Uncomplicated urinary tract infection

In uncomplicated UTIs, Escherichia coli is the most common pathogen, typically being isolated from more than 80% of outpatients with acute uncomplicated cystitis across various regions of the world . Staphylococcus saprophyticus accounts for 5% to 15% of these infections and is especially prevalent in younger women who have cystitis. Causative pathogens in the remaining 5% to 10% of cases include aerobic gram-negative rods, such as Klebsiella and Proteus spp, and enterococci. The range of pathogens associated with acute uncomplicated pyelonephritis is similar to that seen in acute uncomplicated cystitis .

The North American Urinary Tract Infection Collaborative Alliance study from 2003 and 2004 determined resistance rates in E coli . Resistance to ampicillin was 38%, 21% to trimethroprim/sulfamethoxazole, 1% to nitrofurantoin, and 6% to ciprofloxacin . The ARESC Project, an international surveillance study that involved nine countries in Europe and Brazil, monitored antimicrobial susceptibility of uropathogens from 2004 to 2006. The aim of the study was to rank the current usefulness of drugs used in the therapy of this condition ; 3018 uropathogens, including 2315 E coli pathogens (76.7%), 322 other gram-negative pathogens (10.7%), and 406 gram-positive pathogens (13.5%) were evaluated. Susceptibility in E coli was less common towards ampicillin (mean 41.1%; range 32.6%–60.8%), cotrimoxazole (70.5%; 54.5%–87.7%), and cefuroxime (81.0%; 74.5%–91.3%). Ciprofloxacin susceptibility was 91.3%, but the figures for Spain and Italy were substantially lower (88.1% and 87.0%, respectively). Fosfomycin, mecillinam, and nitrofurantoin were the agents with the highest susceptibility rates (98.1%, 95.8%; and 95.2%, respectively).

Complicated urinary tract infection

The bacterial spectrum of complicated, nosocomial UTI is much more heterogeneous and comprises a wide range of gram-negative and -positive species. In the latest report from the SENTRY antimicrobial surveillance program 2000, the bacterial spectrum of hospitalized urologic patients in North America consisted of 47% E coli , 13% Enterococcus spp, 11% Klebsiella spp, 8% Pseudomonas spp, 5% Proteus mirabilis , 4% Enterobacter spp, and 3% Citrobacter spp (less frequently isolated species not mentioned) . Antibiotic resistance in E coli for ampicillin was 37%, 4% for ciprofloxacin, and 23% for trimethoprim/sulfamethoxazole; in Pseudomonas aeruginosa resistance for ciprofloxacin was 29%. Vancomycin resistance in Enterococcus spp was 7%, and the presence of extended-spectrum β-lactamase in E coli was 4% and 19% in Klebsiella spp.

Antibiotics that act on the DNA

Fluoroquinolones act directly on the bacterial DNA. The target structures are the bacterial topoisomerases II and IV, which introduce so-called negative “supercoils” into DNA and achieve a higher order by coiling. Four molecules of the quinolone substance form a ternary complex together with topoisomerases and DNA, which causes DNA double-strand breakage .

Sulfonamides, such as sulfamethoxazole, lead to the formation of ineffective forms of tetrahydrofolate (dihydropteroic acid) from para-aminobenzoic acid and pteridine by substituting para-aminobenzoic acid. Tetrahydrofolate physiologically is further catalyzed to dihydrofolic acid (folate), which is further catalyzed into tetrahydrofolic acid by dihydrofolate-reductase.

Pyrimethamines, such as trimethoprim, competitively inhibit the bacterial dihydrofolate-reductase. Purine synthesis is inhibited .

Antibiotics that inhibit protein synthesis

The aminoglycosides bind irreversibly to distinct parts of the 30S and 50S subunits of the bacterial ribosomes. Consequently, the amino acid translocation is inhibited by preventing the binding of elongation factor G. The elongation stage in bacterial translation is inhibited . Oxazolidinones bind to the 23S rRNA of the 50S subunit of the bacterial ribosomes and inhibit the formation of the 70S initiation complex. The initiation stage of bacterial translation is inhibited .

Antibiotics that inhibit peptidoglycan synthesis

β-Lactams inhibit the last stage of peptidoglycan synthesis. They bind to penicillin-binding proteins (PBP), which act as enzymes (eg, transpeptidases, carboxypeptidases, and endopeptidases) in the formation and preservation of parts of the bacterial cell wall. The affinity of distinct penicillins for certain PBPs might be different. Penicillins inhibit the process of cross-linking of the long polysaccharide chains by short polypeptides. They are analogous substrates of the acyl- d -alanyl- d -alanine moieties and acylate transpeptidases. Consequently, the peptidoglycan wall is weakened . The glycopeptide antibiotics bind to the acyl- d -alanyl- d -alanine moieties and inhibit the process of transglycosilation of the peptidoglycan wall .

Fosfomycin acts as an analog of phosphoenolpyruvate and forms a covalent bond with the active site cysteine residue (Cys 115) of UDP- n -acetylglucosamine enolpyruvyltransferase (MurA), which is a key enzyme of peptidoglycan synthesis . It inhibits cell wall synthesis other than β-lactam antibiotics.

Antibiotics that act on the DNA

Fluoroquinolones act directly on the bacterial DNA. The target structures are the bacterial topoisomerases II and IV, which introduce so-called negative “supercoils” into DNA and achieve a higher order by coiling. Four molecules of the quinolone substance form a ternary complex together with topoisomerases and DNA, which causes DNA double-strand breakage .

Sulfonamides, such as sulfamethoxazole, lead to the formation of ineffective forms of tetrahydrofolate (dihydropteroic acid) from para-aminobenzoic acid and pteridine by substituting para-aminobenzoic acid. Tetrahydrofolate physiologically is further catalyzed to dihydrofolic acid (folate), which is further catalyzed into tetrahydrofolic acid by dihydrofolate-reductase.

Pyrimethamines, such as trimethoprim, competitively inhibit the bacterial dihydrofolate-reductase. Purine synthesis is inhibited .

Antibiotics that inhibit protein synthesis

The aminoglycosides bind irreversibly to distinct parts of the 30S and 50S subunits of the bacterial ribosomes. Consequently, the amino acid translocation is inhibited by preventing the binding of elongation factor G. The elongation stage in bacterial translation is inhibited . Oxazolidinones bind to the 23S rRNA of the 50S subunit of the bacterial ribosomes and inhibit the formation of the 70S initiation complex. The initiation stage of bacterial translation is inhibited .

Antibiotics that inhibit peptidoglycan synthesis

β-Lactams inhibit the last stage of peptidoglycan synthesis. They bind to penicillin-binding proteins (PBP), which act as enzymes (eg, transpeptidases, carboxypeptidases, and endopeptidases) in the formation and preservation of parts of the bacterial cell wall. The affinity of distinct penicillins for certain PBPs might be different. Penicillins inhibit the process of cross-linking of the long polysaccharide chains by short polypeptides. They are analogous substrates of the acyl- d -alanyl- d -alanine moieties and acylate transpeptidases. Consequently, the peptidoglycan wall is weakened . The glycopeptide antibiotics bind to the acyl- d -alanyl- d -alanine moieties and inhibit the process of transglycosilation of the peptidoglycan wall .

Fosfomycin acts as an analog of phosphoenolpyruvate and forms a covalent bond with the active site cysteine residue (Cys 115) of UDP- n -acetylglucosamine enolpyruvyltransferase (MurA), which is a key enzyme of peptidoglycan synthesis . It inhibits cell wall synthesis other than β-lactam antibiotics.

Alterations of permeability and efflux mechanisms

Intrinsic resistance of gram-negative bacteria against macrolides is caused by impermeability of the outer membrane to these hydrophilic compounds. Enterococcus spp show decreased permeability toward aminoglycosides and are intrinsically low level resistant to aminoglycosides. On the other hand, permeability can be altered by altered production of outer membrane proteins (eg, E coli) , leading to decreased susceptibility to fluoroquinolones or β-lactam antibiotics.

Efflux mechanisms potentially can pump antibiotic substances, such as quinolones or tetracyclines, out of the cell. Thus far, five superfamilies of efflux transport systems are known: ATP-binding cassette (ABC), major facilitator superfamily (MFS), resistance-nodulation division (RND), small multidrug resistance (SMR), and multidrug and toxic compound extrusion (MATE) families. Efflux systems are responsible for low-level resistance and may promote selection of mutations responsible for higher level resistance .

A powerful efflux mechanism in Pseudomonas spp is one constitutively produced system (MexAB-OprM: RND superfamily) that generates intrinsic resistance against most β-lactams, quinolones, tetracycline, chloramphenicol, trimethoprim, and sulfamethoxazole. On the other side, nonconstitutive systems (ie, MexCD-OprJ, MexEF-OprN) can be expressed by mutation. In other species, such as Staphylococcus aureus , coagulase-negative staphylococci, or Citrobacter freundii, efflux is also an important mechanism of clinical resistance against quinolones .

Alterations of target structures

Target structures can be altered by mutations, acquisition of genetic material, or inactivation of antibiotics by enzymatic modification .

Inactivation of antibiotics

β-Lactamases are enzymes produced by bacteria that inactivate β-lactam antibiotics by cleavage of the β-lactam ring. More than 200 different enzymes have been identified thus far, and the substrates comprise penicillins, cephalosporins, or other β-lactam antibiotics. Resistance to penicillin is mediated by a penicillinase that hydrolyses the β-lactam ring of penicillin. More than 90% of S aureus isolates are penicillinase producers. This resistance can be overcome with penicillinase-stable penicillins, such as oxacillin . A frequent resistance mechanism in E coli and Proteus spp is production of TEM-1, a plasmid-mediated β-lactamase that is inhibitor resistant . It confers resistance in strains that have acquired the resistance plasmid (eg, to ampicillin and ampicillin/sulbactam).

The SHV-1 β-lactamase of Klebsiella pneumoniae and the K1 β-lactamase of Klebsiella oxytoca are chromosomally encoded but inhibitor sensitive . It encodes intrinsic resistance in all Klebsiella strains, for example, to ampicillin but not to ampicillin/sulbactam. Enterobacter spp possess a chromosomally encoded ampC β-lactamase that inactivates penicillins and cephalosporins and is not inhibitor sensitive. Resistance, however, results only if the β-lactamase is hyperproduced. Ampicillin is a strong inducer of this enzyme. Mezlocillin is less suitable to induce hyperproduction of this β-lactamase .

The genus Citrobacter comprises such species ( Citrobacter freundii group) that behave like Enterobacter spp and those that produce other less extended β-lactamases ( Citrobacter koseri / diversus ). In Proteus spp, a wide diversity of β-lactamases can be produced, serving as a possible β-lactamase–encoding reservoir . Plasmid-encoded, extended-spectrum β-lactamase production is important in K pneumoniae , E coli , Proteus spp, and C diversus . Other resistances, such as aminoglycoside and trimethoprim-sulfamethoxazole resistance, are often cotransferred on the same plasmid .

Enterobacter spp, C freundii , Serratia spp, K oxytoca , M morganii, and Providencia spp possess a chromosomally encoded β-lactamase that can be induced to hyperproduction by mutation or depression . This hyperproduced β-lactamase also causes a resistance phenotype, comparable to extended-spectrum β-lactamase, although no extended-spectrum β-lactamase is produced. Other inactivating enzymes can inactivate aminoglycosides or macrolides. The expression of a bifunctional aminoglycoside inactivating enzyme, 6′- n -aminoglycoside acetyltransferrase-2′-O-aminoglycoside phosphotransferase, is the most important mechanism of high-level aminoglycoside resistance in Staphylococcus spp and Enterococcus spp . Enterococci are intrinsically low-level resistant; in the case of high-level resistance, aminoglycoside combination therapy would be ineffective.

Among Enterobacteriaceae, combinations of gentamicin-modifying enzymes are common. In Pseudomonas spp the combination of gentamicin-modifying enzymes and decreased permeability is common . Bacteria exhibit an enormous repertoire of different resistance mechanisms. Unspecific mechanisms, such as reduced permeability or efflux, alter the tolerance to antibiotic substances less than specific mechanisms, such as inactivation of the antibiotic. The antibiotic spectrum targeted is much more extensive, however. On the other hand, unspecific mechanisms also can be induced by nonantibiotic substances, such as salicylates. Low-level resistance can be conferred and give bacteria a selection advantage.

Fosfomycin

Fosfomycin tromethamine is the oral applicable salt of fosfomycin. Fosfomycin (cis-(1R,2S)-epoxypropylphosphonic acid) is an oxirane antibiotic unrelated to other substances and is produced as a secondary metabolite by Streptomyces and Pseudomonas spp . (S)-2-hydroxypropylphosphonic acid epoxidase catalyzes the epoxide ring closure of (S)-2-hydroxypropylphosphonic acid to form fosfomycin in an iron-redox mechanism . Hydroxypropylphosphonic acid epoxidase represents a new subfamily of non-haem mononuclear iron enzymes that respond to its substrates with a conformational change that protects the radical-based intermediates formed during catalysis . Fosfomycin is active against gram-positive and -negative bacteria but shows decreased activity against Morganella morganii , Proteus vulgaris , P aeruginosa, and E faecium . Despite many years of use, fosfomycin continues to be characterized by a low incidence of E coli– resistant strains (1%–3%) worldwide . Fosfomycin trometamol has retained its activity against quinolone-resistant strains of E coli, and cross-resistance with other classes of antimicrobial agents is currently not a problem . It is less active against coagulase-negative staphylococci. A meta-analysis of 2048 patients showed that overall single-dose therapy with fosfomycin trometamol exhibits equivalent results as short-term therapy with comparative agents, however . Fosfomycin trometamine has approximately 40% oral bioavailability , and urine recovery is approximately 40% .

Nitrofurantoin

Nitrofurantoin belongs to the nitroheterocyclic compounds. The nitrogroup coupled onto the heterocyclic furan ring represents the proper site of effect. The nitrogroup is inactive and must be activated by microbial nitroreductases after penetration into the microbial cell . Nitrofurantoin interferes with carbohydrate metabolism. The antibacterial activity is generally weak, but in urine the activity against E coli and some other enterobacteria, such as like Klebsiella spp and Enterobacter spp, is sufficient in the treatment of uncomplicated UTI. There is no activity against Proteus spp or P aeruginosa . Low levels of resistance to nitrofurantoin among uropathogens ( E coli <2%) has revived interest in this agent. In women at risk for infection with resistant bacteria or in the setting of a high prevalence of TMP-SMX–resistant uropathogens, nitrofurantoin also can be used. Its use for the empiric treatment of uncomplicated cystitis is supportable from a public health perspective in an attempt to decrease uropathogen resistance because it does not share cross-resistance with more commonly prescribed antimicrobial agents , but short-term therapy is not well established with nitrofurantoin . It is also less active against gram-negative pathogens other than E coli . Urinary excretion is 40% .

In a multicenter clinical trial, single-dose fosfomycin tromethamine, 3 g, was compared with a 7-day course of nitrofurantoin monohydrate/macrocrystal, 100 mg, for the treatment of acute uncomplicated lower UTI in female patients . Seven hundred forty-nine patients were enrolled in the study (375 received fosfomycin and 374 received nitrofurantoin). Overall, 94% of pretreatment isolates were susceptible to fosfomycin and 83% were susceptible to nitrofurantoin. Bacteriologic cure rates at 5 to 11 days after initiation of treatment were 78% and 86% for fosfomycin and nitrofurantoin, respectively ( P = .02). 1 week after treatment they were 87% and 81% for fosfomycin and nitrofurantoin, respectively ( P = .17). Clinical success rate (cure and improvement) was higher than 80% in both treatment groups. Bacteriologic and clinical cure rates were comparable in both treatment groups .

Pivmecillinam

Pivmecillinam is a unique β-lactam antimicrobial agent that has been used for the treatment of acute uncomplicated UTI for more than 20 years. Pivmecillinam is the pro-drug (ester) of mecillinam with specific and high activity against gram-negative organisms such as E coli and other Enterobacteriaceae . Mecillinam is an amidine derivative of the penicillin group. Pivmecillinam is also well absorbed orally . Since its introduction it has been used widely for the treatment of acute uncomplicated cystitis, primarily in the Nordic countries. The level of resistance has remained low; approximately less than 2% of E coli community isolates are resistant to mecillinam . A comparative study (pivmecillinam versus norfloxacin) showed similar outcomes with 7 days of pivmecillinam, 200 mg, twice daily or 3 days of norfloxacin, 400 mg, twice daily when pooling bacteriologic outcomes from two studies . The in vitro minimal inhibitory concentration for S saprophyticus is 8 to 64 mg/L, so these bacteria are considered resistant. The cure rates for this organism were reported between 73% and 92%, however. Pivmecillinam can be considered effective for treatment of cystitis caused by S saprophyticus .

Nicolle and colleagues evaluated the efficacy of a 3-day regimen of pivmecillinam, 400 mg, twice daily versus norfloxacin, 400 mg, twice daily in 954 premenopausal women with symptoms of acute cystitis. Bacteriologic cure at early posttherapy follow-up was achieved in 75% of patients who took pivmecillinam and 91% of patients who took norfloxacin ( P < .001). Clinical cure/improvement 4 days after initiation of therapy was observed in 95% of women who received pivmecillinam and 96% who received norfloxacin ( P = .39). In women younger than 50 years, early clinical cure rates were 84% for pivmecillinam and 88% for norfloxacin ( P = .11). Adverse effects were similar for both regimens, and there was no evidence of the emergence of increasing resistance with therapy. The authors concluded that short-course therapy with norfloxacin was superior to that with pivmecillinam in terms of bacteriologic outcome; however, clinical outcome in young women was comparable .