Assessment of the bactericidal activity of sparfloxacin, ofloxacin, levofloxacin, and other fluoroquinolones compared with selected agents of proven efficacy against Listeria monocytogenes.

The search for alternative therapeutic agents for listeriosis includes the quinolone group. Accordingly, the bactericidal activity of ciprofloxacin, levofloxacin, lomefloxacin, ofloxacin, sparfloxacin, and temofloxacin, in comparison with that of ampicillin and sulfamethoxazole-trimethoprim, was evaluated against Listeria monocytogenes at 24 and 48 h of incubation using time-kill kinetic methodology. The inhibitory concentrations for each agent fell into a narrow range comparable with ampicillin. For example, the minimum inhibitory concentration (MIC) ranges, MIC90 (24 h), and MIC90 (48 h) of the most active quinolone, sparfloxacin, were 0.25-2, 2, and 2 micrograms/ml, respectively, with 4 micrograms/ml achieving > or = 99.9% killing of the inoculum at 24 h with no regrowth by 48 h. At 2-4 times the MIC, bactericidal activity for all quinolones tested was noted at 24 h, unlike the action of ampicillin, which only becomes bactericidal at 48 h. These concentrations are within the achievable range of serum concentrations for a number of these agents. Because selected new fluoroquinolones at two to four times the MIC show bactericidal activity at 24 h, these agents may prove useful as therapeutic alternatives for the treatment of listeriosis.

Multiply resistant Klebsiella pneumoniae strains from two Chicago hospitals: identification of the extended-spectrum TEM-12 and TEM-10 ceftazidime-hydrolyzing beta-lactamases in a single isolate.

Ceftazidime-resistant Klebsiella pneumoniae strains began to appear when ceftazidime usage was increased in two unrelated Chicago hospitals. These strains produced a beta-lactamase with an isoelectric point of 5.6 (RP-5.6) and strong hydrolyzing activity against ceftazidime. Two different restriction digest profiles were associated with the ceftazidime resistance plasmids. A second beta-lactamase with a pI of 5.2 (RP-5.2) was coproduced in two representative strains. The second beta-lactamase hydrolyzed ceftazidime, cefotaxime, and aztreonam with relative hydrolysis rates of < 8% of that observed for benzylpenicillin. Both enzymes were inhibited by clavulanic acid and tazobactam. Nucleotide sequencing of the genes coding for RP-5.2 and RP-5.6 revealed sequences identical to those of the TEM-12 and TEM-10 beta-lactamase genes, respectively. Both genes were derived from a TEM-1 sequence related to that of the gene encoded on the Tn2 transposon. Single point mutations are required to progress from TEM-1 to TEM-12 and from TEM-12 to TEM-10. Extracts from broths grown from single cell isolates of the strain producing TEM-12 and TEM-10 were shown to contain both enzymes. Transconjugants producing either the TEM-12 or the TEM-10 beta-lactamase were obtained. A significant finding was that both enzymes were encoded by plasmids with identical restriction digest patterns. These studies show that mutations leading to extended-spectrum beta-lactamases can occur sequentially in the same organism, with the genes encoding both enzymes maintained stably.

A case of Trichosporon beigelii endocarditis 8 years after aortic valve replacement.

We report a case of Trichosporon beigelii endocarditis in a 77-year-old diabetic man who presented with an embolic stroke 8 years ago after a porcine aortic valve replacement. He was treated successfully with amphotericin, rifampin, and replacement of the original porcine valve; however, he died suddenly 8 months later from unknown causes. Blood cultures 2 months prior to death were negative. The first manifestation of the endocarditis was a left hemiparesis followed some days later by a splenic infarction. Transthoracic echocardiography failed to demonstrate the aortic vegetation, which was clearly visualized subsequently by transesophageal echocardiography. The literature on Trichosporon beigelii endocarditis is reviewed.

The medical complications of drug addiction and the medical assessment of the intravenous drug user: 25 years later.

PURPOSE: To review changes in the medical complications of drug abuse that have occurred since the authors reviewed them 25 years ago. DATA SOURCE: Manual search of the internal medicine and subspecialty literature of the past three decades that was selected by the authors. STUDY SELECTION: Selected studies were of three types--baseline studies for the period ending in 1968, studies after 1968 that emphasized changes from baseline, and studies after 1968 that emphasized change (or the absence of change) and the manner in which clinicians conceptualized problems. DATA EXTRACTION: We extracted data that showed changes in the diseases, the appearance of new diseases, or the disappearance of formerly common diseases. RESULTS OF DATA SYNTHESIS: The diseases complicating drug abuse are now more widely disseminated than they were in the last 25 years. Some former "diseases of addiction" such as tetanus and malaria are now rare. Diseases (such as human immunodeficiency virus infection) not known to exist or rare 25 years ago now occur frequently. The drugs of abuse have also changed; for example, cocaine is now much more common. CONCLUSIONS: Treating the acute medical problems (mostly infectious diseases) in poor, undereducated, and often noncompliant intravenous drug users is far more complex than previously described. Although some features have remained constant, the emergence of human immunodeficiency virus infection and changes in patterns of drug use have radically altered patient management.

Comparative susceptibility of the Bacteroides fragilis group species and other anaerobic bacteria to meropenem, imipenem, piperacillin, cefoxitin, ampicillin/sulbactam, clindamycin and metronidazole.

The in-vitro activity of meropenem, imipenem, piperacillin, cefoxitin, ampicillin/sulbactam, clindamycin and metronidazole was determined against 395 strains of strict and facultative anaerobes, including Gardnerella vaginalis, Lactobacillus spp. and Mobiluncus spp. The activities of meropenem and imipenem were within one dilution of their MIC50 and MIC90 values. One isolate of Bacteroides fragilis, two of Bacteroides distasonis, and two of Bacteroides ovatus showed resistance or diminished susceptibility to meropenem and imipenem. Metronidazole was active against almost all obligate anaerobic isolates. Some non-spore-forming Gram-positive bacilli and lactobacilli were resistant. Ampicillin/sulbactam inhibited almost all isolates at < or = 16/8 mg/L. The activity of clindamycin and cefoxitin was relatively good, but some strains of non-fragilis B. fragilis group species were resistant. Piperacillin was the least active agent tested.

Retroperitoneal abscess caused by Mycobacterium chelonae and treatment.

OBJECTIVE: To report a case of retroperitoneal abscess caused by Mycobacterium chelonae and treatment. DESIGN: Case report. SETTING: Private community teaching hospital. PATIENTS: A patient was admitted to the hospital following a gunshot to the flank. The bullet passed through the iliac crest and lodged in the abdomen. INTERVENTION: The patient was treated with cefazolin, trimethoprim/sulfamethoxazole, and amikacin at different times. OUTCOME: The patient responded well to pharmacologic treatment and at 18-month follow-up, he is disease free. CONCLUSIONS: Antimicrobial agents with in vitro activity against M. chelonae, especially amikacin-containing regimens, are recommended for treating M. chelonae infection.

A comparison of antimicrobial activity of ofloxacin, L-ofloxacin, and other oral agents for respiratory pathogens.

The attainable inhibitory ratios (AR) for oral antibiotics were calculated by using literature reports of concentrations attained in respiratory secretions for amoxicillin-clavulanic acid (AMX/CA), ofloxacin (OFL), L-ofloxacin (L-OFL), cefuroxime (CEFU), ciprofloxacin (CIP), and enoxacin (ENO), and using microdilution minimum inhibitory concentration data of these antimicrobials against the common bacterial respiratory pathogens. AR of each antibiotic against the pathogens was expressed as multiples of the MICs achieved at the respiratory site. Bacteria tested included Staphylococcus aureus, group-A and group-B streptococci, Viridans streptococci, Streptococcus pneumoniae, Brahamella catarrhalis, Klebsiella pneumoniae, Eikenella corrodens, Haemophilus influenzae, H. parainfluenzae, Pseudomonas aeruginosa, and Legionella pneumophila. The antimicrobials with the narrowest spectrum of activity were amoxicillin-clavulanic acid and cefuroxime which had high attainable inhibitory ratios only against Gram-positive cocci. Ofloxacin and L-oflaxacin were among the quinolones with the highest overall ARs against respiratory pathogen, including, L. pneumophila, H. influenzae, and B. catarrhalis. All agents showed no, or inadequately low ARs for P. aeruginosa.

Pleurocerebral Nocardia in a patient with human immunodeficiency virus.

OBJECTIVE: To report a case of Nocardia asteroides pneumonia and subsequent brain abscess in an immunocompromised host. SETTING: Private, community, teaching hospital. PATIENT: A man readmitted to the hospital for a third time with a fatal brain abscess, after responding to (misdirected) therapy in previous admissions. INTERVENTIONS: Treatment with cefuroxime, erythromycin, trimethoprim/sulfamethoxazole at different times. RESULTS: Patient's condition deteriorated and he died after one month of intravenous trimethoprim/sulfamethoxazole therapy. CONCLUSIONS: Because it is an infection of the immunocompromised host, it may be considered an AIDS-defining illness. Several other similar cases have been reported in the literature.

Escherichia coli resistant to ampicillin/sulbactam.

Escherichia coli strains resistant to ampicillin/sulbactam from hospitals in 4 different geographic locations were examined with respect to type and amount of beta-lactamase produced. A total of 5 strains was examined from each region. The isoelectric points of all of the involved beta-lactamases were 5.4, corresponding to TEM-1. Km and Vmax values of the beta-lactamases among the clinical isolates resembled those from the control TEM-1 strain. In an 18-hour broth culture the highly resistant isolates produced 3 times more beta-lactamase as compared to the ampicillin/sulbactam-susceptible isolates. However, the highly resistant strains contained approximately the same amount of plasmid DNA (size of > 6,500 bp) as the susceptible isolates. In transformation experiments, both the resistance and the degree of resistance appeared to have been transferable by plasmids. The mechanism for resistance is likely to be a baseline overproduction of TEM-1 beta-lactamase due to either an alteration in the control of gene expression or simply to an increase in the number of copies of the beta-lactamase gene in the plasmids.

Epidemiological spectrum and current treatment of listeriosis.

To reassess the epidemiology and treatment of listeriosis in the United States, we reviewed greater than 120 cases of listeriosis from four medical centers in three geographically separated cities: Los Angeles County-University of Southern California Medical Center (LAC-USCMC); Rush-Presbyterian-St. Luke's Hospital, Chicago; the University of Illinois Hospital, Chicago; and Vanderbilt University Hospital, Nashville, Tennessee. The epidemiological pattern at LAC-USCMC was relatively narrow; more than two-thirds of the cases occurred during the perinatal period. Cases at Vanderbilt University Hospital represented the opposite end of the spectrum; the majority of these occurred in nonpregnant, older adults who had received organ transplants. An intermediate pattern of cases was observed at the two medical centers in Chicago. Potential risk factors included pregnancy, neonatal status, organ transplantation, renal failure, malignancy, systemic lupus erythematosus, steroid therapy, and AIDS (two cases). Antimicrobial agents noted to be effective were, as expected, penicillin and ampicillin; the cephalosporins were ineffective. The mortality associated with listeriosis occurred mainly among premature infants and stillbirths delivered from infected pregnant women and was markedly less among neonates and adults.

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.

Comparison of the inoculum effect of cefoxitin and other cephalosporins and of beta-lactamase inhibitors and their penicillin-derived components on the Bacteroides fragilis group.

We compared the inoculum effects for 109 recent clinical isolates of the Bacteroides fragilis group of cefoxitin, cefotetan, ceftizoxime, ceftriaxone, and three beta-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) and their penicillin-derived components. Bactericidal activity was assayed and morphologic changes were monitored for selected strains exhibiting a large inoculum effect. Ceftizoxime demonstrated the largest inoculum effect, followed by cefotetan and ceftriaxone. The large inoculum effect of ceftizoxime and ceftriaxone was correlated with filamentous transformation at the high inoculum (10(8) CFU/ml) and lack of bactericidal activity suggesting drug destruction or inactivation. Cefotetan was bactericidal for B. fragilis isolates but not for other members of the B. fragilis group. Cefoxitin showed the least inoculum effect and was consistently bactericidal at high (10(8) CFU/ml), standard (10(6) CFU/ml), and low (10(4) CFU/ml) inocula, followed by ampicillin-sulbactam. Piperacillin-tazobactam and ticarcillin-clavulanic acid showed an intermediate inoculum effect. The degree of inoculum effect observed generally correlated with bactericidal activity at all inocula.

Susceptibility testing of Listeria monocytogenes. A reassessment of bactericidal activity as a predictor for clinical outcome.

In vitro susceptibility testing of Listeria monocytogenes most often reveals both ampicillin and penicillin as inhibitory as opposed to bactericidal with activity comparable to chloramphenicol and tetracycline. Yet, the former two penicillins are more effective for Listeria meningitis than are the latter agents. Accordingly, we reassessed the bactericidal activity of agents used in listeriosis in order to determine in vitro methodology that would be more predictive of clinical outcome. We found that bactericidal activity for greater than 48 hr by either minimum inhibitory-minimum bactericidal concentration (MIC-MBC) testing or time-kill kinetic studies was the best predictor of clinical efficacy. This correlation may be due to Listeria being a slow-growing microorganism. In addition to ampicillin and penicillin, we found trimethoprim-sulfamethoxazole, vancomycin, and imipenem to exhibit bactericidal activity for 48 hr. For the first two agents, this is in agreement with the results of clinical experience.

An in-vitro and in-vivo comparison of the activity of beta-lactamase inhibitor combinations with imipenem and cephalosporins against Escherichia coli producing TEM-1 or TEM-2 beta-lactamase.

Reference strains of Escherichia coli (ampicillin-susceptible and -resistant ATCC strains, and known TEM-1 and TEM-2 beta-lactamase producers) were tested in vitro and in the in-vivo mouse thigh infection model against four beta-lactamase inhibitor compounds (BICs: amoxycillin/clavulanic acid, ampicillin/sulbactam, ticarcillin/clavulanic acid, and piperacillin/tazobactam), selected cephalosporins, and imipenem. The ATCC strains (ampicillin-susceptible and -resistant) were susceptible to the BICs in disc and MIC tests. Three or more logs of killing were observed at the NCCLS breakpoint concentrations. However, the TEM-1 and TEM-2 producers were resistant in disc tests to ampicillin/sulbactam and amoxycillin/clavulanic acid, and showed intermediate susceptibility to ticarcillin/clavulanic acid. MICs were at or near the breakpoint, but bactericidal activity was only noted at the probable breakpoint concentration of piperacillin/tazobactam. Cefoxitin, cefotaxime, cefpirome and imipenem, but not cephalothin, showed greater bactericidal activity and lower MICs for the TEM-producing strains than the BICs. The viable count of the TEM-1 producer was not reduced in the mouse thigh model by ampicillin/sulbactam or amoxycillin/clavulanic acid, but cefpirome and cefotaxime reduced the viable count by approximately three logs. There was a 50% mortality rate in mice receiving the two BICs. The ampicillin-susceptible ATCC strain of E. coli was killed to a similar degree by all agents tested. Overall, the BICs appeared inferior, in both in-vivo and in-vitro tests to selected cephalosporins and imipenem when tested against reference strains of E. coli producing TEM-1 or TEM-2 beta-lactamase. The large inoculum effect and poor bactericidal activity observed with the BICs suggest they could be less effective in certain clinical situations.