suspected in the immunocompromised host, empiric antibiotic coverage should include drugs active against all common aerobic gram-negative bacilli (including P aeruginosa), plus S aureus. Most advocate a beta-lactam plus aminoglycoside combination. Adjunctive treatment with granulocyte transfusions should be reserved for patients not responding to traditional regimens. Immune therapy or prophylaxis has not been fully evaluated for the immunocompromised patient population.     

New developments and concepts in antimicrobial therapy for intra-abdominal infections

Antimicrobial therapy plays an integral role in the management of intra-abdominal infections. Recent developments include increased prevalence of antimicrobial resistance (eg, Streptococcus pneumoniae and Enterococcus species) coupled with general decline in the antimicrobial susceptibility of anaerobes and gram-negative organisms, new antibiotics and dosing regimens, and better understanding of the role of various microbial pathogens and of prophylactic antimicrobial agents. Therapeutic approaches to intra-abdominal infections, such as the various forms of peritonitis, cholecystitis, cholangitis, and diverticulitis, are reviewed here. Specific recommendations for antimicrobial therapy in various clinical settings are provided, with special emphasis on recent trends and developments that reflect changes in understanding or therapy.     

Alterations in the microbial flora and in the incidence of bacteremia at a university hospital after adoption of amikacin as the sole formulary aminoglycoside.

Because of the rapid emergence of resistance to gentamicin and tobramycin among isolates of aerobic and facultative gram-negative bacteria at our university hospital, we designed a prospective study to track aminoglycoside resistance, bacteremic episodes, and bacteremia-associated deaths before and after the institution of amikacin as the sole formulary aminoglycoside. From June 1984 through June 1987 (immediately before this policy change), amikacin accounted for only 20% of patient-days of aminoglycoside therapy, and rates of resistance to gentamicin, tobramycin, and amikacin among aerobic and facultative gram-negative bacterial isolates were 12.8%, 10.8%, and 5.9%, respectively. During the next 30 months (immediately after the change in policy), amikacin accounted for 98% of patient-days of aminoglycoside therapy, and rates of resistance to gentamicin, tobramycin, and amikacin were 6.3%, 5.0%, and 3.3%, respectively. Furthermore, during the latter 30 months, the incidence of both bacteremia and bacteremia-associated death decreased significantly. Hospitals at which resistance to gentamicin or tobramycin is increasing among the gram-negative flora may benefit from the use of amikacin as the principal aminoglycoside.     

Helicobacter pylori infection and antimicrobial agents resistance

PURPOSE: Seven days triple therapies combining a proton pump inhibitor (PPI) and 2 antimicrobial agents (clarithromycin [C], amoxicillin [A], metronidazole [M]), are recommended for the treatment of Helicobacter pylori infection. The eradication failures have increased these last years, particularly in France (about 30%). They are essentially related to the development of antimicrobial agents resistance, mainly concerning macrolides and nitro-imidazoles. CURRENT KNOWLEDGE AND KEY POINTS: Primary resistance to clarithromycin is variable, but reaching now about 10% throughout the world and about 20% in France. It reduces the eradication success rate at 25%. The secondary resistance is very high, contra-indicating the use of clarithromycin in second line regimens. Primary resistance to amoxicillin has recently appeared, but remains very low until now, less than 2%, as the tetracyclin (T) resistance. Primary resistance to metronidazole is 3 times higher than macrolides resistance, but its determination is less accurate. Metronidazole resistance reduces eradication rate of about 25%, leading to the use of metronidazole in second line therapy, in increasing the triple therapy duration at 14 days (PPI-A-M), or in combination with quadruple therapy (Bismuth-PPI-T-M). Other rescue-treatments are efficacious, based on ranitidine bismuth citrate combined regimens or on rifabutine (R) based regimens (PPI-A-R). FUTURE PROSPECTS AND PROJECTS: The recent knowledge of the mutations mainly responsible for H. pylori resistance to antimicrobial agents now allows the development of detection methods based on the study of bacterial DNA. These methods have been validated for clarithromycin and should favour in the near future the determination of resistance by the use of biopsy culture or directly on the gastric biopsy.     

Antimicrobial therapy of intra-abdominal sepsis.

Intra-abdominal sepsis remains a highly morbid and lethal event despite the availability of potent antimicrobial agents and improvements in surgical management and intensive care. Appropriate management consists of source control, antimicrobial agents directed against both facultative gram-negative and anaerobic organisms, and physiologic and metabolic support. A variety of single and dual agent regimens are appropriate for initial therapy, as long as both aerobes and anaerobes are effectively targeted. Culture, Gram stain, and sensitivity testing may provide valuable information, especially when resistant organisms are encountered. Further studies to determine the relative efficacy of various agents need to be carefully designed both to avoid the pitfalls of previous studies and to provide useful and comparable data.     

Treatment options for newly diagnosed patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is an indolent B-cell malignancy for which early intervention has not been shown to extend survival. However, there are many agents available that are active in this disease. Alkylating agents, the purine analogs, and monoclonal antibodies have all been shown to result in high response rates in patients with previously treated and untreated CLL. These classes of agents have been combined based on in vitro data demonstrating synergism. The purine analogs alone or in combination with alkylating agents and monoclonal antibodies result in greater response rates compared with alkylating agent-based therapy alone. However, improvement in overall survival and cure of patients with CLL has yet to be realized with these available regimens. The best initial therapy of patients with CLL remains a matter of debate.     

Drug-resistance encountered in the retreatment of Mycobacterium tuberculosis infections

Patients who had prior anti-tuberculosis medications for pulmonary tuberculosis and who return to the hospital with culture-positive tuberculosis have been considered to be at risk of harboring resistant bacilli (secondary resistance or acquired resistance). The present recommendation for therapy of these patients is to resume earlier anti-tuberculosis medications and to add two new agents until the drug susceptibilities of the bacilli are known. This study reviewed 112 cases of readmissions for active tuberculosis and evaluated the risk of acquired drug resistance in this group. Patients with 6 months or less of prior therapy rarely harbored resistant organisms. Patients with 6-12 months of prior therapy had an 88% possibility of harboring resistant bacilli, but only a 30% risk of harboring multiple-drug resistant bacilli. Patients with 12 months or more of prior therapy had a 66% risk of harboring multiple-drug resistant, difficult-to-treat bacilli. This data would indicate that only those patients who have had prior therapy for 7 months or more require aggressive initial readmission therapy with 4 or more anti-tuberculosis agents. Hopefully this finding will not only help clinicians to identify readmission tuberculosis patients who are at increased risk of harboring resistant organisms but will also help them to be more selective in prescribing aggressive, potentially toxic, multiple-drug regimens.     

Aminoglycosides versus beta-lactams in gram-negative pneumonia.

Newer beta-lactam antibiotics with high levels of activity against gram-negative aerobic bacilli (including Pseudomonas aeruginosa) such as cefoperazone, ceftazidime, imipenem, and aztreonam may be suitable for monotherapy of gram-negative pneumonia. Aminoglycoside antibiotics (gentamicin, tobramycin, amikacin are also highly active against these same organisms and have been more extensively used, but are both ototoxic and nephrotoxic. Key therapeutic questions are whether beta-lactams can safely replace aminoglycosides for the treatment of gram-negative pneumonia, and whether monotherapy or aminoglycoside and beta-lactam combination antibiotic treatment is superior. There is remarkably little definitive clinical data in the literature to answer these questions, but available studies suggest that beta-lactam monotherapy may be adequate for Escherichia coli and Klebsiella pneumoniae pneumonias, but that combination therapy may be preferred for Pseudomonas aeruginosa, Serratia sp, Enterobacter sp, and Acinetobacter sp, largely based on rates of bacterial persistence and emergence of resistance. At this time, there are more data available to support aminoglycoside monotherapy than beta-lactam monotherapy in gram-negative pneumonia and remarkably little data to suggest superiority of two antibiotics over single agents when they have been compared prospectively. Thus, combination therapy remains a conservative recommendation until better studies are available.     

Can guidelines for the treatment of respiratory infections lead to reduced rates of antibiotic resistance?

Guidelines have been developed for the therapy of both community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP), and, potentially, if applied appropriately, could lead to a containment or reduction in the frequency of antibiotic resistance. In the therapy of CAP, guidelines could minimize the use of excessive antibiotic therapy, and if they also improve the accuracy of therapy, they could minimize the emergence of resistant organisms in the community. However, the impact of such guidelines on resistance remains to be shown. In the near future, CAP guidelines could help contain the growing problem of quinolone-resistant pneumococci by advocating the use of the most effective of the new agents, administered at the optimal dosages. When managing HAP, the use of guidelines could improve outcome by leading to a greater percentage of patients receiving adequate empiric antibiotic therapy. It remains uncertain whether such an approach can minimize the emergence of antibiotic resistance, particularly in the intensive care unit (ICU), but it is clear that if guidelines are to be accurate, they must account for the resistance patterns that are unique to each individual hospital setting. To date, the use of computer-assisted guidelines for the therapy of nosocomial infections has been successful in minimizing the frequency of inadequate therapy, with no negative impact on antibiotic resistance. Antibiotic restriction policies have been proposed as a way to have an impact on resistance, with variable effects. In the future, antibiotic rotation is likely to be studied as a way to reduce resistance, particularly in the ICU, but a number of practical issues may limit the efficacy of such an approach.     

Management of cardiovascular risk with RAS inhibitor/CCB combination therapy

Hypertension is a significant risk factor for cardiovascular disease (CVD), including stroke, myocardial infarction, kidney disease and heart failure. Considerable research has been undertaken to delineate the differential effects of various classes of antihypertensive agents in delaying or preventing cardiovascular morbidity and mortality. Although possible benefits may result from specific agents or classes of agents in certain high-risk subgroups, prompt and intensive blood pressure (BP) reduction to target levels remains the most crucial factor in this benefit. Despite this, the BP remains above the target level in a large majority of patients, reinforcing the need for improved treatment paradigms. Among antihypertensive agents, inhibitors of the renin-angiotensin system--angiotensin-II receptor blockers and angiotensin-converting enzyme inhibitors--and long-acting dihydropyridine calcium channel blockers (DHP-CCBs) have been shown to provide safe, effective and well-tolerated BP control. These agents have also been proven as effective as, and in some cases superior to, other classes of agents in reducing cardiovascular morbidity and mortality. As the majority of high-risk patients require at least two and possibly even three medications to achieve the target BP, combination therapy with these two classes of drugs is a rational approach to therapy. Whether fixed-dose combination therapy with a renin-angiotensin system inhibitor plus a DHP-CCB affords greater clinical benefit compared with other combination regimens remains to be determined in large, prospective clinical trials. Meanwhile, such a combination offers effective, convenient, well-tolerated control of the most important modifiable risk factor for CVD.     

Pharmacologic aspects of eradication therapy for Helicobacter pylori Infection

The commonly used regimens for the eradication of Helicobacter pylori infection consist of administration of proton pump inhibitors (PPIs) and 1 to 3 antimicrobial agents, such as amoxicillin, clarithromycin, metronidazole, fluoroquinolone, or tetracycline. Each agent has its own pharmacologic characteristics. PPIs are metabolized by cytochrome P450 2C19 (CYP2C19), which is polymorphic. CYP2C19 genotypic differences in the pharmacokinetics and pharmacodynamics of PPIs influence the eradication rates of H pylori infection by PPI-containing regimens. Amoxicillin is a time-dependent antibiotic, whereas clarithromycin, metronidazole, tetracycline, and fluoroquinolone are not. The plasma half-life of antimicrobial agents also differs among these antibiotics. To achieve consistently high eradication rates, the eradication regimens must be designed based on a good understanding of the resistance patterns of the bacteria and the pharmacologic characteristics of the agents used for H pylori eradication therapy.     

Antimicrobial resistance--pharmacological solutions

The interaction between microbial resistance and antibacterial agents occurs in a direct and an indirect fashion. Directly--through the development of resistance to the agent used, or to agents of the same class--as exemplified by the induction of beta-lactamase by both gram-positive and gram-negative bacteria. It also takes place through the development of resistance to compounds of different classes to the compound used, as exemplified by the loss of Streptococcus pneumoniae susceptibility to penicillin that is accompanied by a parallel loss of sensitivity to erythromycin and to tetracycline. As for the indirect way--microbial resistance may develop through selection of resistant organisms when the patient is treated with antibiotics, when the environment is contaminated with antibiotics (hospital) or when antibacterial agents are used in agriculture and animal husbandry.     

Sulfonamide-containing regimens for disease caused by rifampin-resistant Mycobacterium kansasii

Fourteen wild strains and 14 relapse or treatment failure isolates of Mycobacterium kansasii were tested and found to be highly susceptible to sulfamethoxazole (SMX), with 26 of 28 isolates having minimal inhibitory concentrations (MIC) of less than or equal to 4 micrograms/ml), using a broth microdilution method. Treatment failure isolates frequently exhibited resistance to rifampin (RMP) (greater than 2 micrograms/ml), isoniazid (INH) (greater than 4 micrograms/ml), and ethambutol (EMB) (greater than 4 micrograms/ml) not seen among the wild strain isolates. Eight patients with cavitary disease caused by RMP-resistant M. kansasii were treated with SMX-containing regimens that also included high dose INH (900 mg), EMB (25 mg/kg), and an aminoglycoside (either streptomycin or amikacin). Patients were treated initially in the hospital for 4 to 10 wk. In 7 of the 8 patients, sputum cultures became negative in a mean of 10 wk (range, 7 to 14 wk). Acquired drug resistance to INH, RMP, and EMB can be demonstrated in M. kansasii, and SMX in combination with other agents chosen on the basis of MIC determinations are effective in the treatment of disease caused by RMP-resistant M. kansasii.     

Antibiotic susceptibility profiles of 941 gram-negative bacteria isolated from septicemic patients throughout Canada. The Canadian Study Group.

The choice of antimicrobial therapy for the treatment of bacteremia is often empirical and based on the knowledge of antibiotic susceptibility profiles of the most common bacteria causing such infections. It therefore is crucial to survey the susceptibility of bacteria causing sepsis. This study examines the susceptibility profiles of 941 gram-negative bacteria, isolated from septic patients in 10 Canadian hospitals, to 28 antimicrobial agents. Among the isolates, 30 different species were represented; Escherichia coli dominated, representing 52.5% of isolates. More than 50% of all bacteria were resistant to ampicillin. Only 67% of the E. coli isolates were susceptible to ampicillin, while 30% of all strains were resistant to ticarcillin. Of the cephalosporins, ceftazidime and cefoperazone/sulbactam were the agents to which isolates were the most susceptible (90%). Only 51% of the E. coli strains were susceptible to cephalothin, while 91% were still susceptible to cefazolin. A total of 93% and 98% of the strains were susceptible to aztreonam and imipenem, respectively. Aminoglycosides were highly active against most isolates, in general in the following order: netilmicin greater than tobramycin greater than gentamicin greater than amikacin. Tobramycin was the most active against Pseudomonas aeruginosa. Nearly all isolates were susceptible to the quinolones. Tolerance (MBC/MIC ratio, greater than or equal to 32) was rarely observed. This survey of the susceptibility of gram-negative bacteria causing sepsis provides valuable information for implementing the chemotherapy for gram-negative septicemia and demonstrates that several older and newer agents, alone or in combination, can be used as adequate initial therapy for gram-negative sepsis in Canada.     

Salvage treatment in HIV disease

The need for salvage treatment is related to the imperfection of current antiretroviral therapy. Sequential therapy with suboptimally suppressive regimens results in a need for this intervention. The aim of salvage treatment is as yet uncertain; virological suppression; immunoenhancement or stability or avoidance of clinical disease. Therapeutic options are constantly improving and the knowledge base concerning individual agents and different combinations comprising highly active antiretroviral treatment (HAART) regimens increases daily. The utility of new agents in salvage appears vital with numbers of new or recycled agents to which no demonstrable resistance exists is a major predictive factor of a positive outcome in this setting. Patient commitment, physician knowledge and an informed supportive environment are also conducive to success in salvage treatment.     

Gentamicin resistance among gram-negative bacillary blood isolates in a hospital with long-term use of gentamicin

Between 1977 and 1985, gentamicin was the only formulary aminoglycoside at the Buffalo Veterans Administration Medical Center. During this time, there was a significant increase in the amount of gentamicin purchased. Amikacin represented 11% or less of the total aminoglycoside purchased in the same period, but purchases of this agent also significantly increased. Because of this long-term use of gentamicin, a retrospective analysis of gentamicin resistance among gram-negative bacillary blood isolates was performed. The results of this review revealed no significant change in the overall incidence of gram-negative bacteremia; approximately 75% of these bacteremic episodes were hospital acquired. The mean yearly gentamicin-resistance rate of gram-negative blood isolates was 13.2% (range, 6% to 18%) with no significant change in the rate for the period reviewed. However, for certain strains there were fluctuations in the percentage of resistance from year to year, suggesting that clusters of infections due to these organisms had occurred. Bacteremic infection due to resistant organisms was a major contributor to the overall level of gentamicin resistance among blood isolates. Amikacin resistance among gram-negative blood isolates was rare. In conclusion, despite the predominant use of gentamicin there was no change in the gentamicin resistance rate among gram-negative bacillary blood isolates during a nine-year period. The rate of gentamicin resistance among blood isolates appeared to be related to outbreaks/clusters of infections due to resistant strains rather than the frequency of use of gentamicin.     

Overview of patency as an end point of thrombolytic therapy.

Underlying the use of thrombolytic therapy is the hypothesis that reestablishment and maintenance of coronary blood flow (coronary patency) are the primary mechanisms of therapeutic benefit in patients with acute myocardial infarction. Early achievement and maintenance of adequate coronary blood flow (patency) in the infarct-related artery are the primary goals of thrombolytic therapy. One third of patients may achieve spontaneous patency within a few days following acute myocardial infarction. When antithrombotic therapy (i.e., heparin) is administered, this rate increases to greater than 50%, but patency is achieved only gradually and mortality reductions comparable to thrombolytic therapy are not achieved. After administration of a thrombolytic agent, early (90-minute) patency rates are greater with alteplase or anistreplase than with streptokinase. However, patency rates for alteplase decline by 10-30% if intravenous heparin is not given concurrently. When patency is assessed greater than 24 hours following thrombolytic therapy, no significant difference exists among the agents. A single angiographic observation of the artery at 90 minutes, although useful, may be inadequate to distinguish among the beneficial clinical effects of different thrombolytic regimens. The overall reperfusion or patency profile is probably a better basis for assessing relative benefits. Intravenous thrombolytic regimens that are increasingly effective in rapidly achieving and maintaining coronary patency are now available and in further development.