The Epidemiology,Evolution, and Treatment of KPC-Producing Organisms

Purpose of Review

The purpose of this review is to investigate the evolution and epidemiology of Klebsiella pneumoniae carbapenemase (KPC)-producing organisms and the current and future treatment options for infections caused by KPC-producing isolates.

Recent Findings

The emergence of resistance in Enterobacteriaceae producing carbapenemases globally has increased the challenges in treating infections caused by these organisms. One of the prominent mechanisms of resistance is the production of KPC enzymes. Infections caused by organisms producing KPCs have limited treatment options and are associated with poor clinical outcomes. The rapid rise of KPC-producing organisms necessitated the use of drugs with pharmacokinetic and toxicity limitations, including polymyxins, tigecycline, fosfomycin, and aminoglycosides. The availability of new beta-lactamase inhibitor combinations that are effective against KPC-producing organisms represent an advance in safety and efficacy. Several agents are currently being studied that have activity against KPC-producing organisms and appear to represent promising additions to our armamentarium.

Summary

KPC-producing organisms cause infections with high morbidity and mortality. Limited treatment options are available, though new therapies have been developed. Pipeline agents are likely to have a place in therapy for the treatment of infections caused by KPC-producing isolates.

     

Lactobacillemia--report of nine cases. Important clinical and therapeutic considerations

Serious infections due to lactobacilli have been rarely cited. We report our findings in nine recent patients with lactobacillemia. In the combined literature and current experience, endocarditis and sepsis from localized suppuration were the most common clinical syndromes, most frequently arising from prior oropharyngeal infections. Lactobacillus endocarditis showed a predilection for left-sided cardiac involvement (100 per cent) and systemic arterial embolization (55 per cent). The nine clinical isolates were tested for minimal inhibitory and bactericidal concentrations (MICs and MBCs) against five drugs with broad gram-positive spectrums; of note, these organisms demonstrated a high incidence of both unachievable MBCs (64 per cent) and widely disparate (greater than 100 fold) MIC:MBC ratios (38 per cent). This is in accord with observations in Lactobacillus endocarditis of poor in vivo clinical response despite "appropriate" regimens and achievable MICs of the organisms. Bactericidal synergistic studies on two endocarditis isolates indicated that the penicillins plus aminoglycosides may be potentially useful in the treatment of deep-seated Lactobacillus infections when single antimicrobials fail to achieve a cure.     

Pneumonia due to Chlamydia pneumoniae in children: epidemiology, diagnosis, and treatment

The term "atypical" pneumonia has been used to differentiate infections caused by Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella, and other related organisms from pneumonia caused by classic bacteria, the prototype being Streptococcus pneumoniae. However, recent studies demonstrated that the clinical presentation of pneumonia due to atypical pathogens cannot readily be differentiated from those caused by "typical" bacteria. This is further complicated by the observation that coinfections with atypical pathogens and other bacteria are frequent. Nonetheless, the term "atypical" can be useful, as these organisms share a number of characteristics that separate them from "typical" bacteria. They are either obligate or facultative intracellular parasites that cannot be isolated using routine microbiologic methods. The most commonly used method of diagnosis of these infections is serology, which has significant limitations. Although C. pneumoniae is now recognized worldwide as a common cause of respiratory infections in adults and children, major gaps remain in our knowledge of the biology of this organism and how it causes disease, in major part due to the lack of readily available, standardized diagnostic methods.     

Biofilm formation: a clinically relevant microbiological process.

Microorganisms universally attach to surfaces and produce extracellular polysaccharides, resulting in the formation of a biofilm. Biofilms pose a serious problem for public health because of the increased resistance of biofilm-associated organisms to antimicrobial agents and the potential for these organisms to cause infections in patients with indwelling medical devices. An appreciation of the role of biofilms in infection should enhance the clinical decision-making process.     

Infectious colitis excluding E. coli O157:H7 and C. difficile

Colitic infection caused by a variety of organisms may have an extremely varied presentation, course, and treatment response. Current data have provided great insights into the pathophysiology of these various organisms and their clinical presentation, course, and treatment outcomes. As clinicians develop a better understanding of the colon, its immunologic defense mechanisms, and the virulence factors of such organisms, they will be better able to evaluate these infections as well as newer colonic infections yet unknown. It is important to know if and when to treat such organisms to prevent the dilemma of drug-resistant strains, as seen already in a variety of well-known infections, such as Campylobacter and others. Knowledge of such colonic targets will be more important in an era of ever-growing resistance to and wide use of antibiotic regimens.     

A challenging case of carbapenemase-producing <Emphasis Type="Italic">Klebsiella pneumoniae</Emphasis> septic thrombophlebitis and right mural endocarditis successfully treated with ceftazidime/avibactam

Introduction

The emergence of carbapenemase-producing Klebsiella pneumonia (KPC-Kp) has become a significant problem in terms of public health and clinical outcome in many hospitals in Southern Europe. Treatment options are usually limited and effective treatment of infections caused by these pathogens is a considerable challenge for clinicians. Ceftazidime–avibactam has been recently approved for the treatment of difficult-to-treat infections due to aerobic Gram-negative organisms in patients with limited treatment options.

Case report

We reported the first case of KPC-Kp septic thrombophlebitis and right atrial endocarditis associated with metastatic lung abscesses successfully treated with a prolonged ceftazidime/avibactam plus ertapenem treatment course, suggesting that this combination therapy could be safe and effective for serious Gram-negative infections. Interestingly, we also observed an apparent discrepancy between clinical and microbiological courses: the patient became rapidly afebrile; hemodynamically stable and his procalcitonin levels showed a prompt decreasing trend. Nevertheless, blood cultures remained persistently positive for a prolonged period.

Conclusion

In conclusion, ceftazidime–avibactam plus ertapenem was a safe and effective therapy of serious endovascular infection due to KPC-Kp. Moreover, in this setting, follow-up blood cultures might represent an irreplaceable tool to guide the therapy.

     

Nontuberculous mycobacteria

The nontuberculous mycobacteria are for the most part ubiquitous environmental organisms that only rarely cause disease in humans. Therefore, the normal host defense against these organisms must be quite robust, as exposure is universal and disease is rare. The organisms that are most commonly encountered in clinical practice, Mycobacterium avium, M. intracellulare, M. kansasii, M. fortuitum, M. abscessus, and M. chelonae, are frequently found in water sources and soil. These organisms share significant structural and biochemical similarities with their more pathogenic relative, M. tuberculosis (MTB). Because they are of significantly lower pathogenicity than MTB, patients with abnormal susceptibility to these infections should include those with defects that may be identifiable. Study of these patients should lead to determination of the mechanisms underlying resistance to these organisms, which in turn are likely to be highly informative regarding host defense against these infections and their more virulent relative MTB. Furthermore, recognition of host factors that permit infection with nontuberculous mycobacteria in otherwise normal hosts will identify pathways that can be targeted for therapeutic intervention. Thus, the search for genetic and acquired susceptibility to nontuberculous mycobacteria is also a search for susceptibility factors for MTB as well as an opportunity to recognize endogenous pathways that can be exploited therapeutically.     

Infection due to the fungus Acremonium (cephalosporium)

Human infections due to fungi belonging to the genus Acremonium occur uncommonly, but unlike infections due to other filamentous fungi, usually affect immunocompetent individuals. Mycetoma, which usually develops following trauma, is the most common infection caused by Acremonium spp. Other sites of infection include the eye (generally following abrogation of ocular defenses), colonizing disease of the lung and gastrointestinal tract, as well as locally invasive infections such as osteomyelitis, sinusitis, arthritis, and peritonitis. Pneumonia and disseminated infections including meningitis, endocarditis, and cerebritis rarely have been reported. Optimal treatment of acremonium infections is not well defined both because infections due to these organisms are rare, and because many reports antedate effective antifungal therapy. In addition, susceptibility testing of filamentous fungi is poorly standardized, and in vitro sensitivity may not correlate with clinical response. Based on anecdotal reports, treatment of most invasive acremonium infections requires a combination of surgical intervention, when possible, and a regimen of amphotericin B. Some azoles also display inhibitory activity. Until more details are available regarding susceptibility of these organisms to antifungal agents, amphotericin B is recommended as initial therapy with the addition of either ketoconazole or fluconazole in infections of a life-threatening nature.     

Bone marrow aspiration, biopsy, and culture in the evaluation of HIV-infected patients for invasive mycobacteria and histoplasma infections

Bone marrow (BM) aspiration and biopsy are used commonly in clinical practice to diagnose invasive tissue infections caused by Mycobacterium avium intracellulare (MAC), Mycobacterium tuberculosis (TB), and Histoplasma capsulatum (HC) in patients with human immunodeficiency virus-1 (HIV) infection. However, the value of these invasive procedures relative to other diagnostic approaches has not been clearly defined. To determine the value of BM culture and BM histology in the diagnosis of opportunistic MAC/TB and HC infections in immunosuppressed patients with HIV, we retrospectively reviewed the records of 56 adult patients with HIV who underwent a single BM aspiration, biopsy, and culture because of unexplained fever and/or other clinical features suggestive of MAC/TB or HC infection. Thirty-two patients (57%) were ultimately diagnosed with MAC/TB or HC infection by positive cultures of BM, blood, sputum, or bronchoalveolar lavage fluid or by the histologic detection of organisms in biopsies of BM or other tissues. The diagnostic sensitivity of BM cultures was equal to that of blood cultures (20/32, or 63%). Granuloma and/or histologically apparent organisms were seen in BM biopsy specimens in 11 of 32 individuals (34%) ultimately diagnosed with MAC/TB or HC infections. Among these 11 cases, both granuloma and acid-fast staining organisms were found in the BM biopsy specimens of 2 individuals for whom both BM and blood cultures were negative. Certain clinical symptoms and signs at the time of BM examination were found by logistic regression analysis to be significantly associated with a subsequent diagnosis of MAC/TB or HC infections; these included high fever, long duration of febrile days prior to BM examination, and elevated direct bilirubin. In conclusion, while the diagnostic sensitivity of BM cultures was found to be no greater than that of blood cultures in detecting MAC/TB or HC infections in immunosuppressed HIV+ patients, histopathologic examination of BM specimens resulted in the relatively rapid identification of nearly one third of infected patients who underwent BM examination, and also identified infections in some patients who were culture negative. These findings support the continued use of BM aspiration, biopsy, and culture for the diagnosis of opportunistic MAC/TB or HC infections in immunosuppressed HIV+ patients, particularly when selected clinical features are present.     

The Role of Fluoroquinolones in the Treatment of Skin and Soft Tissue Infection

Skin and soft tissue infections vary widely in their nature and severity, and their nomenclature is complex. Most are readily recognized and easily treated, but more severe infections may masquerade in forms similar to those of more innocent infections, causing delay in diagnosis and treatment that may result in loss of limb or life. Antimicrobial therapy is clearly beneficial for both recovery from these infections as well as preventing disease progression. The fluoroquinolones are potent broad-spectrum antimicrobial agents. The older fluoroquinolones mainly have excellent in vitro activity against gram-negative bacilli and borderline activity against clinically important gram-positive organisms, but newer fluoroquinolones were developed to have enhanced activity against both gram-positive and anaerobic organisms while retaining broad-spectrum anti-gram-negative activity. Several comparative trials using fluoroquinolones suggest that the efficacy of these agents is similar to that ofà-lactam antimicrobial agents. Additional clinical trials are necessary to determine the overall role of newer fluoroquinolones as alternatives for skin and soft tissue infections.     

Implications of acquired oxacillin resistance in the management and control of Staphylococcus aureus infections

Refinements in testing for resistance to penicillinase-resistant penicillins (PRP) in Staphylococcus aureus have resulted in confusion in classifying isolates as PRP susceptible or resistant. Specifically, a group of organisms has been identified that produce large amounts of beta-lactamase and appear borderline resistant. These organisms have been called "occult resistant" or "acquired oxacillin-resistant" S. aureus (AORSA). A retrospective study was conducted to evaluate the implication of this in vitro phenomenon in managing patients with AORSA infections. Among 134 patients with S. aureus infections, 89 were infected with oxacillin-susceptible S. aureus (OSSA), 26 with AORSA, and 19 with oxacillin-resistant S. aureus (ORSA). There were no significant differences in outcomes when OSSA and AORSA infections were treated with PRP (chi 2MH = .990; P = .32). These results do not suppor the contention that AORSA infections should be managed differently from OSSA infections. Identifying AORSA may not be helpful in guiding antimicrobial therapy or predicting the outcome of infections with AORSA.     

Infections of cardiac implantable electronic devices: a retrospective multicenter observational study

Infections of cardiac implantable electronic devices (CIED) can cause significant morbidity, mortality, and financial burden. Although staphylococcal organisms account for most infections of these cardiac devices, approximately 20% of all CIED-related infections are caused by non-Staphylococcus species. Herein we describe and compare the demographics, clinical presentation, and outcomes of Staphylococcus aureus and non-staphylococcal infections of CIED.We performed a retrospective, multicenter, observational study of patients from 4 academic hospitals in Houston between 2002 and 2009. All 80 identified non-staphylococcal CIED-related infections were matched, at a 1:1 ratio, to S. aureus infections.Although the demographics and general comorbidities in the 2 study groups were relatively similar, the S. aureus group had a higher proportion of patients with coronary artery disease, diabetes mellitus, and end-stage renal disease. Additionally, 81% of S. aureus compared with only 48.5% of the non-staphylococcal CIED-related infections were health care-associated (p < 0.001). Furthermore, when compared to non-staphylococcal infections, the S. aureus group had more indwelling intravascular foreign material (p < 0.001), more rapid clinical progression (p < 0.001), and overall worse clinical presentation (p < 0.001). However, after stratifying by clinical presentation, the mortality rates in the 2 groups were similar (p = 0.45).Since approximately one-fifth of all CIED-related infections are caused by non-staphylococcal organisms, and untimely antibiotic treatment can result in serious complications, it may be prudent to broaden empiric antimicrobial therapy to cover both Gram-positive and -negative bacteria, until the causative organism is identified.     

Uncommonly encountered, motile, anaerobic gram-negative bacilli associated with infection

Motile, anaerobic gram-negative bacilli belonging to the genera Butyrivibrio, Succinimonas, Succinivibrio, Anaerovibrio, Wolinella, Campylobacter, Desulfovibrio, Selenomonas, and Anaerobiospirillum are being recognized in clinical specimens with increasing frequency. Over a 12.5-year period at the VA Wadsworth Medical Center, 13 clinical specimens yielded one of these organisms. Six isolates were recovered from infected wounds, five from respiratory tract specimens obtained from patients with anaerobic pleuropulmonary infection, and two from peritoneal fluid of patients with intraabdominal infection. The distribution of isolates among the genera was as follows: Wolinella, five; Selenomonas, three; unidentifiable motile gram-negative bacilli, two; Desulfovibrio vulgaris, one; Campylobacter concisus, one; and Succinimonas, one. Our experience provides the first case reports of infection involving the last two organisms mentioned. Clinical features of the infections caused by these motile anaerobes were studied, and the current medical literature on such infections was reviewed.     

Localized and systemic infection due to Vibrio species

Many important species have been added to the genus Vibrio in the past several years. Vibrios have been associated with a wide variety of clinical syndromes ranging from mild gastroenteritis to life-threatening cellulitis. Most Vibrio infections follow consumption of raw shellfish or exposure to sea water. Although much has been learned about these organisms in the past several years, additional information is needed concerning pathogenesis, diagnosis, treatment, and prevention of Vibrio infections.     

Systemic salmonellosis in patients with disseminated histoplasmosis. Case for 'macrophage blockade' caused by Histoplasma capsulatum

Five patients are described with disseminated histoplasmosis and systemic salmonellosis. Four of these patients were also immunocompromised because of the acquired immunodeficiency syndrome in two patients and renal transplantation in another two patients. Histologic studies in two patients showed histiocytes that were heavily laden with Histoplasma capsulatum yeast-phase organisms. We postulate that diffuse parasitization of the reticuloendothelial system (RES) by Histoplasma organisms may cause "RES blockade," which then predisposes to systemic salmonellosis, as reported in certain other infections and in sickle cell anemia.     

Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on gram-positive and resistant bacteria.

Over the past 3 decades, considerable changes have occurred in the types of bacteria causing infection in febrile patients with neutropenia and cancer. Twenty years ago, gram-negative bacteria caused approximately 70% of bloodstream infections. As a probable consequence of long-dwelling intravascular devices, fluoroquinolone prophylaxis, and high-dose chemotherapy-induced mucositis, there has been a shift toward gram-positive coccal bacteremia. In most centers today, approximately 70% of bacteremic isolates are gram-positive cocci. Of potential concern is that antimicrobial-resistant gram-positive organisms are becoming increasingly frequent in patients with neutropenia. Fluoroquinolone-resistant Escherichia coli are being isolated from several cancer centers. Several "new" organisms, such as Stomatococcus mucilaginosus, Bacillus cereus, Leuconostoc species, Corynebacterium jeikeium, Rhodococcus species, Stenotrophomonas maltophilia, Moraxella catarrhalis, Burkholderia cepacia, and Bartonella species, now cause infections in these patients. Careful application of infection-control principles, judicious prophylaxis, appropriate evaluation of new antibiotics, and prompt effective therapy will maximize benefits for these patients.     

The role of anaerobic bacteria in upper respiratory tract and other head and neck infections

Anaerobes are common pathogens in chronic upper respiratory tract and head and neck infections. They can be recovered in chronic otitis media and sinusitis, play a role in tonsillitis, and predominate in complications of these infections, causing deep oral and neck infections and abscesses. In addition to their direct pathogenicity, they play an indirect role through the production of the enzyme β-lactamase, “shielding” non-β-lactamase-producing bacteria from penicillins. Failure to provide adequate therapy against anaerobes may lead to clinical failures. Management of anaerobic infection is complicated by the slow growth of these organisms, by their polymicrobial nature, and by their growing resistance to antimicrobials. Antimicrobials are often the only form of therapy needed, but surgical approach is needed in some cases. Because anaerobes often are mixed with aerobic organisms, the antimicrobials given should provide adequate coverage against all pathogens.     

Current and new antimicrobial agents

Background

Infections may complicate cardiovascular surgery or may require surgery as an adjunct to successful treatment. Staphylococci, which are among the major pathogenic bacteria causing such infections, can be resistant to many of the older antibiotics.

Methods

The properties of several newer antimicrobial agents, recently approved or still investigational, were reviewed, with an emphasis on in vitro activities against staphylococci.

Results

The 2 approved agents, linezolid and quinupristin-dalfopristin, and several investigational agents being developed demonstrate in vitro antimicrobial activity against staphylococci. Three of these agents, daptomycin, which was approved by the US Food and Drug Administration in September 2003, and oritavancin and dalbavancin, which are in advanced stages of clinical development, are discussed.

Conclusions

Although clinical studies are required, the in vitro anti-staphylococcal activities of several agents suggest that these antimicrobial agents might be useful options for some infections in patients who are intolerant of older antibiotics or who are infected with organisms that are resistant to older agents.     

Experimental leishmaniasis in humans: review

Experimental infection of humans with Leishmania parasites has contributed significantly to the understanding of the etiology, transmission, and pathogenesis of leishmaniasis and the immunity associated with it. Leishmania organisms recovered from human and animal tissue, insect vectors, and in vitro cultures have all produced cutaneous or visceral leishmaniasis in human subjects who were voluntarily inoculated with them. Volunteers bitten by infected Phlebotomine sandflies also developed cutaneous or visceral disease. In these experiments, it appeared that the parasite must undergo certain developmental changes within the sandfly for it to become infective and that the parasites in sandflies were far more efficient in causing full-blown infection than were cultured Leishmania organisms. The clinical manifestations of these experimental infections did not differ from infections that were acquired naturally. Natural or experimental infections appeared to confer resistance to subsequent leishmanial infection. This immunity was best documented to be a species-specific phenomenon; however, a small number of studies have demonstrated cross protection between some Leishmania species. In this review article, data from human experimental infections are summarized and discussed in light of recent advances in the field.