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We will be provided with an authorization token (please note: passwords are not shared with us) and will sync your accounts for you. The increasing prevalence of hospital and community-acquired infections caused by multidrug-resistant (MDR) bacterial pathogens is limiting the options for effective antibiotic therapy. Antimicrobial resistance is one of the greatest threats to human health worldwide (Walker et al., 2009). Bacterial strains resistant to newly developed antibiotics have emerged recurrently (Long and Vester, 2012). This review aims at providing a non-exhaustive collection of microbiological and clinical data on potentially useful older antibiotics.
The incidence of infections caused by MDR Gram-negative bacteria has increased worldwide over the last decade. Colistin, synthesized by Paenibacillus polymyxa subspecies colistinus, was discovered in 1949 (Komura and Kurahashi, 1979).
Colistin was recommended by the most recent American Thoracic Society Guidelines as a therapeutic option for the treatment of ventilator-associated pneumonia (VAP) caused by MDR Gram-negative organisms (American Thoracic Society, and Infectious Diseases Society of America, 2005). One worrisome problem is the emergence of colistin resistance in KPC-producing bacteria, as seen in up to 20% of isolates in some countries (Kontopidou et al., 2014).
Fosfomycin is an antimetabolite inhibitor that prevents the formation of N-acetylmuramic acid, an essential precursor of peptidoglycan-chain formation in the bacterial wall.
The use of intravenous fosfomycin formulations for the treatment of infections caused by MDR bacteria has shown a high rate of clinical success (Table 1).
One of the first studies on the broad use of fosfomycin in Spain noted development of resistance in 3% of the 959 cases in total but in 10% of the 86 P. The widespread and long-term use of pivmecillinam for UTIs in Scandinavian countries is well documented, with no indication of any significant increase in mecillinam resistance in these countries (Graninger, 2003). Developed and first marketed in the UK in the 1980s, temocillin was quickly abandoned because its lack of activity against Gram-positive organisms, anaerobes and Pseudomonas aeruginosa was perceived as a major limitation (Slocombe et al., 1981). Based on temocillin's relatively narrow spectrum, it is appropriate for use in microbiologically directed therapy, particularly for the UTIs caused by confirmed ESBL producers. The first reported case of breakthrough bacteremia during temocillin treatment occurred in a patient with renal dysfunction and probable insufficient dosing (1 g once daily) (Gupta et al., 2009). Nitrofurantoin (NFT), which is a synthetic antimicrobial derived from furan by the addition of a nitro group and a side chain containing hydantoin, was introduced into clinical practice in its microcrystalline form in 1952.
Chlortetracycline, from which tetracycline was derived in 1953, is produced by Streptomyces aureofaciens. Tetracyclines have been evaluated as an effective oral treatment option for patients with SSTIs caused by MRSA (Ruhe and Menon, 2007). Recently, a MDR strain of CA-MRSA genotype USA300 has emerged, with plasmids that confer resistance to tetracycline, macrolides, and clindamycin (Diep et al., 2008). Chloramphenicol, the active compound of which is produced by Streptomyces venezuelae, inhibits protein synthesis by binding reversibly to the 50S subunit of the bacterial ribosome. Chloramphenicol was found to be effective against vancomycin-resistant Enterococcus faecium (VREf), with bacteriostatic activity (Norris et al., 1995). Clindamycin is produced by chemical modification of lincomycin, which was isolated in 1962 from Streptomyces lincolnensis (McGehee et al., 1968). Staphylococcus aureus beta hemolysis on sheep blood agar and appearance of beta-hemolytic colonies of staph aureus.
Methicillin-resistant Staphylococcus aureus (MRSA, orange) is a Gram-positive, round (coccus) bacterium, shown here on a filamentous surface.
This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button. This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience. Moreover, this alarming spread of antimicrobial resistance has not been paralleled by the development of novel antimicrobials.
It dramatically reduces the probability of effectively treating infections and increases the morbidity and mortality associated with common bacterial diseases (Klevens et al., 2007). Therefore, antimicrobial resistance presents an ongoing challenge that requires a multifaceted approach including (i) biomedical innovation, (ii) improved surveillance of antibiotic consumption and antimicrobial-resistance rates, (iii) prevention of health-care-associated infections and transmission of multidrug-resistant (MDR) bacteria and environmental dissemination, (iv) rapid microbiological diagnosis, and (v) curtailed clinical and veterinary misuse.
Infections caused by multidrug-resistant Gram-negative bacteria successfully treated with old antibiotics.
The spread of colistin resistance may be related to the extensive use of this drug in empiric and targeted treatment and also due to the ecological effect of topical use in selective decontamination protocols in intensive-care units (Oostdijk et al., 2013). It was first identified in Spain in 1969 in the fermentation broths of several strains of Streptomyces sp. This drug for oral use is well tolerated and can be given in patients with impaired renal function, but its usefulness is limited by its lack of activity against Gram-positive organisms and Pseudomonas aeruginosa (Dewar et al., 2014).
Indeed, Pivmecillinam is a prodrug and thus has a low impact on the endogenous microflora (Sullivan et al., 2001).
In this setting, temocillin might be used as an alternative to carbapenems (Livermore and Tulkens, 2009), as temocillin is ecologically safer. NDM-1 and OXA-48 carbapenemases also confer resistance to temocillin (Livermore et al., 2011).
Since the macrocristalline form was developed, the previously frequent gastrointestinal side effects have become less common, giving this drug a good safety profile (Cunha, 1989).

Infections caused by multidrug-resistant Gram-positive bacteria successfully treated with old antibiotics. Trimethoprim is a tetrahydrofolate reductase inhibitor that, when added to sulfamethoxazole, provides a second-step block in the folate biosynthetic pathway (Proctor, 2008). There was also no evidence for selection of organisms with increased resistance to other antimicrobials in relation to increased TMP-SMZ use (Wood et al., 2012). In the late 1960s, the second-generation long-acting compounds doxycycline (in 1966) and minocycline (in 1967) were semi-synthetically derived and commercialized. Minocycline, associated with surgical drainage, resulted in rapid resolution of MRSA-associated cutaneous abscesses (Cunha, 2013). A retrospective analysis of the outcomes of six patients with bacteremia caused by VREf also showed that this agent was effective (Ricaurte et al., 2001). This drug works by binding to the 50S ribosomal subunit of rRNA and inhibiting the initiation of peptide-chain synthesis. It is still one of the five most common causes of nosocomial infections, often causing postsurgical wound infections. Since the discovery of penicillin in 1928, antimicrobial resistance has been linked to antibiotic use.
It is alarming that although bacterial resistance continues to emerge, the rate at which antibiotics are being developed is decreasing.
Their mechanism of action includes attachment to the outer cell membrane of Gram-negative bacteria, leading to membrane-permeability changes and cell death. But, the most common mechanism of colistin resistance is modification of LPS (Park et al., 2011). These rates of emergence appear to be stable over time in countries where fosfomycin use has been used for decades (Falagas et al., 2008). Since its introduction in the 1970s, it has been widely used for the treatment of acute lower UTIs, primarily in the Nordic countries (Graninger, 2003). Although poorly studied, mecillinam resistance have been shown to be caused by mutations in the genes affecting the elongation process of the bacteria, and associated with substantial fitness cost in vitro to the resistant E. Temocillin is mainly excreted renally and therefore requires dosage adjustment in patients with renal impairment. Research in Belgium suggests that temocillin is also effective in severe infections such as VAP if the organism appears susceptible in vitro (De Jongh et al., 2008).
Although poorly studied, the main mechanisms of resistance to temocillin are efficient efflux or reduced PBP binding that could explain high MICs to Pseudomonas aeruginosa (Livermore and Tulkens, 2009). Currently, NFT is recommended as a first-line treatment for uncomplicated UTIs by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases (Gupta et al., 2011).
Resistance among these pathogens to first-line agents such as methicillin and vancomycin continues to rise, while isolates with reduced susceptibility to newer agents, including linezolid, are also emerging (Patel et al., 2013).
Moreover, a recent report has shown high rates of susceptibility to TMP-SMZ (94%) in community-acquired MRSA (CA-MRSA) isolates (Chen et al., 2006). Tetracyclines are a class of broad-spectrum bacteriostatic antibiotics active against Gram-positive and Gram-negative bacteria, as well as against intracellular organisms. Doxycycline has intrinsic activity against enterococci, including VRE, and has been stated as an option for oral treatment of VRE cystitis (Heintz et al., 2010). Studies relating the MICs of tetracycline, doxycycline, and minocycline to the presence of these genes suggest a crossresistance between doxycycline and tetracycline in all strains of S.
Several anecdotic reports of effective treatment with chloramphenicol in MDR bacterial severe infections been reported (Table 2). According to the SENTRY Antimicrobial Surveillance Program, the rate of chloramphenicol resistance among E. Although concern about Clostridium difficile colitis has limited the use of clindamycin, it remains an important antibiotic in the treatment of severe anaerobic infections. In this context, the rational use of older antibiotics could represent an alternative to the treatment of MDR bacterial pathogens. In this context, the reintroduction of previously used antibiotics active against MDR bacteria represents a new alternative for the control of antimicrobial resistance (Pulcini et al., 2012).
Colistin was initially used in Japan and in Europe during the 1950s and was used in the United States in the form of colistimethate sodium in 1959 (Reed et al., 2001).
As it chromosomal, it is not prone to spread horizontally, but relies exclusively on clonal expansion. Fosfomycin has a broad spectrum of antimicrobial activity, including a rapid bactericidal effect against several Gram-negative and Gram-positive aerobic bacteria (Falagas et al., 2009).
But, fosfomycin resistance is in many bacterial species caused by plasmid-mediated fosfomycin genes (Suárez and Mendoza, 1991).
It is also a potential alternative treatment option for mild-to-moderate UTIs caused by KPC-producing Enterobacteriaceae (Adams-Haduch et al., 2009).
Chromosomally resistance-conferring mutations have been identified in the nsfA and nsfB genes that encode oxygen-insensitive nitroreductases, and associated with substantial fitness cost in vitro to the resistant E. Only one randomized, prospective trial compared TMP-SMZ to vancomycin for the treatment of S. These characteristics, together with the low cost and rarity of major side effects, have made tetracyclines a widely used class of antibiotics (Nelson and Levy, 2011). Bacteremia caused by VRE has been successfully treated with doxycycline (Moreno et al., 1994). Furthermore, chloramphenicol has good oral bioavailability and excellent tissue penetration.

As old antibiotics have rarely been subjected to contemporary drug-development procedures or compared to commonly used antibiotics, they are less considered in practice guidelines.
Intravenous formulations of colistin and polymyxin B were gradually abandoned in most parts of the world in the early 1980s because of the reported high incidence of nephrotoxicity (Biswas et al., 2012). Several other mechanisms have been suggested, most of which involve changes in the outer membrane (Li et al., 2006).
Unlike many alternatives, fosfomycin formulations are generally well tolerated, with minimal toxicity (excepting thrombophlebitis when administered via peripheral venous catheter). Treatment with pivmecillinam was successful in a case of relapsing pyelonephritis caused by ESBL-producing E. Notably, it lacks activity against Pseudomonas aeruginosa, Serratia marscecens, and Proteus mirabilis (Cunha et al., 2011). But this drug has also been considered to favor the selection and spread of resistant microorganisms on a population level. However, it should be noted that these drugs are contraindicated in pregnant woman, neonates, and young children because of their particular effects on skeletal growth and dentition (Demers et al., 1968).
Caution is therefore recommended in the use of tetracyclines, given its ability to induce resistance in areas in which strains carry the inducible resistance genes (Schwartz et al., 2009). Its spectrum of activity is broad, including Gram-positive and Gram-negative bacteria, anaerobes, spirochetes, rickettsiae, chlamydiae, and mycoplasma. This complex ecological phenomenon depends on individuals, bacterial strains, and mechanisms of resistance (Andersson and Hughes, 2010).
Indeed, most of the drug is excreted in the urine, and dose adjustment is required in patients with renal failure. Paenibacillus polymyxa subspecies colistinus, also produces colistinase, which inactivates colistin. These properties lead to a decreased potential for the selection of clinically relevant resistance. In this study, TMP-SMZ was inferior to vancomycin only for the treatment of methicillin-susceptible S. One study found that the mechanism was the selection for a class 1 integron, resulting in MDR Enterobacteriaceae in the intestinal flora of children (Van der Veen et al., 2009).
Besides, long-term use of tetracyclines in veterinary medicine has been associated with resistance emergence in commensal Escherichia coli in veal calves (Bosman et al., 2014). But, soon after chloramphenicol was released in the United States in 1949, reports linked this drug to rare but potentially lethal hematological side effects that restricted its use as last-resort therapy.
We will review here the successful treatment of MDR bacterial infections with the use of old antibiotics and discuss their place in current practice. Old and new antibiotics vary in their impact on the emergence and spread of resistant bacteria (Sullivan et al., 2001). Recent studies have shown that better management of intravenous formulations led to considerably less toxicity than was reported in old studies (Falagas and Kasiakou, 2005). However, enzymatic resistance of bacteria to colistin has not been reported in clinical practice (Falagas and Kasiakou, 2005). Chromosomally resistant mutants have also been well described (Suárez and Mendoza, 1991). Currently, the use of pivmecillinam as first-line treatment for uncomplicated UTIs is recommended by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases (Gupta et al., 2011). Knowing that integrons are transferable genetic elements capable of expressing multiple resistance genes, the use of TMP-SMZ should be cautiously monitored regarding this potential collateral damage. However, as it is readily available and inexpensive, it is still used in many resource-limited settings (Falagas and Kopterides, 2007). Chloramphenicol use for the treatment of VRE infections should take into account the potential for the development of resistance (Lautenbach et al., 2004).
Interestingly, decades of colistin use in veterinary medicine has not been associated with an increased resistance prevalence in commensal Escherichia coli isolated from animals (Wasyl et al., 2013). Further studies are needed to update its toxicity risk with more accurate dosing and monitoring (Lautenbach et al., 1998).
Indeed, high levels of resistance likely due to the widespread and unregulated use in resource-limited settings have been reported, particularly for the treatment of severe disease caused by MDR Salmonella sp. Although promising results have been reported, more data are needed to establish its appropriate role in mechanically-ventilated patients (Michalopoulos and Falagas, 2014). Regarding Acinetobacter baumanii, colistin resistance has emerged worldwide (Cai et al., 2012).
Then, when used to treat systemic infections, intravenous fosfomycin may be a component of combination therapy administered (Pogue et al., 2011).
Although it associated with impaired virulence (Rolain et al., 2011), combination therapy might be the best antimicrobial strategy. Most resistance mechanisms are efflux pumps such as floR and cmlA, as well as inactivating enzymes such as chloramphenicol acetyl-transferase cat1 (Frye and Jackson, 2013). Besides, optimization of colistin use should prevent the emergence of species naturally resistant to colistin, such as S. Furthermore, the association between fluoroquinolone use and chloramphenicol-resistant VRE emergence is of concern, since fluoroquinolone use has dramatically increased in recent years (Gould et al., 2004).

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