Public health consequences of use of antimicrobial agents in food animals in the United States

The use of antimicrobial agents in food animals has caused concern regarding the impact these uses have on human health. Use of antimicrobial agents in animals and humans results in the emergence and dissemination of resistant bacteria. Resistant bacteria from food animals may be passed through the food chain to humans resulting in resistant infections. Increasing resistance to antimicrobial agents that are important in the treatment of human diseases, such as fluoroquinolones and third-generation cephalosporins for the treatment of Salmonella and Campylobacter infections, has significant public health implications. Efforts to mitigate the effects of increasing resistance require collaboration by several partners, including the farming, veterinary, medical, and public health communities.     

Tigecycline: in-vitro performance as a predictor of clinical efficacy

The incidence of nosocomial disease caused by Gram-negative pathogens is increasing, and infections caused by Enterobacter, Klebsiella, Acinetobacter, Escherichia coli and Pseudomonas aeruginosa are more commonly refractive to traditional antimicrobial agents, including aminoglycosides, fluoroquinolones and broad-spectrum cephalosporins. The most important mechanism of resistance to beta-lactam antibiotics among Gram-negative bacilli involves the production of beta-lactamases. Extended-spectrum beta-lactamases are particularly worrisome, since they are often associated with multidrug resistance phenotypes, which can pose a significant therapeutic challenge. Novel agents for the treatment of Gram-negative infections are uncommon, as recent emphasis has been placed on the development of agents targeting drug-resistant strains of Gram-positive bacteria, e.g., streptococci, enterococci and staphylococci. Tigecycline, a semi-synthetic derivative of minocycline, has a unique and novel mechanism of action, which not only allows this agent to overcome the well-known tet gene-encoded resistance mechanisms, but also maintains its activity against Gram-negative pathogens producing a broad array of extended-spectrum beta-lactamases. Tigecycline is the first example of a new class of glycylcyclines with activity against a wide range of clinically important Gram-negative pathogens. Tigecycline has potent antimicrobial activity, and has been associated with an excellent therapeutic response in animal infection models and recently reported clinical trials, which reflect the effectiveness of tigecycline against pathogens causing intra-abdominal, skin and soft-tissue infections, including susceptible or multidrug-resistant strains of most Enterobacteriaceae, as well as anaerobic pathogens.     

Origins and consequences of antimicrobial-resistant nontyphoidal Salmonella: implications for the use of fluoroquinolones in food animals

Human Salmonella infections are common; most infections are self-limiting, however severe disease may occur. Antimicrobial agents, while not essential for the treatment of Salmonella gastroenteritis, are essential for the treatment of thousands of patients each year with invasive infections. Fluoroquinolones and third-generation cephalosporins are the drugs-of-choice for invasive Salmonella infections in humans; alternative antimicrobial choices are limited by increasing antimicrobial resistance, limited efficacy, and less desirable pharmacodynamic properties. Antimicrobial-resistant Salmonella results from the use of antimicrobial agents in food animals, and these antimicrobial resistant Salmonella are subsequently transmitted to humans, usually through the food supply. The antimicrobial resistance patterns of isolates collected from persons with Salmonella infections show more resistance to antimicrobial agents used in agriculture than to antimicrobial agents used for the treatment of Salmonella infections in humans. Because of the adverse health consequences in humans and animals associated with the increasing prevalence of antimicrobial-resistant Salmonella, there is an urgent need to emphasize non-antimicrobial infection control strategies, such as improved sanitation and hygiene, to develop guidelines for the prudent usage of antimicrobial agents, and establishment of adequate public health safeguards to minimize the development and dissemination of antimicrobial resistance and dissemination of Salmonella resistant to these agents.     

Two cases of infections due to multidrug-resistant Bacteroides fragilis group strains

Bacteroides fragilis group strains are still considered susceptible to most antimicrobial agents used for the treatment of infections caused by anaerobic organisms. We describe two cases of infections due to isolates simultaneously resistant to clindamycin, tetracycline, cefoxitin, piperacillin-tazobactam, and imipenem and, in one of the two cases, to metronidazole. Such infections, although still rare, do exist and tend to complicate treatment.     

Neutropenia during HIV Infection: Adverse Consequences and Remedies

Neutropenia frequently occurs in patients with Human immunodeficiency virus (HIV) infection. Causes for neutropenia during HIV infection are multifactoral, including the viral toxicity to hematopoietic tissue, the use of myelotoxic agents for treatment, complication with secondary infections and malignancies, as well as the patient's association with confounding factors which impair myelopoiesis. An increased prevalence and severity of neutropenia is commonly seen in advanced stages of HIV disease. Decline of neutrophil phagocytic defense in combination with the failure of adaptive immunity renders the host highly susceptible to developing fatal secondary infections. Neutropenia and myelosuppression also restrict the use of many antimicrobial agents for treatment of infections caused by HIV and opportunistic pathogens. In recent years, HIV infection has increasingly become a chronic disease because of progress in antiretroviral therapy (ART). Prevention and treatment of severe neutropenia becomes critical for improving the survival of HIV-infected patients.     

Liposomes as carriers of antimicrobial agents or immunomodulatory agents in the treatment of infections

Targeting of antimicrobial agents by means of liposomes is under investigation and may be of importance in the treatment of infections that prove refractory to conventional forms of antimicrobial treatment. The ability to achieve a significantly longer residence time of liposomes in plasma and limited uptake of liposomes by the mononuclear phagocyte system opens up new areas of investigation and potential therapeutic application. By manipulating the liposomal composition, rates of uptake and intracellular degradation can be influenced and thereby the rates at which liposome-encapsulated agents are released and become available to exert their therapeutic action. With respect to the targeting of macrophage modulators at the mononuclear phagocyte system by means of liposomes for maximal stimulation of the nonspecific antimicrobial resistance, experimental evidence is now available of the potential usefulness of liposomes as carriers of these agents. This approach may also be of importance for the potentiation of treatment of severe infections.     

From clinical microbiology to infection pathogenesis: how daring to be different works for Staphylococcus lugdunensis

Staphylococcus lugdunensis has gained recognition as an atypically virulent pathogen with a unique microbiological and clinical profile. S. lugdunensis is coagulase negative due to the lack of production of secreted coagulase, but a membrane-bound form of the enzyme present in some isolates can result in misidentification of the organism as Staphylococcus aureus in the clinical microbiology laboratory. S. lugdunensis is a skin commensal and an infrequent pathogen compared to S. aureus and S. epidermidis, but clinically, infections caused by this organism resemble those caused by S. aureus rather than those caused by other coagulase-negative staphylococci. S. lugdunensis can cause acute and highly destructive cases of native valve endocarditis that often require surgical treatment in addition to antimicrobial therapy. Other types of S. lugdunensis infections include abscess and wound infection, urinary tract infection, and infection of intravascular catheters and other implanted medical devices. S. lugdunensis is generally susceptible to antimicrobial agents and shares CLSI antimicrobial susceptibility breakpoints with S. aureus. Virulence factors contributing to this organism's heightened pathogenicity remain largely unknown. Those characterized to date suggest that the organism has the ability to bind to and interact with host cells and to form biofilms on host tissues or prosthetic surfaces.     

Potential role of fluoroquinolones in the treatment of bacterial meningitis

The search for new antimicrobial agents in the treatment of bacterial meningitis is justified by a rate of mortality that currently remains unacceptably high and by the emergence of bacterial resistance. Because of their excellent in vitro activity against gramnegative organisms and good penetration into the cerebrospinal fluid, the new fluoroquinolones may have a potential role in the treatment of central nervous system (CNS) infections. Although there are few reports on the use of fluoroquinolones in treatment of patients with CNS infections, experience to date indicates that pefloxacin, the most intensively studied agent, and ciprofloxacin provide effective treatment for patients with meningitis caused by susceptible pathogens. Since they cannot be used in patients whose skeletal growth is incomplete, the place of the fluoroquinolones in the treatment ofHaemophilus influenzae meningitis is obviously very limited.Neisseria meningitidis is still exquisitely sensitive to penicillin G and ampicillin, and there is thus no reason to replace these agents by fluoroquinolones, except when patients are allergic to beta-lactam agents, or when parental administration is impossible. A potential use of the new fluoroquinolones would be in the treatment of meningitis due to gram-negative bacilli, includingPseudomonas aeruginosa, andAcinetobacter.     

Safeguarding future antimicrobial options: strategies to minimize resistance

Current antimicrobial therapy for community-acquired respiratory tract infections (RTIs) is empirical and is influenced by local differences in etiology and bacterial susceptibility. As the rates of resistance and cross-resistance to currently available classes of antimicrobial agents increase, their effectiveness becomes compromised. These issues demand improved strategies for antimicrobial usage, and the development of new agents that do not select resistance are essential to safeguard future antimicrobial efficacy. Strategies to minimize antimicrobial resistance among common RTIs include reducing antimicrobial consumption and controlling the development and spread of resistance through appropriate prescribing and the use of short-duration, once-daily treatments to improve patient compliance. Importantly, the ketolides, which are a new family of antimicrobials, have been recently developed specifically for the treatment of community-acquired RTIs. The first member of this new family, telithromycin, has been shown to have potent activity against common and atypical respiratory pathogens, including β-lactam- and macrolide-resistant strains, and has a low potential to select for or induce cross-resistance. These properties, combined with its good tolerability across patient groups, make telithromycin an attractive option for the first-line empiric treatment of RTIs with the potential to limit the future development of resistance.     

Pathogenesis of catheter-related infections: lessons for new designs

In the last decade, two main strategies have been employed in the prevention of catheter-related infections: the creation of anti-adhesive biomaterials using physicochemical methods, and the incorporation of antimicrobial or antiseptic agents into current polymer biomaterials. There has been limited success with the first approach. Intravascular catheters and cuffs with an antimicrobial coating have been developed in recent years. Nevertheless, preventive strategies should avoid the use of therapeutic antibiotics. Exposure to antimicrobial agents could favor the development of resistance or the expression of genes responsible for biofilm formation. The use of these catheters should be restricted to situations where the rate of infection is high despite adherence to other strategies that do not incorporate antimicrobial agents. Better knowledge of the pathogenesis of catheter-related infections will facilitate the design of new devices that avoid the use of antimicrobial agents and decrease the risk of associated bloodstream infections. This could include the use of 'biospecific polymers' coated with anti-adhesive molecules or the use of agents which might block the expression of genes controlling biofilm formation for the most prevalent pathogens.     

Bacteremia by multidrug-resistant Capnocytophaga sputigena.

A case of bacteremia caused by a multiresistant strain of Capnocytophaga sputigena in a patient with hematological malignancy is described. The strain presented with a pattern of marked resistance to beta-lactams, with MICs of > 256 mg/liter for ampicillin, ticarcillin, piperacillin, cefazolin, and cefuroxime, 64 mg/liter for cefotaxime, and 32 mg/liter for ceftazidime. In addition, the MIC of ciprofloxacin was 16 mg/liter. Both of these groups of antimicrobial agents are frequently used in the empiric treatment of infections in immunocompromised patients. The appearance of resistant strains suggests the need for antimicrobial susceptibility studies in all patients with severe infections caused by Capnocytophaga spp. or other capnophilic organisms present in the oral microflora of these patients.     

Comparative in vitro activity of penicillin G, levofloxacin, moxifloxacin, telithromycin, pristinamycin, quinupristin–dalfopristin and linezolid against ofloxacin-intermediate and -resistant Streptococcus pneumoniae

Screening by ofloxacin disk was carried out on 1158 strains of Streptococcus pneumoniae in order to investigate the in vitro bacteriostatic activity of penicillin G, levofloxacin, moxifloxacin, telithromycin, linezolid, pristinamycin and quinupristin–dalfopristin against ofloxacin-intermediate and -resistant S. pneumoniae strains. It was concluded that these new antimicrobial agents could be useful for the treatment of pneumococcal infections caused by penicillin-sensitive and -resistant S. pneumoniae , and would represent a valid therapeutic option for patients allergic to β -lactams, should they prove to be potent in vivo.     

Mycoviruses: future therapeutic agents of invasive fungal infections in humans?

Invasive fungal infections are relatively common opportunistic infections in immunocompromised patients and are still associated with a high mortality rate. Furthermore, these infections are often complicated by resistance or refractoriness to current antimicrobial agents. Therefore, an urgent need exists for new therapeutic strategies based on the identification of new microbial targets and novel antimicrobial agents. One such hypothetical therapeutic strategy may involve the use of mycoviruses that are able to selectively infect fungi. Current knowledge of mycoviruses of human pathogenic fungi and the scope for using (recombinant) mycoviruses as future biological control agents are reviewed here.     

Current antimicrobial therapy of anaerobic infections

The treatment of many anaerobic infections involves antimicrobial therapy, appropriate surgical drainage of abscesses, and debridement of devitalized tissue. Most anaerobic infections are polymicrobial and require treatment with agents active against an array of aerobic and anaerobic bacteria. Bacterial resistance, especially to penicillins and tetracyclines, but also to newer agents of other classes, continues to increase. As a result, treatment with more than one drug is often required. Combination therapy is often necessary in serious infection, and is indicated for empiric treatment before receiving culture results. In the past combination therapy has been the mainstay of antimicrobial therapy, but more recent studies suggest that monotherapy for anaerobic infections may dominate the future. Selection of an agent requires consideration of the site of infection and the most likely etiologic agents. In vitro susceptibility is important, but it is not the only determinant of antimicrobial effectiveness. The pharmacology of the drug — absorption, distribution, concentrations in body fluids and tissues, excretion and metabolism — also plays an important role. The nature and severity of the underlying illness are important factors in selecting empiric therapy. Although it is a clinical judgement, in patients considered to have mild to moderate infections, several factors in selecting antimicrobial agents may be considered, including cost, whereas in patients judged to have severe or life-threatening infections, the most potent agents should be chosen as initial therapy, regardless of cost. Finally, the toxicities of the agent must also be considered.     

Salmonella enterica serotype Choleraesuis: epidemiology, pathogenesis, clinical disease, and treatment

Nontyphoid Salmonella strains are important causes of reportable food-borne infection. Among more than 2,000 serotypes, Salmonella enterica serotype Choleraesuis shows the highest predilection to cause systemic infections in humans. The most feared complication of serotype Cholearesuis bacteremia in adults is the development of mycotic aneurysm, which previously was almost uniformally fatal. The advances in diagnostic techniques, surgical care, and antimicrobial therapy have greatly improved the survival of these patients. However, the recent emergence of serotype Choleraesuis that is resistant to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and, notably, fluoroquinolone antibiotics has aroused concern about the use of these agents for the empirical treatment of systemic infection caused by this organism. In view of the serious implications of the situation, the chain of transmission and mechanism of resistance should be carefully studied to reduce the spread of infection and threat to human health. To date, there are no vaccines available to prevent serotype Choleraesuis infections in humans. The availability, in the near future, of the genome sequence of serotype Cholearesuis will facilitate the development of effective vaccines as well as the discovery of new targets for novel antimicrobial agents.     

Safety and tolerability of the antimicrobial peptide human lactoferrin 1-11 (hLF1-11)

Background  

The treatment of patients with haematological malignancies by means of haematopoietic stem cell transplantation (HSCT) is often accompanied by life threatening infections. With emerging antimicrobial resistance there is an increased need for new agents, with a beneficial safety profile. Therefore we evaluated the safety of the promising new antimicrobial peptide human lactoferrrin 1-11 (hLF1-11) in healthy volunteers and patients.     

Iliac osteomyelitis and gluteal muscle abscess caused by Streptococcus intermedius

Streptococcus intermedius, included in the 'milleri group', is a commensal of the mouth and upper respiratory tract but it has often been associated with various pyogenic infections, such as endocarditis, pneumonia, abdominal or cerebral abscess, rarely with osteomyelitis, and exceptionally with muscular abscess. The first observed case of iliac osteomyelitis with gluteal muscle abscess caused by S. intermedius is reported. It is essential to recognise members of the 'milleri group' as possible agents of bone and muscle pyogenic infection because its management requires a timely diagnosis and prolonged antimicrobial treatment to achieve complete clinical and radiological recovery.     

Efficacy and Safety of Linezolid in the Treatment of Skin and Soft Tissue Infections

The vast majority of community-acquired skin and soft tissue infections (SSTIs) are caused by gram-positive cocci or are polymicrobial in nature. Hospital-acquired SSTIs are caused by gram-positive cocci in more than 50% of patients. Multidrug-resistant gram-positive cocci are rarely associated with community-acquired SSTIs but are frequently found in hospital-acquired SSTIs. Linezolid is the first member of a new class of antibiotics, the oxazolidinones. These antimicrobial agents have a unique mechanism of action and exhibit excellent activity against a variety of gram-positive organisms, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Linezolid is 100% orally absorbed, allowing for easy intravenous-to-oral continuation therapy. There is considerable clinical experience with the use of linezolid in SSTIs in phase II and III clinical trials. In comparative trials, linezolid was as effective as oxacillin-dicloxacillin or flucloxacillin in patients with complicated SSTIs caused by gram-positive organisms. Linezolid was also associated with significantly earlier hospital discharge than comparator agents among patients with SSTIs. It was equally effective as vancomycin in patients with SSTIs caused by methicillin-resistant Staphylococcus aureus and has also demonstrated efficacy in patients with SSTIs caused by vancomycin-resistant enterococci. Linezolid is well tolerated: the most common adverse events (gastrointestinal effects, headache) are reported in frequencies similar to those reported for comparator agents. Myelosuppression has been reported after prolonged administration but is reversible after discontinuation of the drug. Overall, linezolid has favorable efficacy and safety profiles and will be an increasingly useful option for the treatment of SSTIs, particularly those due to multidrug-resistant, gram-positive organisms. Electronic Publication     

Clinical relevance of antimicrobial susceptibility testing

In recent years, significant resistance to antimicrobial agents has been encountered among certain anaerobic bacteria. Susceptibility patterns vary from region to region, but even within a given region susceptibility is not always predictable. Initially, therapy of mixed anaerobic infections must be empirical, based on the nature of the infection, the usual flora of such infections, anticipated modification of this flora by pathophysiologic processes or prior antimicrobial therapy, and evaluation of Gram stains from appropriate specimens. If the infection does not respond well or the patient requires long-term therapy, antimicrobial susceptibility testing may be indicated in order to provide optimum therapy. Susceptibility testing is also indicated for determination of the usual patterns in a particular hospital, for monitoring geographical patterns, and to determine the activity of new antimicrobial agents.     

Case of Mycobacterium marinum infection with unusual patterns of susceptibility to commonly used antibiotics

Mycobacterium marinum, found commonly in salt water and freshwater, is the causative agent of disease in many species of fish and occasionally in humans. MICs to most antimicrobial agents are relatively low. Susceptibility testing is not routinely performed, and single-drug therapy is used for the treatment of most infections. Here, we report an infection caused by a drug-resistant M. marinum strain in an otherwise healthy patient.