Carbapenems and monobactams: imipenem, meropenem, and aztreonam

Imipenem and meropenem, members of the carbapenem class of beta-lactam antibiotics, are among the most broadly active antibiotics available for systemic use in humans. They are active against streptococci, methicillin-sensitive staphylococci, Neisseria, Haemophilus, anaerobes, and the common aerobic gram-negative nosocomial pathogens including Pseudomonas. Resistance to imipenem and meropenem may emerge during treatment of P. aeruginosa infections, as has occurred with other beta-lactam agents; Stenotrophomonas maltophilia is typically resistant to both imipenem and meropenem. Like the penicillins, the carbapenems have inhibitory activity against enterococci. In general, the in vitro activity of imipenem against aerobic gram-positive cocci is somewhat greater than that of meropenem, whereas the in vitro activity of meropenem against aerobic gram-negative bacilli is somewhat greater than that of imipenem. Daily dosages may range from 0.5 to 1 g every 6 to 8 hours in patients with normal renal function; the daily dose of meropenem, however, can be safely increased to 6 g. Infusion-related nausea and vomiting, as well as seizures, which have been the main toxic effects of imipenem, occur no more frequently during treatment with meropenem than during treatment with other beta-lactam antibiotics. The carbapenems should be considered for treatment of mixed bacterial infections and aerobic gram-negative bacteria that are not susceptible to other beta-lactam agents. Indiscriminate use of these drugs will promote resistance to them. Aztreonam, the first marketed monobactam, has activity against most aerobic gram-negative bacilli including P. aeruginosa. The drug is not nephrotoxic, is weakly immunogenic, and has not been associated with disorders of coagulation. Aztreonam may be administered intramuscularly or intravenously; the primary route of elimination is urinary excretion. In patients with normal renal function, the recommended dosing interval is every 8 hours. Patients with renal impairment require dosage adjustment. Aztreonam is used primarily as an alternative to aminoglycosides and for the treatment of aerobic gram-negative infections. It is often used in combination therapy for mixed aerobic and anaerobic infections. Approved indications for its use include infections of the urinary tract or lower respiratory tract, intra-abdominal and gynecologic infections, septicemia, and cutaneous infections caused by susceptible organisms. Concurrent initial therapy with other antimicrobial agents is recommended before the causative organism has been determined in patients who are seriously ill or at risk for gram-positive or anaerobic infection.     

Recent trend and development of novel antimicrobial agents for MRSA infections]

Gram-positive organisms such as Staphylococcus aureus (including MRSA), coagulase-negative staphylococci, Enterococcus spp., and Streptococcus spp. have in recent years emerged as significant pathogens in hospitals and are now being isolated more frequently than gram-negative bacilli. These organisms are often multidrug resistant. Therefore, alternative agents with potent activity against gram-positive organisms are of considerable interest. In addition to the glycopeptide antibiotic vancomycin and the aminoglycoside antibiotic arbekacin, which can be used in MRSA infections, teicoplanin, RP 59500 and daptomycin are now under basic research in Japan. These antimicrobial agents are very active against gram-positive organisms, including MRSA and appear to be potent agents against infections due to gram-positive cocci, particularly MRSA.     

Antimicrobial therapy for infants and children: guidelines for the inpatient and outpatient practice of pediatriac infectious diseases

In this article, we discuss antimicrobial regimens for both outpatient and inpatient use in infants and children. A substantial number of pediatric patient visits annually result in the prescribing of antimicrobial drugs. The emergence of bacteria resistant to commonly used antimicrobial agents is a growing concern. Information on newer drugs such as meropenem, which is active against penicillin-resistant Streptococcus pneumoniae and gram-negative bacilli, and cefepime, which has activity against gram-negative bacilli including Pseudomonas aeruginosa and against gram-positive cocci is also presented. Management of patients with congenital or acquired immunodeficiencies continues to be challenging in regard to the use of antimicrobial drugs to treat various fungal and viral infections. New formulations of older drugs such as aerosolized tobramycin and amphotericin B lipid complex are available. New antiviral agents have been approved, most of which are antiretroviral agents. Childhood tuberculosis is an ongoing concern, and regimens to treat Mycobacterium tuberculosis in children are discussed.     

Bactericidal effects of antibiotics on slowly growing and nongrowing bacteria

Antimicrobial agents are most often tested against bacteria in the log phase of multiplication to produce the maximum bactericidal effect. In an infection, bacteria may multiply less optimally. We examined the effects of several classes of antimicrobial agents to determine their actions on gram-positive and gram-negative bacteria during nongrowing and slowly growing phases. Only ciprofloxacin and ofloxacin exhibited bactericidal activity against nongrowing gram-negative bacteria, and no antibiotics were bactericidal (3-order-of-magnitude killing) against Staphylococcus aureus. For the very slowly growing gram-negative bacteria studied, gentamicin (an aminoglycoside), imipenem (a carbapenem), meropenem (a carbapenem), ciprofloxacin (a fluoroquinolone), and ofloxacin (a fluoroquinolone) exhibited up to 5.7 orders of magnitude more killing than piperacillin or cefotaxime. This is in contrast to optimally growing bacteria, in which a wide variety of antibiotic classes produced 99.9% killing. For the gram-positive and gram-negative bacteria we examined, antibiotic killing was greatly dependent on the growth rate. The clinical implications of slow killing by chemotherapeutic agents for established bacterial infections and infections involving foreign bodies are unknown.     

Clindamycin, metronidazole, and chloramphenicol.

Clindamycin, metronidazole, and chloramphenicol are three antimicrobial agents useful in the treatment of anaerobic infections. Clindamycin is effective in the treatment of most infections involving anaerobes and gram-positive cocci, but emerging resistance has become a problem in some clinical settings. Metronidazole is effective in the treatment of infections involving gram-negative anaerobes, but it is unreliable in the treatment of gram-positive anaerobic infections and is ineffective in treating aerobic infections. Additionally, metronidazole is often the drug of choice in treating infections in which Bacteroides fragilis is a serious concern. Chloramphenicol is effective in the treatment of a wide variety of bacterial infections, including serious anaerobic infections, but is rarely used in Western countries because of concerns about toxicity, including aplastic anemia and gray baby syndrome.     

Pathogens resistant to antibacterial agents

Resistance to antimicrobial drugs is increasing at an alarming rate among both gram-positive and gram-negative bacteria. Traditionally, bacteria resistant to multiple antimicrobial agents have been restricted to the nosocomial environment. A disturbing trend has been the recent emergence and spread of resistant pathogens in nursing homes, in the community, and in the hospital. This article reviews the epidemiology, molecular mechanisms of resistance, and treatment options for pathogens resistant to antimicrobial drugs.     

Appropriate prescribing of oral beta-lactam antibiotics

Beta-lactam antibiotics include penicillins, cephalosporins and related compounds. As a group, these drugs are active against many gram-positive, gram-negative and anaerobic organisms. Information based on "expert opinion" and antimicrobial susceptibility testing supports certain antibiotic choices for the treatment of common infections, but less evidence-based literature is available to guide treatment decisions. Evidence in the literature supports the selection of amoxicillin as first-line antibiotic therapy for acute otitis media. Alternative drugs, such as amoxicillin-clavulanate, trimethoprim-sulfamethoxazole and cefuroxime axetil, can be used to treat resistant infections. Penicillin V remains the drug of choice for the treatment of pharyngitis caused by group A streptococci. Inexpensive narrow-spectrum drugs such as amoxicillin or trimethoprim-sulfamethoxazole are first-line therapy for sinusitis. Animal and human bites can be treated most effectively with amoxicillin-clavulanate. For most outpatient procedures, amoxicillin is the preferred agent for bacterial endocarditis prophylaxis. Beta-lactam antibiotics are usually not the first choice for empiric outpatient treatment of community-acquired pneumonia. Based on the literature, the role of beta-lactam antibiotics in the treatment of bronchitis, skin infections and urinary tract infections remains unclear.     

Antimicrobial activities of clofazimine and B669 are mediated by lysophospholipids.

The susceptibilities of a range of gram-positive and gram-negative microbial pathogens to clofazimine and its analog B669 (0.1 to 32 micrograms/ml), as well as the effects of these agents on membrane phospholipid metabolism in Staphylococcus aureus and Escherichia coli, have been investigated in vitro. Gram-positive bacteria were found to be generally susceptible to these agents, whereas gram-negative organisms were uniformly resistant. Exposure of S. aureus to both agents (1 to 5 micrograms/ml), especially B669, caused dose-related enhancement of the activity of phospholipase A2, according to an increase in the release of 3H-radiolabeled arachidonate and lysophosphatidylethanolamine ([3H]LPE) from bacterial-membrane phospholipids. Treatment of E. coli with the riminophenazines also increased the release of [3H]arachidonate and [3H]LPE. Growth of gram-positive but not gram-negative bacteria was inhibited by LPE and lysophosphatidylcholine. Moreover, coincubation with alpha-tocopherol (vitamin E), a lysophospholipid complex-forming agent, or with lysophospholipase protected gram-positive bacteria against the riminophenazines as well as against lysophospholipids. The results from this study are consistent with a mechanism whereby lysophospholipids mediate the activities of the two drugs.     

Occurrence of clindamycin-resistant anaerobic bacteria isolated from cultures taken following clindamycin therapy.

MICs of clindamycin were determined by the agar dilution method against anaerobic organisms isolated from endometrial cultures in women with pelvic soft tissue infections. Cultures were obtained from 100 women both before and after clindamycin therapy, from 107 women before therapy with clindamycin or another antimicrobial agent or after treatment with an antimicrobial agent other than clindamycin, and from 9 women 1 to 9 weeks after they were discharged from the hospital following clindamycin therapy. Only 5 (0.7%) of 685 isolates tested from women who had not received clindamycin therapy were resistant to clindamycin. From the 100 cultures taken immediately after clindamycin therapy, 57 anaerobic bacteria were isolated from 28 cultures. Of the 40 anaerobic organisms for which MICs of clindamycin were determined, 25 (62.5%) were resistant to clindamycin (MIC greater than or equal to 8 micrograms/ml). The most common organisms isolated after therapy were the anaerobic gram-positive cocci (of which 32 isolates were discovered); of 28 coccal isolates tested, 64% were clindamycin resistant. Four of seven (57%) of the Bacteroides isolates tested, one unidentified gram-positive nonsporing rod, one unidentified gram-negative coccus, and one Mobiluncus sp. were also clindamycin resistant. Of 18 anaerobic isolates from the nine cultures taken 1 to 9 weeks after hospital discharge, 55% were resistant to clindamycin. The clinical significance of these findings is unknown since all patients recovered without incident and remained well. However, the data suggest that physicians need to be aware that patients with recent exposure to clindamycin may have clindamycin-resistant anaerobic organisms in a current infection. This may prevent the infection from responding to clindamycin treatment.     

Current concepts in antimicrobial therapy against resistant gram-negative organisms: extended-spectrum beta-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa

The development of antimicrobial resistance among gram-negative pathogens has been progressive and relentless. Pathogens of particular concern include extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Classic agents used to treat these pathogens have become outdated. Of the few new drugs available, many have already become targets for bacterial mechanisms of resistance. This review describes the current approach to infections due to these resistant organisms and elaborates on the available treatment options.     

Clinical evaluation of moxalactam: evidence of decreased efficacy in gram-positive aerobic infections.

Moxalactam was used as initial, empirical therapy in 69 patients with a variety of serious bacterial infections, 32% of which were accompanied by bacteremia. Overall, the success rate was 83% and drug-related adverse effects were minimal. The drug was less efficacious in infections caused by aerobic gram-positive pathogens than it was in those caused by gram-negative pathogens. The following gram-positive organisms were associated with special problems during moxalactam therapy: Streptococcus pneumoniae (development of meningitis and a relapse of pneumonia with a more resistant strain), Staphylococcus epidermidis (in vivo emergence of moxalactam resistance, and the enterococci (failure of therapy and a fatal superinfection. Moxalactam performed well in infections caused by most gram-negative organisms, including aminoglycoside-resistant strains, but the previously reported emergence of gram-negative bacillary resistance to moxalactam during therapy was reconfirmed in our series with Serratia marcescens. The use of moxalactam in the treatment of gram-negative meningitis was further supported by a patient with meningitis-ventriculitis caused by Bacteroides fragilis who was cured with moxalactam after failure on chloramphenicol.     

Imipenem versus gentamicin combined with either cefuroxime or cephalothin as initial therapy for febrile neutropenic patients.

A prospective randomized study was conducted to determine the efficacy of imipenem-cilastatin (hereafter referred to as imipenem) (500 mg four times daily) versus combination therapy for febrile neutropenic patients receiving either no prophylaxis or ciprofloxacin for prevention of infections. Combination therapy consisted of gentamicin (80 mg every 8 h) plus either cefuroxime (1,500 mg every 8 h) or cephalothin (1,000 mg every 4 h) for suspected catheter-related infections. Ninety-four neutropenic fever episodes in 87 patients were evaluable for efficacy. The overall clinical rate of response to imipenem was significantly higher than that to combination therapy (91 versus 74%; P = 0.05). The difference in efficacy was most pronounced in patients with microbiologically documented infections (89 versus 53%; P = 0.025), which were predominantly caused by gram-positive bacteria. Differences in susceptibility may have caused the better rate of response to imipenem. Two of 29 gram-positive bacteria were imipenem resistant, whereas 10 were resistant to cephalothin and cefuroxime and 12 were resistant to gentamicin. No causative gram-negative bacterium and 24 gram-positive bacteria were isolated in 61 fever episodes with ciprofloxacin prophylaxis (oral). In contrast, nine causative gram-negative and five gram-positive bacteria were isolated in 33 episodes without prophylaxis. The difference in distribution proved to be statistically significant for gram-negative (P = 0.0001) as well as gram-positive (P = 0.025) bacteria, indicating that ciprofloxacin effectively prevented the occurrence of gram-negative bacteria and may have contributed to the relatively large number of gram-positive bacteria isolated. Empirical initial therapy with imipenem may be a valuable alternative to combination therapy for neutropenic fever episodes.     

Bactericidal agents in the treatment of MRSA infections--the potential role of daptomycin

Over the last decade, methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged as serious pathogens. These strains are often multiresistant to several antibiotic classes and are a major cause of serious hospital- and now community-acquired infections and associated morbidity and mortality. As a result of increasing antimicrobial resistance, glycopeptides, such as vancomycin, are widely used as first-line therapy for serious MRSA infections. However, the emergence of glycopeptide tolerance and resistance has complicated treatment and there remains a clinical need for new antibiotics with suitable pharmacokinetic properties with activity against MRSA and other gram-positive pathogens. Infections caused by MRSA and other bacteria usually respond as well to bacteriostatic agents as to bactericidal ones. Nevertheless, there is evidence that rapid bacterial killing has potential clinical advantages over bacteriostatic therapy in certain infections. Daptomycin, the first of the cyclic lipopeptides, shows rapid bactericidal activity against S. aureus, including strains tolerant or resistant to other agents. This review outlines the methods by which bactericidal and bacteriostatic properties are defined and tested, discusses the potential importance of bactericidal therapy in MRSA and other infections and examines the potential role of daptomycin in treatment.     

New uses for older antibiotics: nitrofurantoin, amikacin, colistin, polymyxin B, doxycycline, and minocycline revisited

Nitrofurantoin, amikacin, colistin, polymyxin B, doxycycline, and minocycline are antibiotics with proven effectiveness against selected pathogens. These antibiotics have not developed resistance over time. As "low-resistance potential antibiotics" that are effective against an increasing number of infections due to resistant gram-positive or gram-negative pathogens, these antimicrobials remain an important part of the antibiotic armamentarium. They will be used increasingly in the future, as highly resistant organisms continue to be important clinically and therapeutic options remain limited.     

Antibiotics in the intensive care unit: focus on agents for resistant pathogens

Antibiotic resistance is increasing faster than the drug industry can develop and market new antibiotics. Medical personnel commonly must deal with the resistant gram-positive pathogens including MRSA and VRE, in addition to the problem gram-negative bacteria, Pseudomonas, Acinetobacter, and ESBL producing strains of Klebsiella and E. coli. Clinicians should be familiar with treatment strategies for these resistant pathogens. Because of the lack of novel agents to treat resistant infections, clinicians must use antibiotics judiciously and appropriately to limit further development of resistance. Early, appropriate cultures of the blood, urine, sputum and suspected source, ideally obtained before antibiotic initiation, allow for future de-escalation of antibiotics, or the decision to discontinue antibiotics.     

Clinical experience with drotrecogin alfa in treating gram-positive and -negative pathogens in patients with severe sepsis.

BACKGROUND: Newer concepts in the management of severe sepsis and, in particular, in the understanding of the relationship between proinflammatory and procoagulant activities during severe infection have led to the introduction of activated protein C (drotrecogin) into the therapeutic program. The combination of effective antimicrobial therapy, aggressive supportive care, and efforts to antagonize procoagulants and inhibitors of fibrinolysis was used in this study. METHODS: We treated 12 patients with severe sepsis using this combination of antimicrobial agents and drotrecogin. All patients presented with hypotension and organ failure and some with multiple organ failure. Infected patients were separated into those with gram-positive and those with gram-negative infections. RESULTS: In contrast to an expected mortality rate of nearly 40% in this group of patients, only 2 (9%) expired. Both deaths were due to infection by gram-negative organisms in patients with complicated abdominal infections and concurrent cancer. All patients with gram-positive organisms survived. CONCLUSION: Those patients with infections caused by gram-positive organisms seemed to have a better prognosis than those with gram-negative infections, perhaps because their illnesses are less complicated by local disease. Although our study is small, it suggests that activated protein C will have a significant beneficial effect on the future treatment of severe sepsis and can reduce the mortality rate significantly. Further improvement in survival rates will require more effective treatment of local disease and associated noninfectious ailments.     

Antibiotic use in the emergency department. II. The aminoglycosides,macrolides, tetracyclines,sulfa drugs,and urinary antiseptics

The aminoglycoside, macrolide, tetracycline, and sulfa classes of antibiotics provide antimicrobial coverage pertinent to many infectious diseases diagnosed in the emergency department (ED). The aminoglycosides are parenteral agents that are useful in Gram-negative infections and as synergistic drugs in the management of some Gram-positive infections. The macrolides, of which erythromycin is the prototype, are used for a number of Gram-positive and atypical bacterial infections, while the tetracyclines are appropriate for ED treatment of a diverse group of infections such as chlamydiae, spirochetes, and rickettsiae. The sulfa agents are appropriate for many urinary and respiratory tract infections, and also have particular utility in some infections encountered primarily in patients with AIDS. The urinary antiseptics are a group of antimicrobials that may be effective for cystitis but have no systemic efficacy. This article, which is the second in a fourpart series on antibiotic use in the ED, reviews the pharmacology and clinical utility of these diverse agents for the emergency physician.     

Antibacterial properties of Ro 40-6890, a broad-spectrum cephalosporin, and its novel orally absorbable ester, Ro 41-3399.

Ro 41-3399 is a novel orally active ester of Ro 40-6890, an aminothiazolyl cephalosporin with potent in vitro activities against commonly encountered aerobic gram-positive bacteria (streptococci and methicillin-susceptible staphylococci) and gram-negative bacteria (members of the family Enterobacteriaceae, haemophili, meningococci, and gonococci). In terms of the MICs determined by the methods recommended by the National Committee for Clinical Laboratory Standards, for 50 and 90% of gram-positive organisms, the water-soluble free carboxylic acid Ro 40-6890 proved to be at least as active as or two- to fourfold more active than cefpodoxime, cefuroxime, cefaclor, amoxicillin, amoxicillin-clavulanic acid, and ceftriaxone; against aerobic gram-negative organisms, Ro 40-6890 was usually two- to fourfold more active than cefpodoxime, the next most potent of the oral drugs under comparison, but remained usually two- to fourfold weaker than ceftriaxone. Ro 40-6890 showed a high affinity for the essential penicillin-binding proteins of susceptible bacteria and was resistant to hydrolysis by a broad array of beta-lactamases. Ro 41-3399 bopentil was well absorbed in mice when administered by oral gavage and proved effective in several experimental bacterial infections. Further studies with Ro 41-3399 and Ro 40-6890 are in progress.     

Significance of antibiotic resistance in treatment of soft tissue infections

Soft tissue infections are common. The clinical spectrum includes infections of skin, subcutaneous tissue, and of deeper structures such as fascia and muscles. The pathogenesis of these infections is quite variable. Introduction of microorganisms through skin breaks or through trauma of other soft tissue is usually at the origin of such infections. Staphylococci, especially S. aureus, as well as streptococci, mainly group A streptococci cause most soft tissue infections. In immunocompromised patients or in particuluar circumstances gram-negative bacteria may also be found to cause such infections. Occasionally, infections are polymicrobial. Given the predominance of gram-positive cocci, betalactam antibiotics with good antistaphylococcal activity are the drugs of choice for empiric treatment. Penicillins or cephalosporins that are stable against penicillinase should be chosen, since many staphylococci produce penicillinase. Over the course of the last 40 years staphylococci first became resistant against penicillin, and later developed resistance against methicillin. Methicillin-resistant S. aureus (MRSA) is now a significant problem worldwide. There continue to be major differences in the prevalence of MRSA between geographic regions. In areas with a high prevalence of methicillin resistance among S. aureus, empiric treatment of life-threatening soft tissue infections should include treatment with a glycopeptide (i.e. vancomycin or teicoplanin). New antibiotics such as oxazolidinones (i.e. linezolid) or quinupristin/dalfopristin are interesting alternatives to the glycopeptides in the treatment of soft tissue infections.     

The fluoroquinolones for urinary tract infections: a review

The fluoroquinolones are a rapidly growing class of antibiotics with a broad spectrum of activity against gram-negative and some gram-positive aerobic bacteria. These agents, including norfloxacin, ciprofloxacin, ofloxacin, enoxacin, and lomefloxacin, have been extensively studied and have demonstrated efficacy and safety profiles comparable to those of other traditional agents for the treatment of complicated or uncomplicated urinary tract infections and prostatitis. Advantages offered by this class of antibiotics include optimal pharmacokinetics, effectiveness against multidrug-resistant organisms, and oral administration even when parenteral antibiotics are generally used. The fluoroquinolones are also extensively used in urologic surgery.