Influence of third-generation cephalosporin utilization on the occurrence of ESBL-positive Klebsiella pneumoniae strains

BACKGROUND: Klebsiella pneumoniae belongs to important nosocomial pathogens causing mainly hospital-acquired infections. Beta-lactam antibiotics are frequently used in the treatment of infections caused by K. pneumoniae, but by their selection pressure the bacteria become resistant. Excessive use of third-generation cephalosporins is a risk factor for the occurrence and spread of ESBL-producing bacterial strains. The goal of this study was to describe the utilization of third-generation cephalosporins and to analyse their selection pressure on K. pneumoniae in the University Hospital in Olomouc. METHODS: Data on the utilization of antibiotics in the hospital were obtained for the period 1997-2005 from the computerized database and expressed in defined daily doses per 100 bed-days (DBD). The data were processed according to the ATC/DDD system. Klebsiella pneumoniae strains were isolated from clinical material obtained from hospitalized patients. RESULTS: Consumption of third-generation cephalosporins, which was 1.79 DBD in 1997, decreased to 0.93 in 1999, remained stable until 2002, and then increased to 2.40 DBD in 2005. During the 9-year period analysed, a total of 9564 strains of K. pneumoniae were isolated. The ESBL-positive K. pneumoniae strains frequency increased from 8% to 18%. CONCLUSIONS: Increasing utilization of third-generation cephalosporins was associated with a statistically and clinically significant increased incidence of ESBL-positive K. pneumoniae strains.     

Antibiotic therapy for severe infections in infants and children.

In infants and children, the absorption, distribution, metabolism, and excretion of drugs may differ considerably in comparison with these factors in adults; consequently, differences exist in therapeutic efficacy and toxicity of various antibiotic agents. Because of known toxicity, certain drugs--such as chloramphenicol in high doses, the sulfonamides, and tetracycline--should not be used in neonates. Antibiotic therapy should be modified in neonates because of biologic immaturity of organs important for the termination of drug action. Because of poor conjugation, inactivation, or excretion, the serum concentrations of many antibiotics may be higher and more prolonged in neonates than in older infants; thus, lower doses and longer intervals between administration may be necessary. In this article, we suggest dosages of antimicrobial agents for severe infections in children, older infants, and neonates. Included in the discussion are the cephalosporins, especially the third-generation cephalosporins that have assumed an important role in empiric treatment of bacterial meningitis in pediatric patients because of their ability to penetrate the central nervous system and their effectiveness against beta-lactamase-positive and negative strains of Haemophilus influenzae type b, Streptococcus pneumoniae, Neisseria meningitidis, and many gram-negative bacteria in the Enterobacteriaceae group. In patients with congenital or acquired immunodeficiencies, antifungal, antiviral, or anti-Pneumocystis agents are often added to the antimicrobial regimen for severe infections. We review the agents available for such treatment in children, the drugs used for childhood tuberculosis, and certain new antibiotics (aztreonam, ticarcillin-clavulanate, ciprofloxacin, and imipenem-cilastatin) that have proved useful in select cases but whose precise role in pediatric practice will necessitate additional clinical experience.     

Cephalosporin antimicrobial agents and related compounds

Cephalosporins are broad-spectrum antimicrobial agents that are often used empirically to treat suspected bacterial infections and also to treat culture-proven infections due to selected gram-positive and gram-negative microorganisms. Cephalosporins differ widely in their spectrum of activity, susceptibility to beta-lactamases, serum half-life, and penetration of the central nervous system. In general, the first-generation and second-generation agents are most active against staphylococci and streptococci, and the third-generation agents are most active against the Enterobacteriaceae and Pseudomonas. As a group, cephalosporins have a favorable profile of toxicity in comparison with other antimicrobial agents. The development of bacterial resistance has affected all steps of the cephalosporin mechanism of action, including production of beta-lactamases, alterations in penicillin-binding proteins, and modification of the cell wall. New cephalosporins are among the most expensive pharmaceutical agents in use today. Maintaining expertise in the choice and use of these agents will remain a challenge to physicians as additional investigational cephalosporins continue to be developed and introduced into clinical practice.     

重症监护治疗病房革兰阴性杆菌耐药性监测

目的了解本院重症监护治疗病房(ICU)革兰阴性杆菌的分布及药物敏感(药敏)结果,以指导临床抗生素的合理使用。方法2000年起,连续4年每年采用EpsilometertestE试条测定法(Etest法)对连续100株以上革兰阴性杆菌进行细菌药敏监测,同时用Whonet5.1软件进行药敏结果分析。结果亚胺培南在ICU分离细菌中的敏感率最高,达90.8%,敏感率居前的抗生素分别为头孢哌酮/舒巴坦、哌拉西林/他唑巴坦、头孢吡肟、丁胺卡那、头孢他啶,而第三代头孢菌素中头孢噻肟、头孢曲松的敏感率只有42.8%,均不到50.0%。大肠埃希菌超广谱β内酰胺酶(ESBLs)产生率达36.0%,肺炎克雷伯菌ESBLs产生率达25.0%。ESBLs阳性与阴性菌株中除亚胺培南耐药率为0外,其他抗生素间的耐药率差异均有显著性(P均<0.005)。结论ICU的细菌对抗生素耐药性十分严重,必须加强抗生素的耐药监测,同时限制性使用第三代头孢菌素。     

Antibiotic resistance in the institutionalized elderly

Geriatric patients frequently are cared for in long term care facilities (LTCFs), which are now a major component of our health care delivery system. Nearly half of the 2.2 million people who turned 65 years old in 1990 will enter an LTCF at least once before they die. Infections are one of the principal causes of morbidity and mortality in LTCFs. Because LTCFs are a less costly alternative to hospitalization, clinicians are treating many serious infections in the nursing home. As a result of antibiotic use, LTCFs will increasingly be recognized as sources of organisms resistant to multiple antibiotics. b-Lactams are a valuable class of potent antimicrobials with broad-spectrum activity against Gram-negative and Gram-positive organisms. The safety and efficacy of this class of antibiotics make them easy choices for empiric treatment of infections in the elderly. Unfortunately, excessive use of these antibiotics has created serious threats to our therapeutic armamentarium: the emergence of methicillin-resistant Staphylococcus aureus and of Gram-negative pathogens resistant to third-generation cephalosporins such as cefotaxime, ceftazidime, and ceftriaxone. Of these third-generation cephalosporins, resistance to ceftazidime is most frequently recognized. The major mechanism responsible for ceftazidime resistance in Gram-negative bacteria is the production of b-lactamases. This article summarizes the diversity of b-lactamases, highlights the important enzymes that confer ceftazidime resistance in LTCFs, and details some methods used to identify and characterize these enzymes. A clear challenge is to apply these techniques to epidemiologic and molecular studies conducted in LTCFs.     

The selection and use of cephalosporins: a review

Cephalosporins are among the most frequently prescribed antibiotics as a result of their broad spectrum of microbiologic activity, favorable pharmacokinetics, low incidence of adverse reactions, and proven clinical efficacy for a wide variety of infections. Cephalosporins differ in their gram-positive, gram-negative, and anaerobic spectra, serum half-lives, penetration of the cerebrospinal fluid, and resistance to beta-lactamases. The first-generation and some second-generation agents maintain excellent activity against streptococci and staphylococci, while the third-generation agents have expanded gram-negative coverage. Two third-generation cephalosporins, ceftazidime and cefoperazone, are active against Pseudomonas. Ceftizoxime has become the workhorse third-generation cephalosporin. The fourth-generation agent cefepime provides excellent activity against gram-positive and gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae. A major dilemma facing the practitioner is how to select the "right" cephalosporin for a particular patient, as no one drug will satisfy all clinical needs. This review describes a practical approach to selecting an appropriate cephalosporin for common infectious disease problems.     

Therapeutic experience with cefdinir in the treatment of uSSSIs

Uncomplicated skin and skin-structure infections (uSSSIs) are common community-acquired infections which are often caused by Staphylococcus aureus and Streptococcus pyogenes, although other pathogens are often involved. A recent treatment algorithm has recommended the use of cephalosporins as an appropriate antibiotic therapy for uSSSIs and, in particular, highlighted cefdinir as an extended-spectrum, third-generation cephalosporin with good antimicrobial activity and favourable tolerability. This case report briefly reviews the rationale for the use of cefdinir in the treatment of uSSSIs and presents two case studies to highlight the clinical use of this agent.     

The Role of Fourth-Generation Cephalosporins in the Treatment of Serious Infectious Diseases in Hospitalized Patients

For many years, the third-generation cephalosporins have been utilized in the treatment of a broad range of infections. The reduction in the efficacy of these antimicrobials in hospitals seen in recent years is a result of the development of resistance to these compounds. This resistance, caused in part by the production of β-lactamases which can spread from species to species, has intensified the search for alternative agents. Compared with third-generation cephalosporins, fourth-generation cephalosporins possess enhanced activity against Gram-positive organisms, excellent penetration into Gram-negative bacilli, and are more stable against the activity of some β-lactamases. Accordingly, fourth-generation cephalosporins are attractive candidates to replace third-generation cephalosporins for the treatment of many nosocomial infections.     

Cephalosporin, carbapenem, and monobactam antibiotics

Cephalosporin and related antibiotics are highly effective bactericidal agents of relatively low toxicity. The spectrum of activity varies with the drug but is usually broad. The first-generation cephalosporins, and especially cefazolin, are most active against sensitive staphylococci and streptococci. Most second-generation (except cefoxitin) and third-generation cephalosporins show substantial activity against Haemophilus influenzae. All cephalosporins (except cefsulodin) are active against Klebsiella, Escherichia coli, and Proteus mirabilis, whereas only the third-generation agents have pronounced activity against the other Enterobacteriaceae. Imipenem (a carbapenem) is active against essentially all pathogenic organisms, but aztreonam (a monobactam) is active against only aerobic gram-negative bacilli. Advantages associated with some of the new cephalosporins are once-daily administration and high cerebrospinal fluid levels. With the development of new cephalosporins, however, new toxicities have become apparent, and superinfections and induction of resistance have become greater problems. The cephalosporins are among the most expensive antibiotics in use today; thus, use of these expensive agents must be justified by lower toxicity, greater efficacy, or both in comparison with drugs of more reasonable cost.     

The Presence of Urinary Nitrites Is a Significant Predictor of Pediatric Urinary Tract Infection Susceptibility to First- and Third-Generation Cephalosporins

Background: Previous studies in adults have refuted the use of nitrites as a predictor of bacterial resistance to both trimethoprim-sulfamethoxazole and cephalosporins. Some centers now consider first-line outpatient therapy with an oral third-generation cephalosporin appropriate for young children. Objective: The objective of this study was to determine if nitrite-negative pediatric urinary tract infections (UTIs) were more likely than nitrite-positive UTIs to be resistant to cephalosporins. This may enable physicians to adjust antimicrobial therapy before patients leave the Emergency Department (ED) to avoid the complications of ineffectively treated pediatric UTIs. Methods: A retrospective chart review examined, over a 9-month period, 173 pediatric patients who were diagnosed with a clinical UTI in the ED and who also had a positive urine culture and a recorded dipstick at the time of visit. The chi-squared test and Fisher's exact test were used to compare nitrite-negative vs. nitrite-positive UTIs for resistance to third-generation cephalosporins and other empiric antimicrobials. Results: For third-generation cephalosporins, 1.4% of nitrite-positive UTIs were resistant, whereas 14.4% of nitrite-negative UTIs were resistant (95% confidence interval [CI] −0.22 to −0.05). For first-generation cephalosporins, 8.4% were resistant in the nitrite-positive group, compared to 22.2% in the nitrite-negative group (95% CI −0.24 to −0.03). Conclusion: The absence of urinary nitrites is a significant indicator for potential resistance to cephalosporins in pediatric UTIs. Due to low levels of pediatric UTI resistance, cephalosporins continue to represent useful empiric therapy in the general pediatric population. However, in high-risk patients, physicians may opt to alter their empiric choice of antibiotic based on the presence of urinary nitrites.     

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.     

Ceftazidime and cefotaxime--the clinician's choice

A review of two third-generation cephalosporins, ceftazidime and cefotaxime, is presented. Ceftazidime, often used as a single agent, has shown greater activity than cefotaxime against Pseudomonas aeruginosa and other Pseudomonas species, Enterobacteriaceae, Acinetobacter sp, and Enterobacter sp. It has been effective as monotherapy in the treatment of peritonitis, gynecologic infections, chronic bronchitis, and infections in patients with leukemia and granulocytopenia, as has cefotaxime when in combination with an aminoglycoside. Cefotaxime has shown good activity against most aerobic gram-negative bacilli and against Staphylococcus. It has been used in respiratory infections, urinary tract infections, and septicemia. In contrast to first-generation and most second-generation cephalosporins, third-generation cephalosporins have proven useful in some types of meningitis. Ceftazidime and cefotaxime successfully penetrate into the cerebrospinal fluid and cures of bacterial meningitis have been reported with both drugs. Both ceftazidime and cefotaxime have been successfully used in children, infants, and neonates, as well as adults. Safety profiles of ceftazidime compare favorably with those of other third-generation cephalosporins.     

Susceptibility of intestinal anaerobes to new beta-lactam antibiotics

In vitro susceptibility of 473 isolates of anaerobic bacteria derived from patients hospitalized for treatment of abdominal trauma was tested against third-generation cephalosporins--moxalactam, cefotaxime, ceftizoxime, cefmenoxime--and a penicillin--N-formimidoyl thienamycin--by serial agar dilution method in the anaerobic glove box. There were 208 Bacteroides isolates including 80 Bacteroides fragilis and 100 peptococci and peptostreptococci. The minimal inhibitory concentration (MIC) 75% of B. fragilis was less than or equal to 32 micrograms/ml for the cephalosporins tested and less than or equal to 8 micrograms/ml for thienamycin. The MIC of B. fragilis and Bacteroides vulgatus was not much influenced by increased inoculum size. Characteristically, peptostreptococci and peptococci were resistant to all four cephalosporins tested with MIC 75% being 32-64 micrograms/ml. All five antibiotics in this study appear suitable for therapy of intraabdominal suppurative infections, but the poor activity of third-generation cephalosporins on anaerobic cocci can be a cause of concern.     

Home intravenous antibiotic therapy. A practical management approach for the 1980s

The development of antibiotics with extended duration of activity, combined with the social and economic changes in the practice of medicine in recent years, has resulted in use of home intravenous (IV) antibiotic therapy to treat a wide range of infections in selected patients. At Lovelace Medical Center, infections of the musculoskeletal system have accounted for two thirds of the cases for which such therapy is used. First-and third-generation cephalosporins have been used most often and at our institution are almost identical in terms of actual charges to the patient. Although several important medicolegal and ethical problems have yet to be resolved, home IV antibiotic therapy has been shown to be safe, effective, and capable of reducing medical costs to both patients and health care providers.     

Optimum management of Citrobacter koseri infection

Low virulent Citrobacter koseri can cause life threatening infections. Neonates and other immunocompromised patients are particularly susceptible to infection from C. koseri. Any infection due to C. koseri mandates antimicrobial therapy based on the sensitivity of the pathogen microorganism. Various types of antibiotics, including aminoglycosides carbapenems, cephalosporins, chloramphenicol and quinolones, are used for the treatment of C. koseri infections. The rational choice of antimicrobial therapy for Citrobacter infections is a challenge for clinicians because there is a sustained increase in antibacterial resistance. We reviewed antimicrobial agents used for C. koseri infections in this review.     

Genomic Epidemiology of Klebsiella pneumoniae in Italy and Novel Insights into the Origin and Global Evolution of Its Resistance to Carbapenem Antibiotics

Klebsiella pneumoniae is at the forefront of antimicrobial resistance for Gram-negative pathogenic bacteria, as strains resistant to third-generation cephalosporins and carbapenems are widely reported. The worldwide diffusion of these strains is of great concern due to the high morbidity and mortality often associated with K. pneumoniae infections in nosocomial environments. We sequenced the genomes of 89 K. pneumoniae strains isolated in six Italian hospitals. Strains were selected based on antibiotypes, regardless of multilocus sequence type, to obtain a picture of the epidemiology of K. pneumoniae in Italy. Thirty-one strains were carbapenem-resistant K. pneumoniae carbapenemase producers, 29 were resistant to third-generation cephalosporins, and 29 were susceptible to the aforementioned antibiotics. The genomes were compared to all of the sequences available in the databases, obtaining a data set of 319 genomes spanning the known diversity of K. pneumoniae worldwide. Bioinformatic analyses of this global data set allowed us to construct a whole-species phylogeny, to detect patterns of antibiotic resistance distribution, and to date the differentiation between specific clades of interest. Finally, we detected an ∼1.3-Mb recombination that characterizes all of the isolates of clonal complex 258, the most widespread carbapenem-resistant group of K. pneumoniae. The evolution of this complex was modeled, dating the newly detected and the previously reported recombination events. The present study contributes to the understanding of K. pneumoniae evolution, providing novel insights into its global genomic characteristics and drawing a dated epidemiological scenario for this pathogen in Italy.     

Antibiotic resistance

Widespread resistance problems exist today in a global sense because of the incorporation of antibiotics with a high resistance potential into animal feeds and because of the uncontrolled use of antibiotics with a high resistance potential in the clinical setting. The only proven method of controlling nonoutbreak resistance problems in hospitals is to limit the hospital formulary to antibiotics with little or no resistance potential. The control of multiresistant organisms in outbreaks occurring in hospitals is best contained using appropriate infection control containment measures. Physicians treating infections in the community, with all other factors being equal, should preferentially select antibiotics with a low resistance potential. The titles and headings of much of the resistance literature are misleading. Articles should not contain fluoroquinolone resistant in the title when ciprofloxacin-resistant organisms are described. Many articles concerning penicillin-resistant pneumococci are entitled fluoroquinolone-resistant S. pneumoniae. These articles describe ciprofloxacin-resistant S. pneumoniae and not resistance to other fluoroquinolones. The same error is perpetuated in describing third-generation cephalosporins and carbapenems. Virtually all of the resistance problems associated with third-generation cephalosporins and carbapenems are due to ceftazidime or imipenem. More precise titling in the literature would remind physicians that antibiotic resistance is related to a specific agent and not class phenomena.     

Important and Emerging β-Lactamase-mediated Resistances in Hospital-based Pathogens: The Amp C Enzymes

Resistance to third-generation cephalosporins mediated by β-lactamases is an increasing problem for clinical therapeutics. A wide range of Enterobacteriaceae produce these AmpC enzymes (Bush-Jacoby-Medeiros group 1), including Enterobacter spp., Citrobacter freundii, Morganella morganii, Providencia spp., and Serratia marcescens. Resistance via this mechanism has been shown to be statistically correlated with the use of some third-generation cephalosporins, and the infections caused by these stably derepressed enzyme-producing species seem to occur most frequently in the seriously ill. More recently the genes encoding this enzyme have been documented on plasmids capable of transfer into other species such as Klebsiella pneumoniae. Fourth-generation cephalosporins, with stability and low affinity for the Amp C β-lactamases and the ability to penetrate rapidly into the periplasmic space of Gram-negative organisms, offer a viable alternative in the treatment of these infections or as empiric regimens. Furthermore, these compounds (example: cefpirome) possess greater potency against the frequently occurring Gram-positive cocci such as oxacillin-susceptible staphylococci and the streptococci (including some penicillin-resistant strains) as compared to previously used anti-pseudomonal cephalosporias, ceftazidime.     

Identification by 16S ribosomal RNA gene sequencing of an Enterobacteriaceae species with ambiguous biochemical profile from a renal transplant recipient

Traditional ways of identification of bacteria by phenotypic characteristics cannot be used for non-cultivable organisms and organisms with unusual biochemical profiles. In this study, an Enterobacteriaceae was isolated in pure growth from the mid-stream urine of a 67-year old renal transplant recipient with urinary tract infection. Conventional biochemical tests did not reveal a pattern resembling any known member of the Enterobacteriaceae family. The Vitek system (GNI+) showed that it was 18% Leclercia adecarboxylata and 55% Klebsiella ozaenae; whereas the API system (20E) showed that it was 99.8% Rahnella aquatilis. 16S ribosomal RNA gene sequencing showed that there was 7 base differences between the isolate and Enterobacter cloacae, 18 base differences between the isolate and Enterobacter asburiae, 17 base differences between the isolate and Enterobacter cancerogenus, 35 base differences between the isolate and K. ozaenae, 27 base differences between the isolate and L. adecarboxylata, and 72 base differences between the isolate and R. aquatilis, indicating that the isolate most closely resembled a strain of E. cloacae. Identification of the organism in this study is important, as the choice of antibiotics would be radically different. In this case, cephalosporins should be avoided regardless of in-vitro susceptibility as cephalosporins are well-known to select for AmpC derepressed mutants in Enterobacter, and previous administration of third-generation cephalosporins is more likely to be associated with multidrug resistant Enterobacter isolates than is administration of antibiotics that do not include a third-generation cephalosporin.