Antibiotics

Is oral vancomycin prophylaxis (OVP) effective in preventing recurrent Clostridium difficile infection (CDI) in patients requiring systemic antimicrobial therapy (SAT)?

FA Manian MD, MPH, , , , , Leave a comment

Although OVP is often administered to patients with history of CDI who require SAT, evidence to support this practice has been lacking until recently.

In a 2016 retrospective study of 203 patients with prior history of CDI, those who received OVP (125 mg or 250 mg 2x/daily) during the course of their SAT and for up to 1 week thereafter were significantly less likely to have a recurrence than the non-OVP group (4.2% vs 26.6%, respectively, O.R. 0.12 [C.I. 0.04-0.4]) (1). In this study, the mean interval between prior CDI and initiation of prophylaxis was 6.1 months (1-21 months), and the mean duration of prophylaxis following discontinuation of SAT was 1 day (0-6 days). Similar results have been reported by others (2,3).

Despite their retrospective nature, these studies lend support to the use of OVP in reducing the risk of recurrent CDI in patients who require SAT. It is unclear how long OVP should be continued after SAT is completed, if at all, but common practice is 1-2 weeks.

A randomized-controlled study comparing OVP 125 mg daily for the duration of SAT plus 5 days vs placebo appears to be on the way (4)!

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References

  1. Van Hise NW, Bryant AM, Hennessey EK, Crannage AJ, Khoury JA, Manian FA. Efficacy of oral vancomycin in preventing recurrent Clostridium difficile infection in patients treated with systemic antimicrobial agents. Clin Infect Dis 2016; Advance Access published June 17, 2016. Doi.10.1093/cid/ciw401.
  2. Carignan A, Sebastien Poulin, Martin P, et al. Efficacy of secondary prophylaxis with vancomycin for preventing recurrent Clostridium difficile infections. Am J Gastroenterol 2016;111: 1834-40. https://www.ncbi.nlm.nih.gov/pubmed/27619835
  3. Granetsky A, Han JH, Hughes ME, et al. Oral vancomycin is highly effective in preventing Clostridium difficile infection in allogeneic hematopoietic stem cell transplant recipients. Blood 2016;128:2225; http://www.bloodjournal.org/content/128/22/2225?sso-checked=true
  4. https://clinicaltrials.gov/ct2/show/NCT03462459

Disclosure: The author of this post was also a co-investigator of one of the studies cited (ref. 1).

 

 

 

Is oral vancomycin prophylaxis (OVP) effective in preventing recurrent Clostridium difficile infection (CDI) in patients requiring systemic antimicrobial therapy (SAT)?

Is cefpodoxime an appropriate oral antibiotic substitute for ceftriaxone when treating patients with respiratory tract infections caused by penicillin-resistant Streptococcus pneumoniae (PRSP)?

FA Manian MD, MPH, , , , Leave a comment

Short answer: No!

Although cefpodoxime is also a 3rd generation cephalosporin, its invitro activity against PRSP is not comparable to that of ceftriaxone.  In a study of 21,605 strains of S. pneumoniae collected internationally, whereas 89.1% of PRSP isolates were susceptible to ceftriaxone, only 35% were susceptible to cefpodoxime (1).  Among isolates resistant to penicillin and erythromycin, the susceptibility to ceftriaxone was 86.9% compared to that of 22.7% for cefpodoxime.

This information is important since 32%, and 17.6% of all S. pneumoniae isolates tested in this study  were either penicillin-resistant or penicillin- and erythromycin-resistant, respectively.  

So, when it comes to the coverage of PRSP, there is no oral cephalosporin “equivalent” to ceftriaxone and that includes cefpodoxime.  In fact, the package insert of cefpodoxime states that cefpodoxime is active against S. pneumoniae “excluding penicillin-resistant strains” (2).

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References

  1. Pottumarthy S. Fritsche TR, Jones RN. Comparative activity of oral and parenteral cephalosporins tested against multidrug-resistant Streptococcus pneumonia: report from SENTRY Antimicrobial Surveillance Program (1997-2003). Diag Microbiol Infect Dis 2005;51:147-150. https://www.sciencedirect.com/science/article/pii/S0732889304002081    
  2. http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/050674s014,050675s017lbl.pdf; accessed June 20, 2016.
Is cefpodoxime an appropriate oral antibiotic substitute for ceftriaxone when treating patients with respiratory tract infections caused by penicillin-resistant Streptococcus pneumoniae (PRSP)?

Is oral metronidazole (Flagyl®) effective in reducing the risk of recurrent Clostridium difficile infection (CDI)?

FA Manian MD, MPH, , Leave a comment

To date only 1 study has attempted to evaluate metronidazole’s role in preventing CDI1. This work, however,  has significant shortcomings including its retrospective nature, definition of metronidazole prophylaxis as any dose for reasons other than CDI starting 1-3 days before initiation of the primary antibiotic, undefined duration, less comorbidities in the metronidazole group, and surveillance period for CDI limited to only 7 days following initiation of the primary antibiotic. For these reasons, it is difficult to interpret the results of this study whose conclusion was that metronidazole may protective against CDI2.

In fact, there are several reasons why metronidazole prophylaxis may not be effective in CDI.   First, due to its very high bioavailability, concentrations of metronidazole in formed stool are often undetectable2,3 . Consequently, “preventive” metronidazole in patients at risk of CDI but with formed stools would not be expected to achieve high enough concentrations in the colon to be effective.  In additions, metronidazole itself may be associated with CDI4 and  vancomycin-resistant enterococci5,  and has several potential drug-interactions and adverse effects6 .

References

  1. Rodriguez S, Hernandez MB, Tarchini G, et al. Risk of Clostridium difficile infection in hospitalized patients receiving metronidazole for a non-C difficile infection. Clin Gastroenterol Hepatol 2014;12:1856-61. https://www.ncbi.nlm.nih.gov/pubmed/24681079
  2. Dupont HL. Chemoprophylaxis of Clostridium difficile infections in high-risk hospitalized patients. Clin Gastroenterol Hepatol 2014;12: 1862-63. https://www.ncbi.nlm.nih.gov/labs/articles/24768812/
  3. Bolton RP, Culshaw MA. Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile. Gut 1986;27:1169-1172. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1433873/pdf/gut00370-0065.pdf
  4. Daly JJ, Chowdary KV. Pseudomembranous colitis secondary to metronidazole. Dig Dis Sci 1983;28:573-4.
  5.  Carmeli Y, Eliopoulos GM, Samore MH. Antecedent treatment with different antibiotic agents as a risk factor for vancomycin-resistant enterococcus. Emerg Infect Dis 2002;8:802-807. https://wwwnc.cdc.gov/eid/article/8/8/pdfs/01-0418.pdf
  6. Salvatore M, Meyers BR. Metronidazole. In Mandel, Douglas, Bennett’s Principles and Practice of Infectious Diseases-7th Ed. p. 419-426. 2010, Churchill Livingstone, Philadelphia.

 

 

Is oral metronidazole (Flagyl®) effective in reducing the risk of recurrent Clostridium difficile infection (CDI)?

Is there any utility in screening for methicillin-resistant Staphylococcus aureus (MRSA) colonization when selecting empiric antibiotic therapy for skin and soft tissue infections (SSTIs)?

FA Manian MD, MPH, , Leave a comment

The reported rates of MRSA colonization in patients with community-associated MRSA SSTI have been surprisingly low, ranging from 7% to 41% (55% among hospitalized patients) (1), making it difficult to exclude MRSA as a causative pathogen based on a negative screening test alone.

The concordance between what grows from the nares and what is isolated from the SSTI site is also far from ideal.  Among patients with methicillin-sensitive S. aureus (MSSA) SSTI , 12% may be colonized with MRSA and of those with MRSA SSTI, 32% may be colonized with MSSA (1). 

In the absence of a reliable screening test to help us select an empiric antibiotic regimen in patients with SSTI, we should pay special attention to the clinical features of the SSTI.  Empiric MRSA antibiotic coverage should be considered for patients with purulent SSTIs, deep tissue infections, or those with systemic toxicity( 2), irrespective of colonization status.  

References

1. Ellis MW, Schlett CD, Millar EV, et al. Prevalence of nasal colonization and strain concordance in patients with community-associated Staphylococcus aureus skin and soft tissue infections. Infect Control Hosp Epidemiol 2014;35:1251-6. https://www.ncbi.nlm.nih.gov/pubmed/25203178  

2. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:e18-55.2. https://www.ncbi.nlm.nih.gov/pubmed/21208910 

 

Is there any utility in screening for methicillin-resistant Staphylococcus aureus (MRSA) colonization when selecting empiric antibiotic therapy for skin and soft tissue infections (SSTIs)?

Should we routinely cover for methicillin-resistant Staphylococcus aureus (MRSA) when treating patients for cellulitis?

FA Manian MD, MPH, , , Leave a comment

No! Despite the MRSA epidemic, β-hemolytic streptococci (BHS) are still considered the primary cause of non-purulent cellulitis (e.g. without abscesses, or infections involving deep soft tissues, wounds, or ulcer).

In a prospective study of patients admitted to the hospital for “diffuse,  non-culturable “(i.e. many of our patients), most had serological evidence of acute  BHS, and >95% responded to a β-lactam antibiotic treatment (1) . 

The current Infectious Diseases Society of America guidelines do not endorse empiric coverage of  MRSA for non-purulent cellulitis,  unless there is systemic toxicity or poor response to  β-lactam  monotherapy (2). More specifically, the guidelines recommend a  β-lactam antibiotic for treatment of non-purulent cellulitis in hospitalized patients with modification to MRSA coverage if no clinical response.

One advantage to β-lactam monotherapy is the ease of switch to an equivalent oral antibiotic (e.g. cephalexin) when transitioning from parenteral antibiotic therapy.  

References

1. Jeng A, Beheshti M, Li J, et al. The role of beta-hemolytic streptococci in causing diffuse nonculturable cellulitis: a prospective investigation. Medicine (Baltimore) 2010;89:217-26. https://www.ncbi.nlm.nih.gov/pubmed/20616661

2. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:e18-55. https://www.ncbi.nlm.nih.gov/pubmed/21208910

 

Should we routinely cover for methicillin-resistant Staphylococcus aureus (MRSA) when treating patients for cellulitis?

Should corticosteroids (CS) be routinely considered in the treatment of hospitalized patients with community-acquired pneumonia (CAP)?

FA Manian MD, MPH, , Leave a comment

A recent systematic review on the subject concluded that for hospitalized adults with CAP, systemic CS may reduce mortality by about ~3% (primarily in severe CAP), mechanical ventilation need by ~5%, and hospital stay by ~1 day (1). But determining who might benefit the most and at what CS dosage regimen without undue risk of side effects (e.g. hyperglycemia) may be tricky.  

A randomized control trial of patients with CAP on prednisone 50 mg daily x 7d (vs placebo) showed a significant shorter time to clinical stability (3 vs 4.4 d) and higher in-hospital hyperglycemia in the CS group (2).; this study was not powered to detect significant difference in mortality, however.  Less treatment failure with adjunctive CS but without impact on mortality was recently reported in a small study involving patients with serum CRP >150 mg/L (i.e. high inflammatory state) (3).

Fortunately, a multicenter trial (ESCAPe, Extended Steroid in CAP) is currently underway. In the meantime, before considering CS, we need to be confident of the diagnosis and severity of CAP, its potential adverse effects in individual patients, and the appropriateness of the antibiotic (s) on board.

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References

1. Siemieniuk RAC, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis. Ann Intern Med 2015;165:519-528. https://www.ncbi.nlm.nih.gov/pubmed/26258555

2. Blum CA, Nigro N, Briel M. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multi-centre, double-blind randomized, placebo-controlled trial. Lancet 2015;385:1511-1518. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62447-8/abstract

3. Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA 2015;313:677-86. https://www.ncbi.nlm.nih.gov/pubmed/25688779

 

Should corticosteroids (CS) be routinely considered in the treatment of hospitalized patients with community-acquired pneumonia (CAP)?

How should minimum inhibitory concentrations (MICs) reported by the microbiology lab be interpreted?

FA Manian MD, MPHLeave a comment

MIC is the minimum inhibitory concentration of an antibiotic (AB) that inhibits an organism invitro, By itself, MIC does NOT take into account the pharmacokinetics (PKs) or pharmacodynamics (PDs) of an AB which ultimately determine its susceptibility cut-offs.

“Susceptible” implies that the isolate is inhibited by the usually achievable concentrations of the AB when recommended dosage is followed for the specific site of infection. “Intermediate” suggests that the MIC approaches usually attainable blood and tissue levels but at less- than-desirable expected clinical response rates, and generally should be avoided when an alternative AB exists. “Resistant” refers to isolates that are not inhibited by the usually achievable AB concentrations. In the absence of PK/PD data, comparing MICs can be misleading (i.e. lower MIC does not necessarily suggest a more potent AB).

Short answer: you can generally skip the MIC data and make antibiotic selection based on susceptibility report alone.

Please also see a related pearl on P4P at https://pearls4peers.com/2016/12/19/when-should-i-pay-attention-to-the-minimum-inhibitory-concentration-mic-of-an-antibiotic-despite-the-lab-reporting-it-to-be-in-the-susceptible-range/

 

Reference

Turnridge J, Paterson DL. Setting and revising antibacterial susceptibility breakpoints. Clin Microbiol Rev 2007;20:391-408. https://www.ncbi.nlm.nih.gov/pubmed/17630331  

How should minimum inhibitory concentrations (MICs) reported by the microbiology lab be interpreted?

What is the mechanism of fluoroquinolone(FQ)-induced tendonopathy?

FA Manian MD, MPH, , , Leave a comment

An uncommon but serious side effect of FQs (e.g. ciprofloxacin, levofloxacin, and moxifloxacin) is Achilles tendon rupture.   A putative mechanism for this adverse effect is inhibition of host mitochondrial components (1).

Recall that mitochondria, the ATP-generating machine within our cells, are thought to be archaic bacterial ancestors that have co-evolved with us. Quinolones are inhibitors of bacterial gyrases and topoisomerases and also appear to be associated with DNA degradation of the mitochondria in some mammalian cells. In vitro, FQs appear to have a tropism for mitochondria in tenocytes, chondrocytes, and osteoblasts.  

Thus, it is possible that at least in some patients (e.g. those ≥60 years of age, on higher doses of corticosteroids, or with several renal disease or other idiosyncratic factors) the mitochondrial damage is sufficient to cause serious injury to the Achilles tendon (2).

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1. Barnhill AE, Brewer MT, Carlson SA. Adverse effects of antimicrobials via predictable or idiosyncratic inhibition of host mitochondrial components. Antimicrob Agents Chemother 2012;56:4046-4051.

2. Shakibaei M, Stahlmann R. Ultrastructure of Achilles tendon from rats after treatment with fleroxacin. Arch Toxicol 2001;75:97-102.

What is the mechanism of fluoroquinolone(FQ)-induced tendonopathy?

In hospitalized patients with community-acquired pneumonia (CAP), has empiric treatment with beta-lactam plus macrolide or a quinolone been shown to be superior to beta-lactam monotherapy ?

FA Manian MD, MPH, , , , , , , Leave a comment

Actually no!

In fact, a 2015 study of CAP from Netherlands, published in New England Journal of Medicine, demonstrated that empiric treatment with beta-lactam monotherapy was not inferior to strategies using a beta-lactam-macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality, or length of hospital stay (1). To help exclude Legionella pneumonia (often accounting for <5% of CAP[2]), urine Legionella antigen was routinely performed in this study.

So once Legionella has been reasonably excluded, unless suspicion for other atypical causes of CAP (i.e. Mycoplasma pneumoniae or Chlamydophila pneumoniae) remains high, empiric monotherapy with a beta-lactam (e.g. ceftriaxone) may be just as effective in many cases of CAP.

References

1. Postma DF1, van Werkhoven CH, van Elden LJ, et al. CAP-START Study Group Antibiotic treatment strategies for community-acquired pneumonia in adults. N Engl J Med. 2015;372:1312-23.  https://www.ncbi.nlm.nih.gov/pubmed/25830421  

2. von Baum H, Ewig S, Marre R, et al. Competence Network for Community Acquired Pneumonia Study Group. Community-acquired Legionella pneumonia: new insights from the German competence network for community acquired pneumonia. Clin Infect Dis 2008;46:1356. https://www.ncbi.nlm.nih.gov/pubmed/18419436

Contributed by Jessica A. Hennessey, MD, PhD, Mass General Hospital, Boston, MA

In hospitalized patients with community-acquired pneumonia (CAP), has empiric treatment with beta-lactam plus macrolide or a quinolone been shown to be superior to beta-lactam monotherapy ?

My patient with foot osteomyelitis due to methicillin-sensitive Staphylococcus aureus (MSSA) is ready to go home on IV antibiotic therapy. Is daily ceftriaxone therapy an appropriate option?

FA Manian MD, MPH, , , , Leave a comment

Yes, it appears to be!  Ceftriaxone is active against MSSA and may be an option for treatment of infections due to this organism at least in certain situations.  

In a retrospective study comparing ceftriaxone to oxacillin for osteoarticular infections due to MSSA, there was no difference in treatment success at 3-6 and > 6 months following completion of IV antibiotics; oxacillin had to be discontinued more often due to toxicity, however (1).    

In another retrospective study comparing cefazolin to ceftriaxone for treatment of MSSA infections ( ≥50% of patients with osteomyelitis),  favorable outcomes, adverse events and complications were similar between the 2 groups (2). 

Several other studies have reported no significant difference in treatment failure between cefazolin and ceftriaxone in MSSA infections (3).  A smaller retrospective study, however, reported higher rate of treatment failure (defined to include unplanned extension of parenteral therapy) with ceftriaxone in MSSA bacteremia without finding any difference in time to blood culture clearance, or rates of persistent bacteremia, relapse after treatment, achievement of source control, mortality or readmission (3).

References

1. Wieland BW, Marcantoni JR, Bommarito KM, et al. A retrospective comparison of ceftriaxone versus oxacillin for osteoarticular infections due to methicillin-susceptible Staphylococcus aureus. Clin Infect Dis 2012;54:585-590. https://www.ncbi.nlm.nih.gov/pubmed/22144536

2.  Winans SA, Luce Am, Hasbun R. Outpatient parenteral antimicrobial therapy for the treatment of methicillin-susceptible Staphylococcus aureus: a comparison of cefazolin and ceftriaxone. Infection 2013;41:769-774. https://www.ncbi.nlm.nih.gov/pubmed/23686435

3. Carr DR, Stiefel U, Bonomo RA, etal. A comparison of cefazolin versus ceftriaxone for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia in a tertiary care VA medical center. Open Forum Infectious Diseases, Volume 5, Issue 5, 1 may 2018, ofy089. https://academic.oup.com/ofid/article/5/5/ofy089/4999397

 

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My patient with foot osteomyelitis due to methicillin-sensitive Staphylococcus aureus (MSSA) is ready to go home on IV antibiotic therapy. Is daily ceftriaxone therapy an appropriate option?