Impact of ureido/carboxypenicillin resistance on the prognosis of ventilator-associated pneumonia due to Pseudomonas aeruginosa.

INTRODUCTION: Although Pseudomonas aeruginosa is a leading pathogen responsible for ventilator-associated pneumonia (VAP), the excess in mortality associated with multi-resistance in patients with P. aeruginosa VAP (PA-VAP), taking into account confounders such as treatment adequacy and prior length of stay in the ICU, has not yet been adequately estimated. METHODS: A total of 223 episodes of PA-VAP recorded into the Outcomerea database were evaluated. Patients with ureido/carboxy-resistant P. aeruginosa (PRPA) were compared with those with ureido/carboxy-sensitive P. aeruginosa (PSPA) after matching on duration of ICU stay at VAP onset and adjustment for confounders. RESULTS: Factors associated with onset of PRPA-VAP were as follows: admission to the ICU with septic shock, broad-spectrum antimicrobials at admission, prior use of ureido/carboxypenicillin, and colonization with PRPA before infection. Adequate antimicrobial therapy was more often delayed in the PRPA group. The crude ICU mortality rate and the hospital mortality rate were not different between the PRPA and the PSPA groups. In multivariate analysis, after controlling for time in the ICU before VAP diagnosis, neither ICU death (odds ratio (OR) = 0.73; 95% confidence interval (CI): 0.32 to 1.69; P = 0.46) nor hospital death (OR = 0.87; 95% CI: 0.38 to 1.99; P = 0.74) were increased in the presence of PRPA infection. This result remained unchanged in the subgroup of 87 patients who received adequate antimicrobial treatment on the day of VAP diagnosis. CONCLUSIONS: After adjustment, and despite the more frequent delay in the initiation of an adequate antimicrobial therapy in these patients, resistance to ureido/carboxypenicillin was not associated with ICU or hospital death in patients with PA-VAP.

[Gastrointestinal carriage of Pseudomonas aeruginosa in children residing in chronic care institutes in Jerusalem: high prevalence and high rates of antibiotic resistance].

BACKGROUND: Pseudomonas aeruginosa carriage in the gastrointestinal tract is uncommon in healthy children. Children living in chronic care institutions are often carriers of P. aeruginosa in the respiratory tract, but data is lacking regarding gastrointestinal carriage in these children. AIMS: To examine the carriage rate of P. aeruginosa in children living in chronic care institutions in Jerusalem and to assess resistance rates of the bacteria to different classes of antibiotics. METHODS: Rectal swabs were taken from all children residing in two chronic care institutions in Jerusalem: "St. Vincent" and "Aleh". The swabs were examined for presence of Pseudomonas aeruginosa. The authors used disk diffusion technique and E Test to assess resistance for different antibiotics. RESULTS: Gastrointestinal carriage of P. aeruginosa was detected in 37 out of 125 of the children (30%); 16% of the P. aeruginosa isolates were resistant to carbapenems; 16% were resistant to aminoglycosides, 14% to ureidopenicillins and 11% to quinolones. All isolates were sensitive to ceftazidime and colistin. In 84% of the isolates, the minimal inhibitory concentration (MIC) for meropenem was significantly lower than the MIC for imipenem. SUMMARY: P. aeruginosa is a common colonizer of the gastrointestinal tract of children living in chronic care institutions. Empiric antibiotic treatment against P. aeruginosa should be considered when treating children with acute gastrointestinal pathologies. Antibiotic resistance, and particularly carbapenem resistance, is common in this population. There is a significant difference between the MICs for imipenem and meropenem. Future studies are needed to understand the clinical significance of this finding.

Metal-carbenicillin framework-based nanoantibiotics with enhanced penetration and highly efficient inhibition of MRSA.

The development of effective therapies to control methicillin-resistant Staphylococcus aureus (MRSA) infections is challenging because antibiotics can be degraded by the production of certain enzymes, for example, ß-lactamases. Additionally, the antibiotics themselves fail to penetrate the full depth of biofilms formed from extracellular polymers. Nanoparticle-based carriers can deliver antibiotics with better biofilm penetration, thus combating bacterial resistance. In this study, we describe a general approach for the construction of ß-lactam antibiotics and ß-lactamase inhibitors co-delivery of nanoantibiotics based on metal-carbenicillin framework-coated mesoporous silica nanoparticles (MSN) to overcome MRSA. Carbenicillin, a ß-lactam antibiotic, was used as an organic ligand that coordinates with Fe3+ to form a metal-carbenicillin framework to block the pores of the MSN. Furthermore, these ß-lactamase inhibitor-loaded nanoantibiotics were stable under physiological conditions and could synchronously release antibiotic molecules and inhibitors at the bacterial infection site to achieve a better elimination of antibiotic resistant bacterial strains and biofilms. We confirmed that these ß-lactamase inhibitor-loaded nanoantibiotics had better penetration depth into biofilms and an obvious effect on the inhibition of MRSA both in vitro and in vivo.

Piperacillin v Carbenicillin in the therapy for serious infections.

One hundred seven patients were treated with either piperacillin (56) or carbenicillin (51) in an open randomized trial of hospitalized patients with pleuropulmonary (40), urinary tract (26), gynecologic (21), skin and soft-tissue (eight), joint (five), bone (three), and miscellaneous other infections (four). Patients with urinary tract infections were given 150 mg/kg/day of piperacillin sodium or 200 mg/kg/day or carbenicillin sodium in divided doses every six hours intravenously. Patients with other infections were given 250 mg/kg/day of piperacillin sodium and 450 mg/kg/day of carbenicillin sodium; 53/56 (95%) patients treated with piperacillin and 45/51 (88%) patients treated with carbenicillin were cured clinically. In general, the drugs were well tolerated. There were, however, more adverse experiences in the groups taking carbenicillin. Of special interest was the finding of liver function test abnormalities in 17/78 (21%) carbenicillin recipients (evaluative and nonevaluative cases). We concluded that piperacillin was effective and safe. It has potential for use in a great variety of infections.

Sternoarticualr pyoarthrosis due to gram-negative bacilli. Report of eight cases.

Of eight patients with Gram-negative bacillary sternoarticular pyoarthrosis, seven were long-term intravenous heroin abusers. Clinical onset was insidious and a long delay (one month or more) in seeking hospitalization was usually noted. Anterior chest discomfort and painful, restricted homolateral shoulder motion were the chief complaints. Fever and monoarticular arthritis were universally present, Open synovial biopsy examination was frequently required for etiologic diagnosis. Pseudomonas aeruginosa was the most common pathogen isolated. Roentgenographic evidence of associated osteomyelitis was usually seen, but tomography was often necessary to delineate this lesion. Intraoperatively, associated osteomyelitis of the clavicular head and/or sternum was present in all eight cases and a perisynovial and/or retrosternal abscess was found in five patients. Early surgical exploration and prolonged antimicrobial therapy yielded excellent results.

Pseudomonas aeruginosa ventilator-associated pneumonia: comparison of episodes due to piperacillin-resistant versus piperacillin-susceptible organisms.

We sought to determine the epidemiological characteristics of patients in an intensive care unit (ICU) who developed ventilator-associated pneumonia (VAP) caused by piperacillin-resistant Pseudomonas aeruginosa (PRPA; n=34) or piperacillin-susceptible P. aeruginosa (PSPA; n=101). According to univariate analysis, the factors associated with the development of PRPA VAP were presence of an underlying fatal medical condition, immunocompromised status, longer previous hospital stay, less-severe illness at the time of ICU admission, duration of mechanical ventilation before onset of VAP, number of classes of antibiotic received, and previous exposure to imipenem or fluoroquinolone. Multivariate logistic regression analysis identified the following significant independent factors: presence of an underlying fatal medical condition (odds ratio [OR], 5.6), previous fluoroquinolone use (OR, 4.6), and initial disease severity (OR, 0.8). We concluded that the clinical characteristics of patients who develop PRPA VAP differ from those of patients who develop PSPA VAP. Restricted fluoroquinolone use is the sole independent risk factor for PRPA VAP that is open to medical intervention.

Carbenicillin therapy in patients with normal and impaired renal function.

Optimun therapy with carbenicillin entails the use of high serum concentrations and the risk of significant dose-related toxicity. We report a study of serum clearance method of dose adjustment of carbenicillin patients with normal and imparied renal function. This method was found to provide serum concentrations considered to be satisfactory in every instance, by either constant-rate or intermittent infusion, and should enable greater precision in the use of the antibiotic. Implications of these findings aimed at providing dosage schedules for patients with renal failure are discussed.

A randomized comparative trial of three aminoglycosides--comparison of continuous infusions of gentamicin, amikacin and sisomicin combined with carbenicillin in the treatment of infections in neutropenic patients with malignancies.

Continuous infusions of gentamicin, amikacin or sisomicin combined with carbenicillin were compared in a randomized study in the treatment of 572 febrile episodes in 281 patients with cancer. The three treatments (C+A, C+A and C+S) were equally effective with no significant differences in response rate overall (67%, 68%, 67%) or in any infection, except septicemia where C+G had a significantly lower response rate than the other two groups. Pneumonia, the most common infection, had the lowest response rate for all three groups (45-50%). Klebsiella spp. were the most common pathogens and showed a lower response rate than other gram-negative bacilli (P = 0.003). Patients with persistent severe neutropenia had a response rate of 56%. Azotemia was significantly less common in patients with documented infection treated with C+A than in the C+S group. Combinations of carbenicillin plus an aminoglycoside antibiotic are effective for the treatment of infections in neutropenic patients.

Neurological sequelae of malignant external otitis.

The neurological sequelae of malignant external otitis (MEO) form a characteristic syndrome. Following Pseudomonas external otitis, usually in an elderly, diabetic patient, either isolated facial nerve paralysis or multiple cranial nerve palsies develop. Once extensive neurological signs have developed, recovery rarely occurs. We saw a patient with MEO and multiple cranial nerve palsies who recovered following an extended course of gentamicin sulfate and carbenicillin disodium therapy.

Malignant external otitis: a severe form of otitis in diabetic patients.

Two cases of malignant external otitis are presented and the literature is reviewed. The disease seems to occur exclusively in elderly diabetic patients. Diagnosis is mostly a clinical one, and requires a high index of suspicion. The characteristic clinical manifestations are pain and severe tenderness of the tissues around the ear and mastoid, persistent drainage and the presence of granulation tissue at the junction of the osseus and cartilagenous portions of the external ear. Roentgenographic findings are not helpful in the early stages. The pathogenesis of this disease depends on the presence of clefts in the cartilage forming the floor of the external auditory canal at its junction with the osseus portion through which infection can spread from the external ear to the deep soft tissues. Serious and often fatal complications may ensue. The most common and earliest symptom to appear if facial nerve palsy. Pseudomonas aeruginosa has been isolated uniformly, in pure or mixed cultures. This entity, therefore, should be borne in mind whenever an elderly diabetic patient presents with external otitis not amenable to the usual methods of therapy. Ps. aeruginosa should be strongly suspected, and its isolation should prompt vigorous systemic treatment with gentamicin and carbenicillin before extensive necrosis of cartilage and bone takes place. Any delay in diagnosis and management will lead to a serious and often fatal complications.

A randomized study of carbenicillin plus cefamandole or tobramycin in the treatment of febrile episodes in cancer patients.

Patients were randomly assigned to receive carbenicillin plus tobramycin by continuous infusion (C+T), carbenicillin plus cefamandole by continuous infusion (C+CC) or carbenicillin plus cefamandole by intermittent infusion (C+IC) during 490 febrile episodes. Carbenicillin was administered over 2 hours every 4 hours. The per cent of cures achieved during the 235 documented infections was 65 per cent for C+CC, 57 per cent for C+IC and 54 per cent for C+T. Among those infections caused by single gram-negative bacilli, C+CC produced a higher cure rate than C+IC or C+T(74 per cent versus 59 per cent versus 50 per cent). C+CC was significantly more effective than C+IC among patients with persistent severe neutropenia of less than 100 neutrophils/mm3 (65 per cent versus 21 per cent, p = 0.03). If the infecting organism was sensitive to both antibiotics, the cure rate which occurred during 12 per cent to 13 per cent of the febrile episodes, regardless of antibiotic regimen. However, it occurred significantly more often during documented infections than during fevers of unknown etiology (20 per cent versus 6 per cent, p less than 0.001). C+CC appears to be the most effective of the three regimens for the treatment of infections in patients with persistent severe neutropenia.

Ofloxacin in the management of complicated urinary tract infections, including prostatitis.

Studies of ofloxacin pharmacokinetics and pathogen susceptibilities suggested that this new fluoroquinolone might be particularly well suited to the treatment of urinary tract infections and prostatitis. Compared with carbenicillin and trimethoprim/sulfamethoxazole in separate studies of complicated urinary tract infection, ofloxacin achieved a significantly higher rate (p = 0.048) of microbiologic cures and more clinical cures than carbenicillin, while essentially matching the efficacy of the trimethoprim/sulfamethoxazole combination. Most common organisms were Pseudomonas aeruginosa in the first study and Escherichia coli in the second. In preliminary data from the prostatitis study comparing ofloxacin 300 mg given twice daily with carbenicillin 764 mg given every six hours, microbiologic cure rates were 100 percent with both medications. However, clinical cure rates were significantly higher (p = 0.048) with ofloxacin. Throughout these trials, ofloxacin has shown excellent safety and tolerability, with a lower incidence of nausea and diarrhea than with carbenicillin, and less nausea and rash than with trimethoprim/sulfamethoxazole. In all treatment groups, clinically significant laboratory abnormalities were uncommon and unrelated to the medications. Overall, these studies indicate that in complicated urinary tract infection the efficacy of ofloxacin is comparable with that of trimethoprim/sulfamethoxazole and superior to that of carbenicillin. In chronic bacterial prostatitis, results to date suggest that ofloxacin may be more effective clinically and as effective microbiologically as carbenicillin.

Granulocytopenia in hospitalized patients. II. A prospective comparison of two antibiotic regimens in the empiric therapy of febrile patients.

The results of empiric antibiotic therapy in 126 hospitalized patients with fever during 192 episodes of granulocytopenia were studied. Febrile granulocytopenic patients were randomly allocated to receive either carbenicillin, methicillin and gentamicin, or carbenicillin and cephalothin. The response rate for the two antibiotic regimens was similar, 49 (60 per cent) of 81 responded to the former and 42 (54 per cent) of 78 to the latter. The response rate in patients receiving other antibiotics because of specific indications or counterindications was 19 (58 per cent) of 33. Thirty-nine (35 per cent) of 110 patients who responded to initial antibiotic therapy had an increase in circulating granulocytes of one log10 or more compared to only 10 (12 per cent) of 79 nonresponders with such an increase. The mortality rate in adult patients receiving carbenicillin, methicillin and gentamicin was eight (16 per cent) of 51, compared to 18 (37 per cent) of 49 in those receiving cephalothin and carbenicillin (P less than 0.05). The significance of this difference in the initial response rate or mortality rate between patients treated with the two antibiotic regimens when only patients with documented bacterial infection were considered. Patients who responded to their initial antibiotic regimen, and patients for whose fever no explanation was found, had the best prognosis.

In vitro models for the study of combination antibiotic therapy in neutropenic patients.

Neutropenic patients are at risk of serious infection caused by gram-negative bacilli and staphylococci. The mortality rate associated with gram-negative bacteremia in these patients is extremely high, especially in those with persistent and profound granulocytopenia. In these latter patients, the best results have been obtained by administering combinations of antibiotics in which both agents are active and/or show in vitro synergism against the infecting organism. Most combinations include an aminoglycoside such as amikacin and a broad-spectrum beta-lactam antibiotic, such as azlocillin, mezlocillin, piperacillin, or ceftazidime. The International Antimicrobial Therapy Project Group of the European Organization for Research and Treatment of Cancer has completed several studies evaluating various antibiotic combinations in the empiric treatment of febrile neutropenic patients. These trials have evaluated cephalothin plus gentamicin, carbenicillin plus gentamicin, and cephalothin plus carbenicillin; carbenicillin plus amikacin and carbenicillin plus amikacin plus cefazolin; azlocillin plus amikacin, ticarcillin plus amikacin, and cefotaxime plus amikacin; and azlocillin plus amikacin versus ceftazidime plus long- or short-course amikacin. The preclinical evaluation of antibiotic combinations usually involves the in vitro testing of antibiotics alone and in combination by the checkerboard method or with the use of time-kill curves. However, these methods expose the bacterial culture to a static or constant concentration of the drugs. During the in vivo treatment of infections, bacteria are exposed to changing concentrations of antibiotics, which are contingent on the individual pharmacokinetics of these drugs. We have designed a two-compartment in vitro pharmacokinetic model that allows the simultaneous study of the activity of two antibiotics with similar or different half-lives against a number of bacteria. Amikacin and azlocillin have been studied alone and in combination in this model against Pseudomonas aeruginosa, a frequent cause of bacteremia in neutropenic patients. In pharmacologically relevant doses, amikacin alone produced rapid bacterial killing, followed by regrowth of resistant subpopulations. Azlocillin alone produced a more gradual reduction of the bacterial inoculum, with ultimate bacteriostasis. Amikacin plus azlocillin produced rapid and complete eradication of the organism. In vitro pharmacokinetic models may prove to be more predictive of clinical outcome than are traditional static in vitro methods used to study antibiotic combinations.

A comparative study of ticarcillin plus tobramycin versus carbenicillin plus gentamicin for the treatment of serious infections due to gram-negative bacilli.

The combination of ticarcillin plus tobramycin (TT) or carbenicillin plus gentamicin (CG) was used to treat 82 patients with severe systemic gram-negative infection in a prospective, randomized study. Pseudomonas aeruginosa was the primary pathogen in 7 (93 per cent) of these patients. Patients treated with TT responded more frequently (92 per cent or 37 of 40) than patients treated with CG (71 per cent or 30 of 42) (p is less than 0.05). This difference was primarily due to a greater response to TT in patients with pulmonary infections (93 per cent versus 68 per cent) and infections due to Pseudomonas (92 per cent versus 70 per cent). Severity of underlying disease was also an important determinant of response. Except for a greater incidence of hepatotoxicity with CG (23 per cent versus 3 per cent; p is less than 0.02), there was no difference in toxicity, colonization with drug-resistant microorganisms or superinfection between the two treatment groups. The combination of TT appears to be superior to CG for the treatment of pulmonary infections due to Pseudomonas aeruginosa.

Pseudomonas bacteremia. Review of 108 cases.

The current circumstances associated with Pseudomonas aeruginosa bacteremia are reviewed in 108 episodes to assess the impact of new antimicrobial drugs on this infection. Since 1961, Pseudomonas bacteremia has apparently become more frequent with proportional increases in middle-aged patients. The respiratory tract has become the major source of infection. Clinical features are not characteristic, but infected patients are almost uniformly severely ill before blood stream invasion occurs. The use of gentamicin, carbenicillin and colistin has not changed the outcome of Pseudomonas bacteremia. Although better than no antimicrobial treatment, these drugs cannot be shown to be superior to any other available antibiotics. A reassessment is needed to evaluate the relationship between the in vitro action and the effectiveness of antibiotics in the treatment of Pseudomonas infection and the use of gentamicin, carbenicillin and colistin in these bacteremias. In view of the poor results with antibiotics, investigation into immunologic prophylaxis and therapy is needed. At the present time, control of the patients' underlying disease contributes most towards assuring survival with Pseudomonas bacteremia.

Gram-negative bacillary endocarditis. Interpretation of the serum bactericial test.

Although the serum bactericidal test is commonly used in the management of infective endocarditis, little has been written about its validity or limitations. We report three cases of gram-negative bacillary endocarditis (Pseudomonas aeruginosa, Vibrio fetus and Serratia marcescens) encountered in 1 year at a Veterans Administration hospital. Serum bactericidal titers were considered necessary to identify inadequate antibiotic regimens or to avoid unnecessary drug toxicity. The limitations of the test, particularly those pertaining to gram-negative infections, are reviewed. Misleading results during treatment with aminoglycoside antibiotics could be due to the tendency of serum to become alkaline on standing. A detailed study of the interaction of the complement-dependent bactericidal system of serum with eight antibiotics is presented. In the context of the serum bactericidal test, the interaction was additive or synergistic in 15 of 16 determinations, indicating the need to include a control study of serum sensitivity of the infecting microorganism in each case.

Antimicrobial drugs used in the management of anaerobic infections in children.

Optimum antimicrobial therapy effective against anaerobes is required to rapidly resolve infections due to these organisms and to prevent serious complications. Selection of antimicrobial therapy should be based on clinical experience and presumptive evidence until culture and sensitivity tests are available. If an abscess should develop, surgical drainage (when possible) is of paramount importance. Antimicrobial therapy for anaerobic infections should usually be given for prolonged periods because of the tendency for relapse, and should include coverage for aerobic bacteria whenever they are present. Penicillin G remains the drug of choice for most anaerobic infections except those caused by beta-lactamase-producing Bacteroides spp. such as B. fragilis and B. melaninogenicus, and some strains of Fusobacterium varium, which can be resistant. Other antimicrobials which are available for treatment of anaerobic infections in paediatric patients, and are generally active against B. fragilis, are carbenicillin, ticarcillin, chloramphenicol, clindamycin and cefoxitin. Experience in the use of metronidazole suggests that it could be a very valuable antimicrobial agent in the treatment of anaerobic infections. Experience with synergistic antimicrobial combinations in the treatment of anaerobic infections is limited; only experimental data are available suggesting synergism between penicillin and aminoglycosides against some Bacteroides spp. beta-Lactamase-producing anaerobic bacteria may protect other penicillin-susceptible bacteria in mixed infections. This phenomenon may explain penicillin failure in eradicating mixed infections.

Gentamicin-resistant Pseudomonas aeruginosa: Mayo Clinic Experience, 1970-1976.

During the period 1970 through 1976, there were 144 patients from whom gentamicin-resistant Pseudomonas aeruginosa (minimum inhibitory concentration [MIC], more than 5 microgram/ml) was isolated. In 20(21 percent) of the 95 patients who acquired such organisms within our institutions, the occurrence was considered clinically significant. Factors that favored the appearance of gentamicin-resistant P. aeruginosa included prolonged hospitalization, previous antibiotic treatment, increased gentamicin usage, underlying disease, and instrumentation (70 percent). Virulence of gentamicin-resistant isolates appeared less than that of susceptible organisms, with bacteremia due to these isolates occurring in only three cases. Resistant isolates with MICs for gentamicin of 8 to 16 microgram/ml were more susceptible to tobramycin than to amikacin, whereas isolates with MICs for gentamicin of 64 microgram/ml or greater were more susceptible to amikacin than to tobramycin. Eighty percent of all strains were susceptible to 128 microgram/ml or less of carvenicillin. Favorable results occurred in 12 or 13 cases treated with gentamicin plus carbenicillin, whereas treatment with either of these agents alone resulted in failure or relapse in 7 of 14 cases.