Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/04/15 For personal use only.
Review
Could chloramphenicol be used against ESKAPE pathogens? A review of in vitro data in the literature from the 21st century Expert Rev. Anti Infect. Ther. 12(2), 249–264 (2014)
Rok Cˇivljak*1, Maddalena Giannella2, Stefano Di Bella2 and Nicola Petrosillo2 1 University of Zagreb School of Medicine, “Dr. Fran Mihaljevic´” University Hospital for Infectious Diseases, Mirogojska 8, 10 000 Zagreb, Croatia 2 Second Division of Infectious Diseases, “Lazzaro Spallanzani” National Institute for Infectious Diseases, Via Portuense 292, 00149 Rome, Italy *Author for correspondence: Tel.: +38 512 826 222; +38 591 401 2547 Fax: +38 514 678 235 [email protected]
The widespread use of antibiotics has been associated with the emergence of antimicrobial resistance among bacteria. ‘ESKAPE’ (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acintobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) pathogens play a major role in the rapidly changing scenario of antimicrobial resistance in the 21st century. Chloramphenicol is a broad spectrum antibiotic that was abandoned in developed countries due to its association with fatal aplastic anemia. However, it is still widely used in the developing world. In light of the emerging problem of multi-drug resistant pathogens, its role should be reassessed. Our paper reviews in vitro data on the activity of chloramphenicol against ESKAPE pathogens. Susceptibility patterns for Gram-positives were good, although less favorable for Gram-negatives. However, in combination with colistin, chloramphenicol was found to have synergistic activity. The risk-benefit related to chloramphenicol toxicity has not been analyzed. Therefore, extra precautions should be taken when prescribing this agent. KEYWORDS: antimicrobials . chloramphenicol . combination therapy . ESKAPE pathogens . resistance
The widespread use of antibiotics has been associated with the emergence of antimicrobial resistance among bacteria. The growing number of elderly patients and patients undergoing surgery, transplantation and chemotherapy will produce an even greater number of individuals at risk of infections from multidrug-resistant (MDR) pathogens [1]. Among MDRs, the so-called ‘ESKAPE’ (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) pathogens have been increasingly recognized as threatening microorganisms mostly because of their ability to ‘escape’ the effects of most antimicrobial agents [2]. Data from the CDC show rapidly increasing rates of infection due to methicillinresistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium [3]. Furthermore, several highly resistant Gramnegative pathogens, such as Acinetobacter www.expert-reviews.com
10.1586/14787210.2014.878647
species, MDR Pseudomonas aeruginosa and carbapenem-resistant Klebsiella species are emerging as significant pathogens in both developed and developing countries [4–6]. Therapeutic options for these pathogens are so limited that clinicians are forced to use older, previously discarded drugs, such as colistin and fosfomycin, which have significant limitations and for which there is a lack of robust data to guide the selection of dosage regimens or duration of therapy [7]. Another old antibiotic that is potentially active against some MDR pathogens is chloramphenicol. Chloramphenicol is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines. As it is both cheap and easy to manufacture, it is frequently an antibiotic of choice in the developing world. Chloramphenicol was originally derived from the bacterium Streptomyces venezuelae, isolated by Ehrlich in 1947 and introduced
2014 Informa UK Ltd
ISSN 1478-7210
249
Review
ˇ ivljak, Giannella, Di Bella & Petrosillo C
Objective definition
520 records identified through database searching
407 studies excluded (not satisfying inclusion criteria)
Research criteria
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/04/15 For personal use only.
113 studies satisfying inclusion criteria
Enterococcus faecium 24 studies
>3.000 tested isolates
MRSA
We reported the activity of chloramphenicol as the rate of strains found to be susceptible and considered all nonsusceptible bacteria, including those with an intermediate MIC, as resistant.
44 studies
Klebsiella pneumoniae 16 studies
Acinetobacter baumannii 7 studies
Pseudomonas aeruginosa 16 studies
Enterobacter spp. 6 studies
15.167 tested isolates
1.822† tested isolates
1.208‡ tested isolates
503 tested isolates
660 tested isolates
All the relevant studies published in the English language on the MEDLINE database from 1 January 2000 to 31 December 2012 were reviewed. NonEnglish-language studies were only included when the data were accessible from the abstract or tables. Case reports or case series with fewer than five pathogens assayed for chloramphenicol susceptibility were not analyzed. Results
Figure 1. Flow diagram of the study. † In 3 studies, Klebsiella spp. was assumed as K. pneumoniae. ‡ In 2 studies, Acinetobacter spp. was assumed as A. baumannii. MRSA: Methicillin-resistant Staphylococcus aureus.
into clinical practice under the trade name Chloromycetin [8]. Since it functions by inhibiting bacterial protein synthesis, chloramphenicol has a very broad spectrum of activity against Gram-positive bacteria (including most strains of MRSA), Gram-negative bacteria and anaerobes [9]. Chloramphenicol has been abandoned in developed countries due to association with serious adverse effects including irreversible and fatal aplastic anemia [10,11]. However, it is still largely used in the developing world, despite discovery of new antimicrobials with better activity and fewer side effects, to treat certain types of serious bacterial infections when other antibiotics cannot be used. We performed a systematic literature review on the in vitro activity of chloramphenicol against clinical ESKAPE pathogens in order to assess whether this antibiotic could play a role in the therapeutic management of infections due to such MDR microorganisms. Methods Review objective
The objective of this review is to assess the in vitro activity of chloramphenicol, alone or in combination with other antimicrobials, against ESKAPE pathogens.
The flow diagram of the systematic research process is shown in FIGURE 1. Overall, 113 studies were analyzed. Most of these included Gram-positive pathogens: 24 for E. faecium and 44 for MRSA, whereas the number of studies assessing chloramphenicol activity against Gram-negative bacteria was limited: 16 for K. pneumoniae, 7 for A. baumannii, 16 for P. aeruginosa and 6 for Enterobacter spp. Below, we report the results according to ESKAPE bacterial species. Enterococcus faecium
As shown in TABLE 1, 24 studies that reported the activity of chloramphenicol against E. faecium met our criteria [12–35]. The susceptibility rates varied from 0 to 100% and were over 80% in most of the studies. The susceptibility of the vancomycin-resistant and vancomycin-susceptible strains to chloramphenicol was similar. In fact, the susceptibility to chloramphenicol seems not to be affected by the vancomycin resistance of E. faecium strains. As a proof of this consideration, in a study conducted in North America on 616 vancomycin-resistant E. faecium strains, 99.7% of the isolates were susceptible to chloramphenicol [17]. In
Review
Could chloramphenicol be used against ESKAPE pathogens? A review of in vitro data in the literature from the 21st century Expert Rev. Anti Infect. Ther. 12(2), 249–264 (2014)
Rok Cˇivljak*1, Maddalena Giannella2, Stefano Di Bella2 and Nicola Petrosillo2 1 University of Zagreb School of Medicine, “Dr. Fran Mihaljevic´” University Hospital for Infectious Diseases, Mirogojska 8, 10 000 Zagreb, Croatia 2 Second Division of Infectious Diseases, “Lazzaro Spallanzani” National Institute for Infectious Diseases, Via Portuense 292, 00149 Rome, Italy *Author for correspondence: Tel.: +38 512 826 222; +38 591 401 2547 Fax: +38 514 678 235 [email protected]
The widespread use of antibiotics has been associated with the emergence of antimicrobial resistance among bacteria. ‘ESKAPE’ (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acintobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) pathogens play a major role in the rapidly changing scenario of antimicrobial resistance in the 21st century. Chloramphenicol is a broad spectrum antibiotic that was abandoned in developed countries due to its association with fatal aplastic anemia. However, it is still widely used in the developing world. In light of the emerging problem of multi-drug resistant pathogens, its role should be reassessed. Our paper reviews in vitro data on the activity of chloramphenicol against ESKAPE pathogens. Susceptibility patterns for Gram-positives were good, although less favorable for Gram-negatives. However, in combination with colistin, chloramphenicol was found to have synergistic activity. The risk-benefit related to chloramphenicol toxicity has not been analyzed. Therefore, extra precautions should be taken when prescribing this agent. KEYWORDS: antimicrobials . chloramphenicol . combination therapy . ESKAPE pathogens . resistance
The widespread use of antibiotics has been associated with the emergence of antimicrobial resistance among bacteria. The growing number of elderly patients and patients undergoing surgery, transplantation and chemotherapy will produce an even greater number of individuals at risk of infections from multidrug-resistant (MDR) pathogens [1]. Among MDRs, the so-called ‘ESKAPE’ (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) pathogens have been increasingly recognized as threatening microorganisms mostly because of their ability to ‘escape’ the effects of most antimicrobial agents [2]. Data from the CDC show rapidly increasing rates of infection due to methicillinresistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium [3]. Furthermore, several highly resistant Gramnegative pathogens, such as Acinetobacter www.expert-reviews.com
10.1586/14787210.2014.878647
species, MDR Pseudomonas aeruginosa and carbapenem-resistant Klebsiella species are emerging as significant pathogens in both developed and developing countries [4–6]. Therapeutic options for these pathogens are so limited that clinicians are forced to use older, previously discarded drugs, such as colistin and fosfomycin, which have significant limitations and for which there is a lack of robust data to guide the selection of dosage regimens or duration of therapy [7]. Another old antibiotic that is potentially active against some MDR pathogens is chloramphenicol. Chloramphenicol is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines. As it is both cheap and easy to manufacture, it is frequently an antibiotic of choice in the developing world. Chloramphenicol was originally derived from the bacterium Streptomyces venezuelae, isolated by Ehrlich in 1947 and introduced
2014 Informa UK Ltd
ISSN 1478-7210
249
Review
ˇ ivljak, Giannella, Di Bella & Petrosillo C
Objective definition
520 records identified through database searching
407 studies excluded (not satisfying inclusion criteria)
Research criteria
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/04/15 For personal use only.
113 studies satisfying inclusion criteria
Enterococcus faecium 24 studies
>3.000 tested isolates
MRSA
We reported the activity of chloramphenicol as the rate of strains found to be susceptible and considered all nonsusceptible bacteria, including those with an intermediate MIC, as resistant.
44 studies
Klebsiella pneumoniae 16 studies
Acinetobacter baumannii 7 studies
Pseudomonas aeruginosa 16 studies
Enterobacter spp. 6 studies
15.167 tested isolates
1.822† tested isolates
1.208‡ tested isolates
503 tested isolates
660 tested isolates
All the relevant studies published in the English language on the MEDLINE database from 1 January 2000 to 31 December 2012 were reviewed. NonEnglish-language studies were only included when the data were accessible from the abstract or tables. Case reports or case series with fewer than five pathogens assayed for chloramphenicol susceptibility were not analyzed. Results
Figure 1. Flow diagram of the study. † In 3 studies, Klebsiella spp. was assumed as K. pneumoniae. ‡ In 2 studies, Acinetobacter spp. was assumed as A. baumannii. MRSA: Methicillin-resistant Staphylococcus aureus.
into clinical practice under the trade name Chloromycetin [8]. Since it functions by inhibiting bacterial protein synthesis, chloramphenicol has a very broad spectrum of activity against Gram-positive bacteria (including most strains of MRSA), Gram-negative bacteria and anaerobes [9]. Chloramphenicol has been abandoned in developed countries due to association with serious adverse effects including irreversible and fatal aplastic anemia [10,11]. However, it is still largely used in the developing world, despite discovery of new antimicrobials with better activity and fewer side effects, to treat certain types of serious bacterial infections when other antibiotics cannot be used. We performed a systematic literature review on the in vitro activity of chloramphenicol against clinical ESKAPE pathogens in order to assess whether this antibiotic could play a role in the therapeutic management of infections due to such MDR microorganisms. Methods Review objective
The objective of this review is to assess the in vitro activity of chloramphenicol, alone or in combination with other antimicrobials, against ESKAPE pathogens.
The flow diagram of the systematic research process is shown in FIGURE 1. Overall, 113 studies were analyzed. Most of these included Gram-positive pathogens: 24 for E. faecium and 44 for MRSA, whereas the number of studies assessing chloramphenicol activity against Gram-negative bacteria was limited: 16 for K. pneumoniae, 7 for A. baumannii, 16 for P. aeruginosa and 6 for Enterobacter spp. Below, we report the results according to ESKAPE bacterial species. Enterococcus faecium
As shown in TABLE 1, 24 studies that reported the activity of chloramphenicol against E. faecium met our criteria [12–35]. The susceptibility rates varied from 0 to 100% and were over 80% in most of the studies. The susceptibility of the vancomycin-resistant and vancomycin-susceptible strains to chloramphenicol was similar. In fact, the susceptibility to chloramphenicol seems not to be affected by the vancomycin resistance of E. faecium strains. As a proof of this consideration, in a study conducted in North America on 616 vancomycin-resistant E. faecium strains, 99.7% of the isolates were susceptible to chloramphenicol [17]. In
