Comparison of Doxycycline or Minocycline to Sulfamethoxazole-Trimethoprim for Treatment of Stenotrophomonas maltophilia Pneumonia.

BACKGROUND: Stenotrophomonas maltophilia is a multidrug-resistant organism with limited antibiotic treatment options. Minocycline and doxycycline may be appropriate, but clinical data are limited. OBJECTIVE: To compare tetracyclines (minocycline and doxycycline [TCN]) with standard of care, sulfamethoxazole-trimethoprim (TMP-SMZ), in S. maltophilia pneumonia treatment. METHODS: This retrospective, 2-center study evaluated patients treated for S. maltophilia pneumonia with TCN or TMP-SMZ for clinical success, defined as resolution of leukocytosis, fever, and tachypnea. Patients were classified as treatment with TCN or TMP-SMZ based on definitive agent used for ≥50% of the treatment course and ≥4 days. Inclusion criteria were age ≥18 years, S. maltophilia confirmed on respiratory culture from January 2013 to November 2020, and appropriate definitive antibiotic dosing. Pregnancy, incarceration, S. maltophilia-resistant or intermediate to definitive therapy, and combination therapy for treatment of S. maltophilia pneumonia were exclusion criteria. Secondary outcomes were microbiologic success and recurrence or reinfection within 30 days requiring treatment. RESULTS: A total of 80 patients were included (21 TCN [15 minocycline, 6 doxycycline], 59 TMP-SMZ). There was no difference in clinical success (28.6% vs 25.4%; P = 0.994), microbiologic success (n = 28, 55.6% vs 66.4%; P = 0.677), or recurrence or reinfection (n = 24, 66.7% vs 26.7%; P = 0.092) between TCN and TMP-SMZ, respectively. CONCLUSION AND RELEVANCE: Clinical and microbiologic success rates were similar in patients treated with TCN compared with TMP-SMZ for S. maltophilia pneumonia. These data suggest minocycline and doxycycline may be options to treat S. maltophilia pneumonia, but conclusive clinical data continue to be lacking.

The Incidence of Ocular Complications in Candidemic Patients and Implications for the Practice of Routine Eye Exams.

Background: Ocular candidiasis is a known complication of candidemia. Given the poor ocular penetration of echinocandins, there is some concern that the increasing use of echinocandins may portend an increased incidence of ophthalmic complications. We examined the changing trends in antifungal prescribing patterns and the incidence of ophthalmic complications after candidemia. Methods: Patients with blood cultures positive for Candida species between January 2014 and June 2020 who underwent screening fundoscopic examination by an ophthalmologist were analyzed. The χ2 analysis was used to compare antifungal prescriptions and ocular exam findings before and after 2016. Trend analysis was also performed to assess temporal changes in prescribing practices and eye exam findings. Results: There were 226 candidemia cases during the study period, 129 (57.1%) of which underwent screening eye exams. From 2014 to 2015, 24 of 37 (64.5%) patients received eye-penetrating antifungals compared to 36 of 92 (39.1%) from 2016 to 2020 (P = .008). Overall, 30 of 129 (23.3%) patients had abnormal eye exams with the prevalence of abnormal findings being 7 of 37 (18.9%) before 2016 compared to 23 of 92 (25%, P = .46) thereafter. A trend analysis revealed an increase in abnormal eye findings over the study period (P = .008). Of the 30 patients who had abnormal eye exams, 9 (30%) had a change in systemic antifungal therapy from echinocandins to eye-penetrating antifungals. Echinocandin use was associated with abnormal eye findings. Conclusions: Prescription of eye-penetrating antifungals for candidemia has trended down since 2016. This was associated with a concomitant increase in abnormal findings on screening fundoscopy. Abnormal eye exams were not uncommon throughout our study period.

Comparison of Ceftriaxone and Antipseudomonal ß-Lactam Antibiotics Utilized for Potential AmpC ß-Lactamase-Producing Organisms.

Background: Induction of antibiotic resistance is associated with increased morbidity and mortality in AmpC ß-lactamase producing Enterobacteriaceae. The use of ceftriaxone is controversial for treatment of these organisms due to concerns for inducible resistance. This study was designed to compare treatment failure rates between ceftriaxone and antipseudomonal ß-lactam antibiotics when used as definitive therapy for organisms most commonly associated with chromosomal AmpC ß-lactamase production. Methods: A retrospective, single-center cohort study was performed enrolling patients hospitalized with monomicrobial Enterobacter, Citrobacter, or Serratia spp. infections. The primary objective compared proportion of treatment failure between groups. All patients received either ceftriaxone or an antipseudomonal ß-lactam alone within 24 hours of culture finalization, and with a duration of at least 72 hours for definitive treatment. Treatment failure was defined as either clinical failure (abnormal white blood cell count or temperature on day 7 or 14 post-antibiotics) or microbiologic failure (regrowth of the same organism at same site within 14 or 21 days). Results: Of 192 total patients, treatment failure was observed in 24/71 patients (34%) receiving ceftriaxone and in 42/121 patients (35%) receiving antipseudomonal ß-lactam (P = .98). No difference was observed between clinical or microbiologic failure rates between groups. The ceftriaxone group had significantly more patients undergoing treatment for urinary tract infections (51% vs 17%, P < .001), but treatment failure rates remained similar between groups when comparing infections of all other sources. Conclusion: Ceftriaxone has comparable treatment failure rates to antipseudomonal ß-lactams for susceptible Enterobacteriaceae infections and may be considered as a therapeutic option. Further, prospective research is needed to validate optimal dosing and application in all sites of infection.

Out of Sight-Out of Mind: Impact of Cascade Reporting on Antimicrobial Usage.

BACKGROUND: There is a paucity of data evaluating the strategy of suppressing broader-spectrum antibiotic susceptibilities on utilization. Cascade reporting (CR) is a strategy of reporting antimicrobial susceptibility test results in which secondary (eg, broader-spectrum, costlier) agents may only be reported if an organism is resistant to primary agents within a particular drug class. Our objective was to evaluate the impact of ceftriaxone-based cascade reporting on utilization of cefepime and clinical outcomes in patients with ceftriaxone-susceptible Escherichia and Klebsiella clinical cultures. METHODS: We compared post-CR (July 2014-June 2015) with baseline (July 2013-June 2014), evaluating utilization of cefepime, cefazolin, ceftriaxone, ampicillin derivatives, fluoroquinolones, piperacillin/tazobactam, ertapenem, and meropenem; new Clostridium difficile infection; and length of stay (LOS) after the positive culture, 30-day readmission, and in-hospital all-cause mortality. RESULTS: Mean days of therapy (DOT) among patients who received any antibiotic for cefepime decreased from 1.229 days during the baseline period to 0.813 days post-CR (adjusted relative risk, 0.668; P < .0001). Mean DOT of ceftriaxone increased from 0.864 days to 0.962 days, with an adjusted relative risk of 1.113 (P = .004). No significant differences were detected in other antibiotics including ertapenem and meropenem, demonstrating the direct association of the decrease in cefepime utilization with CR based on ceftriaxone susceptibility. Average LOS in the study population decreased from 14.139 days to 10.882 days from baseline to post-CR and was found to be statistically significant (P < .0001). CONCLUSIONS: In conclusion, we demonstrated significant association of decreased cefepime utilization with the implementation of a CR based on ceftriaxone susceptibility. We demonstrated the safety of deescalation, with LOS being significantly lower during the post-CR period than in the baseline period, with no change in in-hospital mortality.

Variability in telavancin cross-reactivity among vancomycin immunoassays.

Telavancin is a semisynthetic lipoglycopeptide with a dual mechanism of action against Gram-positive pathogens. Two brief reports have suggested potential cross-reactivity of telavancin with the vancomycin particle-enhanced turbidometric immunoassay (PETIA). The purpose of this study was to evaluate several commercially available vancomycin immunoassays (fluorescence polarization [FPIA], enzyme-multiplied immunoassays [EMIT], PETIA, and chemiluminescent immunoassay [CMIA]) for cross-reactivity with telavancin. Seven sites were selected to analyze serum samples for vancomycin. Each site received a set of samples (n = 18) which combined drug-free serum with telavancin, 7-OH telavancin metabolite, or vancomycin. Immunoassays demonstrating potential cross-reactivity were further evaluated by sending a duplicate sample set to multiple laboratories. Cross-reactivity was defined as the percent theoretical concentration (reported concentration/theoretical concentration × 100). No cross-reactivity was seen with FPIA or EMIT. Within the theoretical concentration range of 5 to 120 µg/ml of telavancin, the Synchron PETIA system reported vancomycin concentrations ranging from 4.7 to 54.2 µg/ml compared to vancomycin concentrations from 1.1 to 5.6 µg/ml for the Vista PETIA system. The Architect CMIA system reported vancomycin concentrations in the range of 0.27 to 0.97 µg/ml, whereas Advia Centaur XP CMIA reported vancomycin concentrations between 1.6 and 31.6 µg/ml. The Architect CMIA immunoassay had the lowest percent cross-reactivity (0.8 to 5.4%), while the Synchron PETIA immunoassay demonstrated the highest percent cross-reactivity (45.2 to 53.8%). Telavancin samples measured by liquid chromatography-mass spectroscopy were within 93.9 to 122% of theoretical concentrations. Vancomycin concentrations were not measured in any 7-OH telavancin-spiked sample. Vancomycin concentrations measured by liquid chromatography-mass spectroscopy were within 57.2 to 113% of theoretical concentrations. PETIA and CMIA measured vancomycin concentrations in telavancin-spiked samples. Significant variability in percent cross-reactivity was observed for each platform regardless of immunoassay method.

Fidaxomicin: a minimally absorbed macrocyclic antibiotic for the treatment of Clostridium difficile infections.

Fidaxomicin was approved for the treatment of Clostridium difficile infections in 2011. It has a novel mechanism of action and narrow spectrum of activity that makes it unique among the currently used therapies for this disease. Phase III clinical studies demonstrated a benefit of fidaxomicin over vancomycin for the outcomes of recurrence and global cure or sustained clinical response. This observation was confirmed within specific populations, including those of older age, immunocompromised due to active cancers, and patients taking concomitant antibiotics. Additionally, fidaxomicin significantly reduced recurrence rates compared to vancomycin among patients receiving treatment for recurrent C. difficile episodes. Fidaxomicin represents an advance in therapy for the treatment of C. difficile infections.

The influence of FGF2 high molecular weight (HMW) isoforms in the development of cardiac ischemia-reperfusion injury.

Fibroblast growth factor 2 (FGF2) consists of multiple protein isoforms (low [LMW] and high molecular weight [HMW]), which are localized to different cellular compartments, indicating unique biological activity. We previously showed that the LMW isoform is important in protecting the heart from myocardial dysfunction associated with ischemia-reperfusion (I/R) injury, but the roles of the HMW isoforms remain unknown. To elucidate the role of HMW isoforms in I/R and cardioprotection, hearts from novel mouse models, in which the murine FGF2 HMWs are knocked out (HMWKO) or the human FGF2 24 kDa HMW isoform is overexpressed (HMW Tg) and their wildtype (Wt) or non-transgenic (NTg) cohorts were subjected to an ex vivo work-performing heart model of I/R. There was a significant improvement in post-ischemic recovery of cardiac function in HMWKO hearts (76+/-5%, p<0.05) compared to Wt hearts (55+/-5%), with a corresponding decrease in HMW Tg function (line 20: 38+/-6% and line 28: 33+/-4%, p<0.05) compared to non-transgenic hearts (68+/-9%). FGF2 LMW isoform was secreted from Wt and HMWKO hearts during I/R, and a FGF receptor (FGFR) inhibitor, PD173074 caused a decrease in cardiac function when administered in I/R in Wt and FGF2 HMWKO hearts (p<0.05), indicating that FGFR is involved in FGF2 LMW isoform's biological effect in ischemia-reperfusion injury. Moreover, overexpression of HMW isoform reduced FGFR1 phosphorylation/activation with no further decrease in the phosphorylation state in the presence of the FGFR inhibitor. Overall, our data indicate that HMW isoforms have a detrimental role in the development of post-ischemic myocardial dysfunction.

Peripheral nociception associated with surgical incision elicits remote nonischemic cardioprotection via neurogenic activation of protein kinase C signaling.

BACKGROUND: Although remote ischemic stimuli have been shown to elicit cardioprotection against ischemia/reperfusion injury, there is little known about the effects of nonischemic stimuli. We previously described a remote cardioprotective effect of nonischemic surgical trauma (abdominal incision) called remote preconditioning of trauma (RPCT). In the present study, we elucidate mechanisms underlying this phenomenon. METHODS AND RESULTS: We used a murine model of myocardial infarction to evaluate ischemia/reperfusion injury, and either abdominal surgical incision, or application of topical capsaicin, to elicit cardioprotection. We show that the cardioprotective effect of RPCT is initiated by skin nociception, and requires neurogenic signaling involving spinal nerves and activation of cardiac sensory and sympathetic nerves. Our results demonstrate bradykinin-dependent activation and repression, respectively, of PKCepsilon and PKCdelta in myocardium after RPCT, and we show involvement of the K(ATP) channels in cardioprotection. Finally, we show that topical application of capsaicin, which selectively activates C sensory fibers in the skin, mimics the cardioprotective effect of RPCT against myocardial infarction. CONCLUSIONS: Nontraumatic nociceptive preconditioning represents a novel therapeutic strategy for cardioprotection with great potential clinical utility.

Biological functions of the low and high molecular weight protein isoforms of fibroblast growth factor-2 in cardiovascular development and disease.

Fibroblast growth factor 2 (FGF2) consists of multiple protein isoforms (low molecular weight, LMW, and high molecular weight, HMW) produced by alternative translation from the Fgf2 gene. These protein isoforms are localized to different cellular compartments, indicating unique biological activity. FGF2 isoforms in the heart have distinct roles in many pathological circumstances in the heart including cardiac hypertrophy, ischemia-reperfusion injury, and atherosclerosis. These studies suggest distinct biological activities of FGF2 LMW and HMW isoforms both in vitro and in vivo. Yet, due to the limitations that only the recombinant FGF2 LMW isoform is readily available and that the FGF2 antibody is nonspecific with regards to its isoforms, much remains to be determined regarding the role(s) of the FGF2 LMW and HMW isoforms in cellular behavior and in cardiovascular development and pathophysiology. This review summarizes the activities of LMW and HMW isoforms of FGF2 in cardiovascular development and disease.

Remote preconditioning-endocrine factors in organ protection against ischemic injury.

Cardiovascular disease is the leading cause of death in the United States and developing world. Experimental and clinical studies have demonstrated that a number of interventions including brief periods of ischemia or hypoxia and certain endogenous factors such as opioids, bradykinin, growth factors or pharmacological agents are capable of protecting the heart against post-ischemic contractile dysfunction, arrhythmias and myocardial infarction. This conventional cardioprotection occurs via an autocrine or paracrine action in which these protective factors are released from the heart to act upon itself. Over the last ten years, a growing body of evidence indicates that a brief ischemic insult on one organ releases endogenous factors that protect other organs against a prolonged ischemic insult. This phenomenon, termed remote preconditioning or preconditioning at a distance, implicates an endocrine action, and may involve humoral or neural-endocrine signaling. This review will summarize the endocrine factors identified and implicated in this inter-organ cytoprotection.

The cardioprotective effect of the low molecular weight isoform of fibroblast growth factor-2: the role of JNK signaling.

UNLABELLED: Our laboratory showed that overexpression of fibroblast growth factor-2 (FGF2) protected the heart against ischemia-reperfusion injury. FGF2 has different protein isoforms (low [LMW] and high [HMW] molecular weight isoforms) produced from alternative translation start sites. However, which FGF2 isoform(s) mediates this cardioprotection, and which signaling pathway (i.e., mitogen-activated protein kinase (MAPK)) elicits FGF2 isoform-induced cardioprotection remains to be elucidated. METHODS AND RESULTS: Wildtype, Fgf2 KO (absence of all FGF2 isoforms) and FGF2 LMWKO (absence of LMW isoform) hearts were subjected to an ex vivo work-performing heart ischemic model of 60 min ischemia and 120 min reperfusion. There was a significant decrease in the recovery of post-ischemic contractile function (p<0.05) in Fgf2 KO and FGF2 LMWKO mouse hearts compared to wildtype hearts. Following ischemia-reperfusion injury, MKK4/7, JNK, and c-Jun were significantly phosphorylated (i.e., activated), and the levels of TUNEL-positive nuclei and caspase 3 cleavage were significantly increased in vehicle-treated Fgf2 KO and FGF2 LMWKO compared to wildtype hearts (p<0.05). A novel JNK pathway inhibitor, CEP11004 (50 nM), significantly restored the post-ischemic contractile function and reduced myocardial cell death, as measured by CK release and apoptotic markers, compared to DMSO-treated cohorts (p<0.05). Overall, our data indicate that the LMW isoform has an important role in restoring cardiac function after ischemia-reperfusion (I/R) injury. These results provide unequivocal evidence that inhibition of JNK signaling is involved in FGF2 LMW isoform-mediated cardioprotection and that the potential mechanism may be through inhibition of the apoptotic process.