Aetiology and antibiotic resistance issues regarding urological procedures Ercole Concia, Anna Maria Azzini Infectious Diseases Unit, Department of Pathology and Diagnostics, University Hospital of Verona, Italy There are specific indications in urological procedures [transurethral resection of the prostate (TURP), transurethral resection of the bladder (TURB), endoscopic procedures, and all interventions classified as contaminated or dirty] requiring antibiotic prophylaxis. Most postoperative infections are caused by enterococci of the Gram-positive strains and Enterobacteriaceae of the Gram-negative ones. As reported by the European Center for Disease Prevention and Control (ECDC), there are increasing numbers of antibiotic-resistant pathogens. Most Enterococcus faecium strains are ampicillin-resistant and the Enterobacteriaceae have a high prevalence of extended-spectrum beta-lactamase (ESBL) producers, for which the cephalosporins and penicillins are not drugs of choice. In recent years, there are also increasing numbers of Gram-negative strains that are able to produce carbapenemases and for which the only therapeutic options are gentamicin, tigecycline and colistin. An alternative to these drugs, from a prophylactic point of view, is fosfomycin, an old antibiotic that maintains bactericidal activity against both enterococci and multidrug-resistant Enterobacteriaceae. Available in an oral formulation as trometamol salt, fosfomycin reaches high plasma and urine concentrations, and is therefore a possible alternative to other drugs both for therapy and urological prophylaxis. Keywords: Urological surgery, Antibiotic prophylaxis, Drug resistance, Fosfomycin trometamol
Introduction In the last 10 years, a lot of efforts have been made to bring to light suitable indications for antibiotic prophylaxis in the field of urology. Starting in the year 2000, many articles have been published by both national research groups (for example, the German Society of Urology,1 the French Association of Urology2) and international groups in Europe (for example, the European Association of Urology3). The aim of antibiotic prophylaxis in urological surgery is to prevent local and systemic infections caused by uropathogens, such as urosepsis, pyelonephritis, prostatitis, epididymitis, as well as those of the surgical wound. To achieve this goal, it is necessary not only to be knowledgeable of the cardinal principles of antibiotic prophylaxis, but also of the urology patient’s characteristics, and of the risks associated with the urological procedure to be undergone.
N
N
Antibiotic Prophylaxis
N
Timing: The time range in which it is reasonable to administer prophylaxis must not be more than 2 hours after the initiation of surgery.4–6 If an oral antibiotic is used (and this must be only if the molecule has excellent bioavailability), it must be
Correspondence to: E. Concia, Sezione di Malattie Infettive, Dipartimento di Patologia, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico ‘G. B. Rossi’, Piazzale Ludovico Antonio Scuro 10, 37124 Verona, Italy. Email: [email protected]
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ß 2014 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1120009X14Z.000000000233
N
administered an hour prior to surgery. An intravenous antibiotic can be administered contemporarily with the anaesthesia. Duration: in most cases, prophylaxis can be given as a single preoperative dose. Very long surgical interventions are an exception to this rule, requiring further doses of antibiotic in relation to the half-life of the molecule used, as well as in patients at high risk (see below and Table 1). In any case, prophylaxis should not exceed 72 hours post-surgery. Antibiotic choice: although there are various guidelines about antibiotic prophylaxis, it is of fundamental importance that the choice of drug be based on local epidemiology. Other than this, it is also necessary to consider other factors such as the presence of previous pathogens isolated at the surgical site, the type of surgery to be carried out, and the intrinsic characteristics of the patient. The most commonly used antibiotics for urological surgical prophylaxis are cotrimoxazole, betalactamase-inhibiting penicillins, II generation cephalosporins, and aminoglycosides. It should be emphasized that the broad-spectrum molecules should be reserved for therapy, rather than prophylaxis. Type of surgical procedure: as anticipated, prophylaxis has a dual aim: to prevent infection of the surgical wound and to prevent the occurrence and/or diffusion of acute urogenital or systemic infection after surgery. Although, as in the first case, the infectious risk is well classified according to the Cruse and Foord7 scheme (Table 2), to accomplish the second aim, it is necessary to evaluate the patient’s risk factors, especially in relation to the type and duration of surgery.
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Table 1 Infection risk factors General risk factors
Risk factors associated with type of surgery
Advanced age (.65 years old) Diabetes mellitus Smoker Malnutrition/obesity Immunocompromised Presence of distal infectious foci
N
Recent hospitalization or long period of preoperative hospitalization Known microbial colonization of surgical site History of recurrent urinary tract infection (UTI) Obstruction/urinary tract calculi Surgery involving intestine Urinary catheter/drainage
Risk factors: although not readily recognizable, risk factors, including general ones and those correlated with an increased infectious risk, are fundamental to the preoperative evaluation of the patient. Table 1 summarizes the risk factors most often correlated with enhanced perioperative risk of infection.
International multicentre studies have identified the three major risk factors correlated with the development of postoperative infections and they are: the presence of urinary catheter and the relative time of its permanence, history of continuing episodes of urinary tract infection (UTI), and long preoperative hospital stay.8 In these cases, antibiotic prophylaxis is strongly recommended.
Indications for Prophylaxis To better evaluate the various indications for use of antibiotic prophylaxis in urological surgery, it is
necessary to categorize the various interventions according to risk, distinguishing between diagnostic and therapeutic procedures, and of these, between endourological/ESWL surgery and laparoscopic or laparotomic surgery. Laparotomy will not be further discussed in this article since the indications for antibiotic prophylaxis are founded on infectious risk correlated with abdominal surgery. Table 3 summarizes the main urological surgical procedures divided into diagnostic or therapeutic categories. A. Diagnostic procedures: needle biopsy of the prostate9–18 is the only procedure for which there is undoubted evidence of the necessity of using antibiotic prophylaxis. In all the other diagnostic procedures, routine use of prophylaxis is not recommended. Prophylaxis should be used only for patients with bacteriuria, recent UTI, and/or those bearing a urinary catheter19–31 (Table 4).
Table 2 The Cruse and Foord classification of urological procedures Classification
Characteristics
Prophylaxis
Clean (1–4% risk)
Intact urinary tract Complete asepsis maintenance No interruption of surgical procedure Operation on uninflamed tissue
No
Clean-contaminated (4–10% risk)
Surgical intervention on urinary tract or intestinal segment with little or no diffusion of their contents in surgical field No or minimal interruption of surgical procedure
Yes
Contaminated (10–15% risk)
Contamination of operative field by modest quantity of faecal/urinary material Surgery on inflamed tissue Presence of recent and open wound at surgical site Major interruption of surgical procedure Perforation of abdominal viscera Presence of previous post-traumatic wound Surgery on infected tissue
Therapy
Dirty (15–40% risk)
Therapy
Endourological procedure Cystoscopy Urodynamic tests Extracorporeal shockwave lithotripsy (ESWL) Transurethral resection of bladder tumour (TURB) of small dimension TURB of large or necrotic tumours Transurethral resection of the prostate (TURP) Ureterorenoscopy Ureteral endoscopic lithotripsy Uncomplicated percutaneous lithotripsy ESWL Prostatic needle biopsy during recent UTI TURP during recent UTI Complicated percutaneous lithotripsy Proximal calculus lithotripsy
Procedures on infected calculi
Table 3 Urological surgical procedures subdivided into diagnostic or therapeutic categories A Diagnostic procedures Prostatic biopsy Cystoscopy Urodynamic tests Radiological examinations of urinary tract Ureteroscopy
B Endourological procedures TURP TURB Mini-invasive prostatic surgery Uroscopic treatment of calculi, tumours Percutaneous surgery of calculi, tumours
ESWL
Note: ESWL: extracorporeal shockwave lithotripsy; TURP: transurethral resection of the prostate; TURB: transurethral resection of the bladder.
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Table 4 Indications for antibiotic prophylaxis in endoscopic urological procedures Procedure
Most frequently isolated pathogens
Diagnostic procedures Prostatic needle biopsy Cystoscopy
Ureteroscopy
Endoscopic surgery ESWL Ureteroscopic lithotripsy/ Extracorporeal shockwave lithotripsy TURP TURB
Enterobacteriaceae Enterobacteriaceae Enterococci Staphylococci Enterobacteriaceae Enterococci Staphylococci
Yes No, unless patient bears a urinary catheter, has bacteriuria or history of continuing UTI
Enterobacteriaceae Enterococci Enterobacteriaceae Enterococci Staphylococci Enterobacteriaceae Enterococci Enterobacteriacea Enterococci
No, unless patient bears internal stent or calculi are presumed to be infected No, unless calculi are of large dimension and/or are in proximal site and/or cause obstruction of urinary tract, or if patient has history of continuing UTI Yes
B. Endoscopic and/or ESWL therapeutic procedures: also in this category, the evidence for the utility of antibiotic prophylaxis varies from procedure to procedure. Even though many studies recommend antibiotic prophylaxis for TURP,32–34 this should be reserved only for patients with specific risk factors as with the other procedures (Table 4):
N N
N
TURB:20,35,36 antibiotic prophylaxis should be reserved to patients with one or more risk factors listed in Table 1 or with large dimension tumours, especially if necrotic core is present. Ureteroscopy/percutaneous removal of calculi: antibiotic prophylaxis should be reserved for those patients with large stones (due to increased risk of bleeding), especially if located at the intrarenal level or in the most proximal part of the excretory canals.37–43 ESWL: antibiotic prophylaxis must be reserved for patients bearing intrarenal stents (such as the double J) and/or those with presumed infected stones.44–48
Table 4 summarizes the indications for antibiotic prophylaxis in diagnostic procedures and endoscopic surgery. C. Laparoscopic/laparotomic procedures: as already mentioned, these procedures are being listed for thoroughness, but will not be further discussed since indications for their antibiotic prophylaxis are strictly correlated with the surgical site and relative infectious risk. The reference classification proposed by Cruse and Foord for clean, clean-contaminated, contaminated, and dirty surgical interventions is useful (Table 2). Clean operations include all those where the urinary tract is not opened, and therefore, the infectious risk is minimal and routine use of antibiotic prophylaxis is unnecessary.49–51 Clean-contaminated operations include those in which the urinary tract and/or part of the intestine are involved, carried out after adequate preparation of the patient and with negligible amount of spillage of faecal/urinary content in the operative field. For surgery in this field, a single dose of antibiotic prophylaxis administered preoperatively, is indicated.52–54 Contaminated operations involving the intestine with partial spillage of
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No, unless patient bears a urinary catheter, has bacteriuria or history of continuing UTI
No, unless tumours are large and/or necrotic
its contents in the operative field, and dirty operations, that is, all those conducted in the absence of preoperative preparation (in other words, urgent operations) or following visceral perforation and spillage in the abdomen or surgery of clearly infected tissue, all necessitate antibiotic therapy (rather than prophylxis) which should be started before surgery and be continued afterwards, according to the duration and specific type of infection.
Table 2 summarizes the various characteristics of urological procedures according to the Cruse and Foord classification in order to determine the risk of infection from the surgery.
Epidemiology of Antibiotic-Resistant Bacteria From what has been discussed previously, it is apparent that the majority of bacteria responsible for postoperative urological infections are Enterobacteriaceae, Pseudomonas aeruginosa, eneterococci, and less frequently, staphylococci. In recent years, unfortunately, there has been the tendency for almost all the abovementioned bacteria to become resistant to numerous classes of antibiotics, making not only therapy difficult but also prophylaxis. Starting from the Gram-positive bacteria, the last report from the European Center for Disease Prevention and Control (ECDC) in 2011 documents that about 80% of Enterococcus faecium strains in Italy are resistant or intermediately resistant to aminopenicillins, and about 50% are highly resistant to gentamicin. On the other hand, they remain highly sensitive to vancomycin, with less than 5% of strains resistant. Enterococcus faecalis, on the contrary, remain highly sensitive to the aminopenicillins with only 10% resistant and 3% resistant to vancomycin, whereas more than 40% are highly resistant to gentamicin. Tables 5 and 6 describe the sensitivity of E. faecium and E. faecalis to the aminopenicillins and vancomycin between 2009 and 2011.
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Table 5 E. faecium and E. faecalis susceptibility to the aminopenicillins in Italy, 2009–2011
E. faecium Sensitive (%) Intermediate (%) Resistant (%) E. faecalis Sensitive (%) Intermediate (%) Resistant (%)
2009
2010
2011
40.1 0 59.9
30.4 0 69.6
17.3 0.8 81.9
80.1 0 19.9
86.8 0 13.2
89.4 0.2 10.4
Approximately 40% of Staphylococcus aureus were found to be methicillin-resistant and this frequency was substantially constant between 2009 and 2011 (Table 7). Resistance of P. aeruginosa in 2011 to piperacillintazobactam and the anti-Pseudomonas carbapenems was about 20%, tending to improve between 2009 and 2011. The number of strains resistant to ceftazidime remained stable at about 15%, whereas there was a decided improvement in sensitivity to the fluoroquinolones, with 26% of strains resistant in 2011 compared to 42% in 2009. Only 5% of strains were resistant to amikacin. Table 8 describes the situation of P. aerugionosa susceptibility to these various classes of antibiotics in Italy between 2009 and 2011. Taking into consideration the Enterobacteriaceae, the 2011 report documents that 40% of Escherichia coli is resistant to fluoroquinolones, with a tendency to worsen from previous years; about 20% is stably resistant to the III generation cephalosporins; 18% is resistant to aminoglycosides and tending to worsen, and 0.2% is resistant to the carbapenems (Table 9). On the other hand, the situation of susceptibility of Klebsiella pneumoniae to antibiotics documented in the same period indicates a clear worsening for all the tested molecules, especially resistance to fluoroquinolones, III generation cephalosporins (around 45%), whereas 35% were found resistant to the aminoglycosides Table 6 E. faecium and E. faecalis vancomycin in Italy, 2009–2011
E. faecium Sensitive (%) Intermediate (%) Resistant (%) E. faecalis Sensitive (%) Intermediate (%) Resistant (%)
susceptibility
2009
2010
2011
95.2 0.5 4.3
95.6 0.5 3.9
95.8 0 4.2
96.3 1.1 2.6
97.2 0.6 2.2
96.9 0.2 2.9
S. aureus Sensitive (%) Intermediate (%) Resistant (%)
2010
2011
62.6 0 37.4
63.5 0 36.5
61.8 0 38.2
Table 8 P. aeruginosa susceptibility antibiotics in Italy, 2009–2011
to
P. aeruginosa Fluoroquinolones Sensitive (%) Intermediate (%) Resistant (%) Ceftazidime Sensitive (%) Intermediate (%) Resistant (%) Piperacillin-tazobactam Sensitive (%) Intermediate (%) Resistant (%) Carbapenems Sensitive (%) Intermediate (%) Resistant (%) Amikacin Sensitive (%) Intermediate (%) Resistant (%)
2009
2010
2011
54.9 3.1 42
63.2 5.8 31
70.1 3.8 26.1
72 11.6 16.5
76.2 6.1 17.7
80.2 3.6 16.2
75.1 0.5 24.3
78.6 0.2 21.2
76.4 1.7 21.9
65.4 3.7 30.9
73.7 4.3 22
74.1 5.4 20.6
91.7 2.1 6.2
87.9 2.8 9.3
89.7 4.7 5.6
various
and 25% to the carbapenems. About 33% of multidrugresistant strains (MDR) were concomitantly resistant to the III generation cephalosporins, fluoroquinolones, and aminoglycosides (Table 10). The principal problem connected with the exponential increase in K. pneumoniae resistance in the last 10 years in various countries, including Italy (Fig. 1 and Table 11),55,56 involves strains which produce carbapenemases. These can be of various types (VIM, OXA, KPC) and have slightly different substrates (Table 12). The most problematic are strains producing KPC, which are phenotypically resistant not only to carbapenems but also to the III and IV generation cephalosporins, aztreonam, and the fluoroquinolones. Generally, the only molecules to which K. pneumoniae is still sensitive or intermediately sensitive are tigecycline, colistin, the aminoglycosides (especially gentamicin), and fosfomycin, making not only therapy very difficult, but also prophylaxis in the genitourinary tract.
to
Table 7 S. aureus susceptibility to methicillin in Italy, 2009–2011 2009
Aetiology and antibiotic resistance issues
Table 9 E. coli susceptibility to various antibiotics in Italy, 2009–2011 E. coli
2009
Fluoroquinolones Sensitive (%) 63.7 Intermediate (%) 0.1 Resistant (%) 36.2 III generation cephalosporins Sensitive (%) 82 Intermediate (%) 1 Resistant (%) 17 Carbapenems Sensitive (%) 100 Intermediate (%) 0 Resistant (%) 0 Aminoglycosides Sensitive (%) 86.6 Intermediate (%) 0.9 Resistant (%) 12.5
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2011
60.6 0.2 39.2
58.8 0.6 40.5
78.4 0.5 21
79.2 1 19.8
99.8 0 0.1
99.8 0 0.2
83.5 1 15.5
79.4 2.3 18.3
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Figure 1 Epidemiological distribution of K. pneumoniae strains producing carbapenemases.55
Antimicrobial Agents To correctly select an antimicrobial agent for use in prophylaxis, it is necessary to consider its spectrum of activity necessary to combat the bacteria most frequently responsible for infection following urological surgery. Although the great majority of postoperative infections are caused by bacteria of the Enterobacteriaceae family and the enterococci, infections due to the staphylococci may occur in those procedures involving artificial sphincters or prosthetic implants. The most frequently used antibiotics for prophylaxis and their relative dosages are summarized in Table 13. Given the previously reported epidemiological data on antimicrobial resistance, it is obvious that it is Table 10 K. pneumoniae susceptibility antibiotics in Italy, 2009–2011
to
K. pneumoniae
2011
2009
2010
Fluoroquinolones Sensitive (%) 78.9 60.3 Intermediate (%) 0.7 1.1 Resistant (%) 2.4 38.5 III generation cephalosporins Sensitive (%) 62.1 52.8 Intermediate (%) 0.7 0.7 Resistant (%) 37.1 46.5 Carbapenems Sensitive (%) 98.7 84.1 Intermediate (%) 0 0.7 Resistant (%) 1.3 15.2 Aminoglycosides Sensitive (%) 79 65.7 Intermediate (%) 1.6 5.2 Resistant (%) 19.4 29.1 MDR (fluoroquinoloneszIII generation cephalosporinszaminoglycosides) Total (%) 12.6 26.3
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52.3 2 45.7 52.3 1.8 45.9 70.4 2.9 26.7 59.8 5.6 34.6
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necessary to limit the use, especially for prophylaxis, of wide-spectrum agents. On the contrary, it is suggested to utilize efficacious antibiotics which are active locally on the urinary tract as ‘antiseptics’, thus reducing the risk of selecting strains which are antibiotic-resistant. As mentioned above, urinary and prostatic infections caused by multidrug-resistant Enterobacteriaceae (MDR-GNB) represent a growing problem. Especially the resistance to the fluoroquinolones is worrying, considering their important role as perioperative prophylaxis for ultrasound-guided transrectal prostatic biopsy and for treatment of prostatitis.57 Several studies have documented the persistence of the susceptibility of many of the Enterobacteriaceae to fosfomycin. Fosfomycin is actually bactericidal against numerous Gram-negative and Gram-positive bacterial strains, due to precocious inhibition of peptidoglycan synthesis by blocking muramic acid synthesis.58–61 Among the Gram-positive bacteria, fosfomycin is particularly active against methicillin-resistant and sensitive S. aureus, penicillin- and cephalosporin-resistant Streptococcus pneumoniae, and Enterococcus spp. including those strains resistant to vancomycin. It is also active against Gram-negative bacteria, including E. coli, Proteus mirabilis, K. pnemoniae, Enterobacter spp., Serratia spp., Shigella spp., Salmonella typhi, and N. meningitidis. It has only moderate activity against P. aeruginosa and is inactive against A. baumannii.60 It is hypothesized that the low level of crossresistance to fosfomycin by the extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae is tied to a different mechanism of transmission. Resistance to the beta-lactam antibiotics, commonly used for treatment of infections caused by this family
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Table 11 Resistance mechanisms in Enterobacteriaceae strains resistant to carbapenems isolated in Italy (15 May–30 June 2011)56 Carbapenemases Species E. coli K. pneumoniae K. oxytoca E. cloacae Other Total
Isolates
Total (%)
5 234 1 15 15 270
2 (40%) 223 (95.3%) 1 (100) 3 (20%) 0 229 (84.8%)
KPC
Non-carbapenemases
VIM-1
1 204 0 0 0 205
OXA-48
1 16 1 3 0 21
of pathogens, is mediated by plasmids, whereas fosfomycin resistance is transmitted through chromosomes.62 Furthermore, fosfomycin remains efficacious against strains contemporarily resistant to the III/IV generation cephalosporins and the fluoroquinolones, thanks to its particular chemical structure and specific mechanism of action. Proof of this emerges from the ECDC 2011 report, indicating that about 59 000 strains of ESBL-producing E. coli, contemporarily resistant to quinolones and aminoglycosides, retained their susceptibility to fosfomycin. Another characteristic of fosfomycin is its capacity to intervene on bacterial adhesion to uroepithelial cells. This adhesion is due to interaction between bacterial wall fimbria and specific receptor structures of the epithelial cell membrane, and represents a fundamental pathogenetic moment, necessary until the bacteria is able to resist urinary flow and successively to invade the bladder wall. Many studies63,64 have demonstrated
Total (%)
0 3 0 0 0 3
3 11 0 12 15 41
(60%) (4.7%) (80%) (100%) (15.2%)
the efficacy of fosfomycin trometamol in reducing this bacterial adhesion to the urothelium, indicating often a concentration-dependent correlation between level of drug dose and inhibition of bacterial adhesion. Urinary concentrations of fosfomycin trometamol equal to those seen after administration of 3 g of the drug, have been demonstrated to be able to efficaciously decrease urothelial adhesion of both E. coli and P. mirabilis strains. In the last 20 years, due to its spectrum of action, low-resistance profile, and simplicity of administration due to excellent oral bioavailability, many studies have hypothesized that fosfomycin would be efficacious also for urological procedure prophylaxis.65 These studies have fully justified the indication for use as prophylaxis against the risk of postoperative UTI or urological diagnostic procedures, as reported in the technical information sheet of fosfomycin trometamol in some of the European countries where it is commercially
Table 12 Possible carbapenemases produced by Gram-negative bacteria Carbapenemases IMP family, VIM, GIM-1, SPM-1 (metallo-beta-lactamases) family
KPC-1, KPC-2, KPC-3 OXA-23, OXA-24, OXA-25, OXA-26, OXA-27, OXA-40, OXA-48
Substrates
Inhibited by clavulanate
Penicillin Wide-spectrum cephalosporins Monobactams Cephamycin Carbapenems Same as above Same as above
Molecular class
0
B
zzzz z
A D
Table 13 The most frequently used antibiotics for urological procedure prophylaxis with relative dosages Procedure/Surgery Nephrectomy, suprarenalectomy, varicocelectomy, orchiectomy, scrotal surgery TURP, TURB*, cystoscopy with bladder biopsy or endoscopic diathermocoagulation, cystolithectomy, bladder/ureteral diverticulectomy, ureteropyeloplasty, ureteroplasty, urethrectomy, ureterocystanastomosis Percutaneous or ureteroscopic lithotripsy
Prostatic adenomectomy, radical prostatectomy with lymph node extraction, radical cystectomy with lymph node extraction Artificial sphincter or prosthetic implant
Antibiotic
Preoperative dose
Cefazolin
2 g i.v.
Ampicillin/sulbactam Ciprofloxacin Gentamicin
3 g i.v. 500 mg oral/400 mg i.v. 1.5 mg/kg i.v.
Ampicillin/sulbactam Ciprofloxacin Gentamicin Ampicillin/sulbactam Gentamicinzmetronidazole
3 g i.v. 500 mg oral/400 mg i.v. 1.5 mg/kg i.v. 3 g i.v. 1.5 mg/kg i.v. z 1 g oral
Cefazolin Vancomycin
2 g i.v. 15 mg/kg (max. 1 g) i.v.
Note: *With indications reported in Table 3.
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Table 14 The in vitro susceptibility of multidrug-resistant bacteria to fosfomycin (modified from Neuner et al.67) MIC (mg/ml) Microorganism (n)
50%
90%
% susceptible
32 8 64 1 1
64 256 64 16 128
92 75 86 100 80 75
K. pneumoniae carbapenem-resistant (13) P. aeruginosa (8) E. faecium vancomycin-resistant (7) E. coli and K. pneumoniae ESBL-positive (7) E. coli (5) Other (4)
available,. Up to now, given the lack of data regarding this antimicrobial agent’s ability to penetrate prostatic tissue, none of the guidelines recommend its use for this indication. In fact, fosfomycin’s high and rapid capacity of tissue distribution in the prostate has only been described and published by Italian scientists in the 1980s.66 Recently, Gardiner et al.57 have confirmed fosfomycin’s capability to reach adequate intraprostatic concentrations, thus stimulating a re-evaluation of this ‘forgotten drug’ and favouring its insertion among the antibiotics recommended in the guidelines for shortterm prophylaxis in urology. Fosfomycin is available in two oral formulations (fosfomycin calcite and fosfomycin trometamol salt) and in a parenteral formulation (fosfomycin sodium) available only in some countries. It is quickly absorbed in the form of trometamol salt, and thus has very high bioavailability (40% versus 12% for the calcite salt).58 About 30–60% of the administered dose of fosfomycin trometamol is excreted in active form and 95% is eliminated through the kidneys without being secreted at a tubular level, with the consequent possibility of reaching high urinary concentrations, even 3000 mg/l, and therefore, well over the minimum inhibitory concentrations (MICs) for most of the uropathogenic species. In strictly microbiological terms, the usual method of defining in vitro susceptibility to fosfomycin is through diffusion on agar or Mueller-Hinton broth supplemented with glucose-6-fosfate. Notwithstanding this standardization, the EUCAST, in its last revision (February 2013), furnished only the sensitivity
breakpoints for oral fosfomycin against Enterobacteriaceae (sensitive if MIC #32 mg/l), without specifying those for staphylococci, enterococci, and P. aeruginosa. Several epidemiological investigations have documented the antibacterial activity and clinical efficacy of fosfomycin used for infections sustained by MDR enterobacteria. Falagas et al.62 systematically reviewed 17 articles, for a total of 5057 enterobacterial clinical isolates (88% of which were ESBL producers), to determine fosfomycin’s antibacterial activity and clinical efficacy for infections caused by MDR bacteria such as ESBL-producing enterobacteria. In 11 of the 17 articles selected, at least 90% of the isolated strains remained sensitive to fosfomycin,62 especially E. coli (96.8%) and K. pneumoniae (81.3%). In one study of 290 clinical isolates of ESBL-producing E. coli, 99.7% of strains were susceptible to fosfomycin,59 while 92.7% of the 138 K. pneumoniae isolates were also susceptible to this drug.59 Neuner et al.,67 in a study about the use of fosfomycin for treatment of 41 patients with UTIs due to MDR bacteria, found that 86% of the isolated strains were susceptible to this antibiotic (Table 14) and its use was associated with microbiological eradication in 59% of patients. Microbiological eradication was also reached in 46% of patients with infections caused by K. pneumoniae resistant to carbapenems, in 38% of those due to P. aeruginosa, in 71% of those due to vancomycin-resistant enterococci, and in 57% of those due to ESBL-producing bacteria.67 Analogous results were obtained by Pullukcu et al.,68 Prakash et al.,69 and Fournier et al.70
Table 15 Studies published in the literature relative to endourological procedures and surgery
the use of
trometamol
for
prophylaxis in
Reference
Year
Indication
Study design
Comparator drug
Patients (n)
Periti et al.74 Periti et al.74 Di Silverio et al.75 Baert et al.72 Di Silverio et al.76 Selvaggi et al.77 Nicoletti et al.73 Szopinski et al.78 Jimenez-Pacheco et al.71
1988 1988 1988 1990 1990 1992 1994 2002 2012
TURP TURB/Cystoscopy ESWL, URSL* TURP TURP, TURB TURP Cystoscopy TURP, PCNL*, URSL Cystoscopy
Randomized Open Open Randomized Open Open Randomized Open Randomized
Amoxicillin Cotrimoxazole … … Placebo … … Placebo … Placebo
900 283 30 61 712 70 174 80 60
Note: *URSL: ureteroscopy lithotripsy; PCNL, percutaneous nephrolithotomy.
20
fosfomycin
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Table 16 Outcome of perioperative antibiotic prophylaxis
TURP (n) Fever .38uC I postoperative day Fever .38uC VI–VIII postoperative days Bacteriuria .105 CFU/ml within 2 weeks Symptomatic infection within 1 week Adverse events
Amoxicillin
Cotrimoxazole
Fosfomycin trometamol
283 6% 3.5% 24.7% 8.1% 6.4%
288 4.9% 3.8% 27.4% 8.3% 8.3%
329 3% 0.3% 16.4%* 3.3%* 3.6%
Note: CFU: colony forming units. *P,0.01: significantly lower compared to results with amoxicillin and cotrimoxazole.
Furthermore, Wagenlehner et al.65 reviewed the use of fosfomycin trometamol as prophylaxis for endourological procedures, analysing a total of 1614 patients from nine clinical studies (four randomized and five open), published between 1988 and 2012 (Table 15). The drug was usually prescribed in most cases at a dosage of 3 g administered 3 hours before the procedure and another 3 g given 24 hours following. The only exceptions were 88 patients undergoing cystoscopy, who were given a single 3 g dose of fosfomycin trometamol 3 hours before the procedure. In all the studies analysed, except that of JimenezPacheco et al.,71 fosfomycin trometamol proved to be at least as efficacious as the other prophylactic regimens employed, and certainly more effective than placebo.72,73 Table 16 reports the results of the study by Periti et al.74 which compared amoxicillin, cotrimoxazole, and fosfomycin trometamol for perioperative urological prophylaxis. Fosfomycin was significantly more efficacious in reducing bacteriuria and symptomatic infections within a week after the procedures than the other two drugs. What emerges from above is that fosfomycin, although being in clinical use for several years, presents numerous interesting attributes in the field of urology — not only for strictly therapeutic but also for prophylactic uses, especially in this period of growing resistance of Gram-negative bacteria to the other antibiotics habitually used in this field.
Disclaimer Statements Contributors The contributors to the article are all the authors. Funding None. Conflicts of interest Professor Concia and Dr Azzini have no conflicts of interest. Ethics approval Since it is a review article, it was not necessary to have any ethics approval.
References 1 Naber KG, Hofstetter AG, Bryhl P, Bichler K, Lebert C. Guidelines for perioperative prophylaxis in interventions of the urinary and male genital tract. Int J Antimicrob Agents. 2001;17(4):321–6.
2 Societe´ Francaise d’Anesthe´sie et de Re´animation (SFAR). Recommendations for antibacterial prophylaxis in surgery. Pyrexie. 1999;3:21–30 3 Naber KG, Schaeffer AJ, Heyns CF, Matsumoto T, Shoskes DA, Bjerklund Johansen TE, et al. Urogenital infections. 1st ed. Arnhem: European Association of Urology; 2010. 4 Burke JF. The effective period of preventive antibiotic action in experimental incision and dermal lesion. Surgery. 1961;50:161–8. 5 Classen DC, Evans RS, Pestotnik SL, Horn SD, Menlove RL, Burke JP. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. NEJM. 1992;326(5):281–6. 6 Bates T, Siller G, Crathern BC, Bradley SP, Zlotnik RD, Couch C, et al. Timing of prophylactic antibiotics in abdominal surgery: trial of a pre-operative versus an intra-operative first dose. Br J Surg. 1989;76(1):52–6. 7 Cruse PJ, Foord R. The epidemiology of wound infections. A 10-year prospective of 62,939 wounds. Surg Clin North Am. 1980;60(1):27–40. 8 Bjerklund-Johansen TE, Naber K, Tenke P. The PanEuropean prevalence study on nosocomial urinary tract infections. Vienna: European Association of Urology; 2004. 9 Aron M, Rajeev TP, Gupta NP. Antibiotic prophylaxis for transrectal needle biopsy of the prostate: a randomized controlled study. BJU Int. 2000;85(6):682–5. 10 Webb NR, Woo HH. Antibiotic prophylaxis for prostate biopsy. BJU Int. 2002;89(8):824–8. 11 Enlund AL, Varenhorst E. Morbidity of ultrasound-guided transrectal core biopsy of the prostate without prophylactic antibiotic therapy. A prospective study in 415 cases. Br J Urol. 1997;79(5):777–80. 12 Larsson P, Norming U, To¨rnblom M, Gustafsson O. Antibiotic prophylaxis for prostate biopsy: benefits and costs. Prostate Cancer Prostatic Dis. 1999;2(2):88–90. 13 Puig J, Darnell A, Bermudez P, Malet A, Serrate G, Bare´ M, et al. Transrectal ultrasound-guided prostate biopsy: is antibiotic prophylaxis necessary? Eur Radiol. 2006;16(4):939–43. 14 Kapoor DA, Klimberg IW, Malek GH, Wegenke JD, Cox CE, Patterson AL, et al. Single-dose oral ciprofloxacin versus placebo for prophylaxis during transrectal prostate biopsy. Urology. 1998;52(4):552–8. 15 Isen K, Ku¨peli B, Slinik Z, So¨zen S, Bozkirli I. Antibiotic prophylaxis for transrectal biopsy of the prostate: a prospective randomized study of the prophylacitic use of single dose oral fluoroquinolones versus trimethoptim-sulfamethoxazole. Int Urol Nephrol. 1999;31(4):491–5. 16 Crawford ED, Haynes AL, Story MW, Borden TA. Prevention of urinary tract infection and sepsis following transrectal prostatic biopsy. J Urol. 1982;127(3):449–51. 17 Melekos MD. Efficacy of prophylactic antimicrobial regimes in preventing infectious complications after transrectal biopsy of the prostate. Int Urol Nephrol. 1990;22(3):257–62 18 Briffaux R, Merlet B, Normand G, Coloby P, Leremboure H, Bruye`re F, et al. Short or long schemes of antibiotic prophylaxis for prostate biopsy. A multicentre prospective randomized study. Prog Urol. 2009;19(1):39–46. 19 Kraklau DM, Wolf JS, Jr. Review of antibiotic prophylaxis recommendations for office-based urologic procedures. Tech Urol. 1999;5(3):123–8. 20 Wilson L, Ryan J, Thelning C, Masters J, Tuckey J. Is antibiotic prophylaxis required for flexible cystoscopy? A truncated randomized double-blind controlled trial. J Endourol. 2005;19(8):1006–8. 21 Latthe PM, Foon R, Toozs-Hobson P. Prophylactic antibiotics in urodynamics: a systematic review of effectiveness and safety. Neurourol Urodyn. 2008;27(3):167–73.
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22 Clark KR, Higgs MJ. Urinary infection following out-patient flexible cystoscopy. Br J Urol. 1990;66(5):503–5. 23 Almallah YZ, Rennie CD, Stone J, Lancashire MJ. Urinary tract infection and patient satisfaction after flexible cystoscopy and urodynamic evaluation. Urology. 2000;56(1):37–9. 24 Burke DM, Shackley DC, O’Reilly PH. The community-based morbidity of flexible cystoscopy. BJU Int. 2002;89(4):347–9. 25 Johnson MI, Merrilees D, Robson DA, Lennon T, Masters J, Orr KE. Oral ciprofloxacin or trimethoprim reduces bacteriuria after flexible cystoscopy. BJU Int. 2007;100(4):826–9. 26 Jimenez Cruz JF, Sanz Chinesta S, Otero G, Dı´az Gonza´lez R, Alvarez Ruiz F, Flores N, et al. Antimicrobial prophylaxis in urethrocystoscopy. Comparative study. Actas Urol Esp. 1993;17(3):172–5. 27 Manson AL. Is antibiotic administration indicated after outpatient cystoscopy. J Urol. 1988;140(2):316–7. 28 Karmouni T, Bensalah K, Alva A, Patard JJ, Lobel B, Guille´ F. Role of antibiotic prophylaxis in ambulatory cystoscopy. Prog Urol. 2001;11(6):1239–41. 29 Tsugawa M, Monden K, Nasu Y, Kumon H, Ohmori H. Prospective randomized comparative study of antibiotic porophylaxis in urethrocystoscopy and urethrocystography. Int J Urol. 1998;5(5):441–3. 30 Cundiff GW, McLennan MT, Bent AE. Randomized trial of antibiotic prophylaxis for combined urodynamics and cystourethroscopy. Obstet Gynecol. 1999;93(5 Pt 1):749–52. 31 Logadottir Y, Dahlstrand C, Fall M, Knutson T, Peeker R. Invasive urodynamic studies are well tolerated by the patients and associated with a low risk of urinary tract infection. Scand J Urol Nephrol. 2001;35(6):459–62. 32 Wagenlehner FM, Wagenlehner C, Schinzel S, Naber KG; Working Group ‘Urological Infections’ of German Society of Urology. Prospective, randomized, multicentric, open, comparative study on the efficacy of a prophylactic single dose of 500 mg levofloxacin versus 1920 mg trimethoprim/sulfamethoxazole versus a control group in patients undergoing TUR of the prostate. Eur Urol. 2005;47(4):549–56. 33 Qiang W, Jianchen W, MacDonald R, Monga M, Wilt TJ. Antibiotic prophylaxis for transurethral prostatic resection in men with preoperative urine containing less than 100,000 bacteria per ml: a systematic review. J Urol. 2005;173(4):1175– 81. 34 Berry A, Barrat A. Prophylactic antibiotic use in transurethral prostatic resection: a meta-analysis. J Urol. 2002;167(2 Pt 1):571–7. 35 Upton JD, Das S. Prophylactic antibiotic in transurethral resection of bladder tumors: are they necessary? Urology. 1986;27(5):421–3. 36 Delavierre D, Huiban B, Fournier G, Le Gall G, Tande D, Mangin P. The value of antibiotic prophylaxis in transurethral resection of bladder tumors. Apropos of 61 cases. Prog Urol. 1993;3(4):577–82. 37 Grabe M. Perioperative antibiotic prophylaxis in urology. Curr Opin Urol. 2001;11(1):81–5. 38 Fourcade RO. Antibiotic prophylaxis with cefotaxime in endoscopic extraction of upper urinary tract stones: a randomized study. The Cefotaxime Cooperative Group. J Antimicrob Chemother. 1990;26(Suppl A):77–83. 39 Knopf HJ, Graff HJ, Schulze H. Perioperative antibiotic prophylaxis in ureteroscopic stone removal. Eur Urol. 2003;44(1):115–8. 40 Hendrikx AJ, Strijbos WE, de Knijff DW, Kums JJ, Doesburg WH, Lemmens WA. Treatment for extended-mid and distal ureteral stones: SWL or uretheroscopy? Results of a multicenter study. J Endourol. 1999;13(10):727–33. 41 Rao PN, Dube DA, Weightman NC, Oppenheim BA, Morris J. Prediction of septicaemia following endourological manipulation for stones in the upper urinary tract. J Urol. 1991;146:955– 60. 42 Charton M, Vallencien G, Veillon B, Brisset JM. Urinary tract infection in percutaneous surgery for renal calculi. J Urol. 1986;135(1): 15–27. 43 Dogan HS, Sahin A, Cetinkaya Y, Akdogan B, Ozden E, Kendi S. Antibiotic prophylaxis in precutaneous nephrolithotomy: prospective study in 81 patients. J Endourol. 2002;16(9):649–53. 44 Deliveliotis C, Giftopoulos A, Koutsokalis H, Raptidis G, Kostakopoulos A. The necessuty of prophylactic antibiotics during extracorporal shock wave lithotripsy. Int Urol Nephrol. 1997;29(5):517–21. 45 Claes H, Vandeursen R, Baert L. Amoxycillin/Clavulanate prophylaxis for extracorpereal shock wave lithotripsy — a
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comparative study. J Antimicrob Chemother. 1989;24(Suppl B):217–20. Pettersson B, Tiselius HG. Are prophylactic antibiotic necessary during extracorporeal shockwave lithotripsy? Br J Urol. 1989;63(5):449–52. Bierkens AF, Hendrikx AJ, Ezz el Gin KE, de la Rosette JJ, Horrevorts A, Doesburg W, et al. The value of antibiotic prophylaxis during extracorporeal shock wave lithotripsy in the prevention of urinary tract infections in patients with urine proven sterile prior treatment. Eur Urol. 1997;31(1):30–5. Pearle MS, Roehrborn CG. Antimicrobial prophylaxis prior to shock wave lithotripsy in patients with urine sterile urine before treatment: a meta-analysis and cost-effectiveness analysis. Urology. 1997;49(5):679–86 Steiner T, Traue C, Schubert J. [Perioperative antibiotic prophylaxis in transperitoneal tumor nephrectomy: does it lower the rate of clinically significant postoperative infections?]. Urologe A. 2003;42(1):34–7. German. Montgomery JS, Johnston WK 3rd, Wolf JS, Jr. Wound complication after hand assisted laparoscopic surgery. J Urol. 2005;174(6):2226–30. Kiddoo DA, Wollin TA, Mador DR. A population based assessment of complications following outpatient hydrocelectomy and spermatolocelectomy. J Urol. 2004;171(2 Pt1): 746–8. Stranne J, Aus G, Hansson C, Lodding P, Pileblad E, Hugosson J. Single-dose orally administered quinolone appears to be sufficient antibiotic prophylaxis for radical retropubic prostatectomy. Scand J Urol Nephrol. 2004;38(2):143–7. Terai A, Ichioka K, Kohei N, Ueda N, Utsunomiya N, Inoue K. Antibiotic prophylaxis in radical prostatectomy: 1-day versus 4-day treatments. Int J Urol. 2006;13(12):1488–93. Takeyama K, Tkahashi S, Maeda T, Mutoh M, Kunishima Y, Matsukawa M, et al. Comparison of 1-day, 2-day and 3-day administration of antimicrobial prophylaxis in radical prostatectomy. J Infect Chemother. 2007;13(5):320–3. Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis. 2013;13:785–96. Giani T, Pini B, Arena F, Conte V, Bracco S, Migliavacca R, et al. Epidemic diffusion of KPC carbapenemases-producing Klebsiella pneumoniae in Italy: results of the first countrywide survey, 15 May to 30 June 2011. Euro Surveill. 2013;18(22). Gardiner BJ, Mahony AA, Ellis AG, Lawrentschuk N, Bolton D, Zeglinski PT, et al. Is fosfomycin a potential treatment alternative for multidrug-resistant Gram-negative prostatitis? Clin Infect Dis. 2014;58(4):e101–5. Michalopoulos AS, Livaditis IG, Gougoutas V. The revival of fosfomycin. Int J Infect Dis. 2011;15:e732–9. Popovic M, Steinort D, Pillai S, Joukhadar C. Fosfomycin: an old, new friend? Eur J Clin Microbiol Infect Dis. 2010;29:127– 42. Raz R. Fosfomycin: an old-new antibiotic. Clin Microbiol Infect. 2011;18:4–7. Periti P, Rizzo M. Ruolo degli antibiotici orali in urologia diagnostica e terapeutica: la fosfomicina trometamolo. Farm Ter (Int J Drugs Ther). 2000;XVII(Suppl 2):3–29. Falagas ME, Kastoris AC, Kapaskelis AM, Karageorgopoulos DE. Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infect Dis. 2010;10(1):43–50. Carlone NA, Borsotto M, Cuffini AM, Savoia D. Effect of fosfomycin trometamol on bacterial adhesion in comparison with other chemotherapeutic agents. Eur Urol. 1987;13(Suppl 1):86–91. Albini E, Arena E, Bellucco G, Marca G. Adhesion of bacteria to human uroepithelial cells and bactericidal activity of fosfomycin trometamol. In: Neu HC, Williams JC, editors. New trends in urinary tract infections. The single dose therapy. Basel: Karger; 1988. p. 250–254. Wagenlehner FM, Thomas PM, Naber KG. Fosfomycin trometamol (3,000 mg) in perioperative antibiotic prophylaxis of healthcare-associated infections after endourological interventions: a narrative review. Urol Int. 2014;;92(2):125–30. Borghi CM, Laveneziana D, Riva A, Marca G, Zannini G. Concentrazioni nel siero e nel tessuto prostatico di fosfomicina con fosfomicina-trometamolo, nuovo derivato della fosfomicina con elevata biodisponibilita` per somministrazione orale. Farm Ter (Int J Drugs Ther). 1986;III(3):216–20.
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67 Neuner EA, Sekeres J, Hall GS, van Duin D. Experience with fosfomycin for treatment of urinary tract infections due to multidrugresistant organisms. Antimicrob Agents Chemother. 2012;56:5744–8. 68 Pullukcu H, Tasbakan M, Sipahi OR, Yamazhan T, Aydemir S, Ulusoy S. Fosfomycin in the treatment of extend spectrum beta-lactamase-producing Escherichia coli-related lower urinary tract infections. Int J Antimicrob Agents. 2007;29:62–5. 69 Prakash V, Lewis JS 2nd, Herrera ML, Wickes BL, Jorgensen JH. Oral and parenteral therapeutic options for outpatient urinary infections caused by Enterobacteriaceae producing CTX-M extended-spectrum beta-lactamases. Antimicrob Agents Chemother. 2009;53:1278–80. 70 Fournier D, Chirouze C, Leroy J, Cholley P, Talon D, Ple´siat P, et al. Alternatives to carbapenems in ESBL-producing Escherichia coli infections. Med Mal infect. 2013;43:62–6. 71 Jimenez-Pacheco A, Lardelli Claret P, Lopez Luque A, LahozGarcia C, Arrabal Polo MA, Nogueras Ocana M. Randomized clinical trial on antimicrobial prophylaxis for flexible urethrocystoscopy. Arch Esp Urol. 2012;65:542–9. 72 Baert L, Billiet I, Vandepitte J. Prophylactic chemotherapy with fosfomycin trometamol versus placebo during transurethral prostatic resection. Infection. 1990;18(Suppl 2):S103–6. 73 Nicoletti G, Nicolosi D, Schito GC, VaraldoM, Carati L. Fosfomycin trometamol in prophylaxisof bacteriuria associated with transurethral diagnostic procedures. Urogynaecologia. 1994;8:123–34.
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74 Periti P, Novelli A, Reali EF, del Bono GP, Fontana P. Prophylactic chemotherapy with fosfomycin trometamol salt in transurethral prostatectomy. A controlled clinical trial. In: Neu HC, Williams JD, editors. New trends in urinary tract infections. The Single-Dose Therapy International Symposium. Basel: Karger; 1988. p. 207–233. 75 di Silverio F, Cruciani E, Ferrone G, Prencipe MG, Lauretti S, Fini D. Evaluation of fosfomycin trometamol in the prevention of urinary tract infections after ESWL and ureteropyeloscopy. In: Neu HC, Williams JD, editors. New trends in urinary tract infections. The Single-Dose Therapy International Symposium. Basel: Karger; 1988. p. 329–332. 76 di Silverio F, Ferrone G, Carati L. Prophylacticchemotherapy with fosfomycin trometamol during transurethral surgery and urological manoeuvres. Results of a multicentre study. Infection. 1990;18(Suppl 2):S98–102. 77 Selvaggi FP, Battaglia M, Grossi FS, Disabato G, Cormio L. Oral prophylaxis with fosfomycin trometamol in transurethral prostatectomy and urological maneuvers: literature review and personal experience. Infection. 1992;20(Suppl 4):S321–4. 78 Szopinski T, Antoniewicz AA, Boro´wka A. [The prophylactic use of phosphomycin in endoscopic procedures associated urinary tract infections]. Urol Pol. 2002;55:1–7. Polish.
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Introduction In the last 10 years, a lot of efforts have been made to bring to light suitable indications for antibiotic prophylaxis in the field of urology. Starting in the year 2000, many articles have been published by both national research groups (for example, the German Society of Urology,1 the French Association of Urology2) and international groups in Europe (for example, the European Association of Urology3). The aim of antibiotic prophylaxis in urological surgery is to prevent local and systemic infections caused by uropathogens, such as urosepsis, pyelonephritis, prostatitis, epididymitis, as well as those of the surgical wound. To achieve this goal, it is necessary not only to be knowledgeable of the cardinal principles of antibiotic prophylaxis, but also of the urology patient’s characteristics, and of the risks associated with the urological procedure to be undergone.
N
N
Antibiotic Prophylaxis
N
Timing: The time range in which it is reasonable to administer prophylaxis must not be more than 2 hours after the initiation of surgery.4–6 If an oral antibiotic is used (and this must be only if the molecule has excellent bioavailability), it must be
Correspondence to: E. Concia, Sezione di Malattie Infettive, Dipartimento di Patologia, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico ‘G. B. Rossi’, Piazzale Ludovico Antonio Scuro 10, 37124 Verona, Italy. Email: [email protected]
14
ß 2014 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1120009X14Z.000000000233
N
administered an hour prior to surgery. An intravenous antibiotic can be administered contemporarily with the anaesthesia. Duration: in most cases, prophylaxis can be given as a single preoperative dose. Very long surgical interventions are an exception to this rule, requiring further doses of antibiotic in relation to the half-life of the molecule used, as well as in patients at high risk (see below and Table 1). In any case, prophylaxis should not exceed 72 hours post-surgery. Antibiotic choice: although there are various guidelines about antibiotic prophylaxis, it is of fundamental importance that the choice of drug be based on local epidemiology. Other than this, it is also necessary to consider other factors such as the presence of previous pathogens isolated at the surgical site, the type of surgery to be carried out, and the intrinsic characteristics of the patient. The most commonly used antibiotics for urological surgical prophylaxis are cotrimoxazole, betalactamase-inhibiting penicillins, II generation cephalosporins, and aminoglycosides. It should be emphasized that the broad-spectrum molecules should be reserved for therapy, rather than prophylaxis. Type of surgical procedure: as anticipated, prophylaxis has a dual aim: to prevent infection of the surgical wound and to prevent the occurrence and/or diffusion of acute urogenital or systemic infection after surgery. Although, as in the first case, the infectious risk is well classified according to the Cruse and Foord7 scheme (Table 2), to accomplish the second aim, it is necessary to evaluate the patient’s risk factors, especially in relation to the type and duration of surgery.
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Table 1 Infection risk factors General risk factors
Risk factors associated with type of surgery
Advanced age (.65 years old) Diabetes mellitus Smoker Malnutrition/obesity Immunocompromised Presence of distal infectious foci
N
Recent hospitalization or long period of preoperative hospitalization Known microbial colonization of surgical site History of recurrent urinary tract infection (UTI) Obstruction/urinary tract calculi Surgery involving intestine Urinary catheter/drainage
Risk factors: although not readily recognizable, risk factors, including general ones and those correlated with an increased infectious risk, are fundamental to the preoperative evaluation of the patient. Table 1 summarizes the risk factors most often correlated with enhanced perioperative risk of infection.
International multicentre studies have identified the three major risk factors correlated with the development of postoperative infections and they are: the presence of urinary catheter and the relative time of its permanence, history of continuing episodes of urinary tract infection (UTI), and long preoperative hospital stay.8 In these cases, antibiotic prophylaxis is strongly recommended.
Indications for Prophylaxis To better evaluate the various indications for use of antibiotic prophylaxis in urological surgery, it is
necessary to categorize the various interventions according to risk, distinguishing between diagnostic and therapeutic procedures, and of these, between endourological/ESWL surgery and laparoscopic or laparotomic surgery. Laparotomy will not be further discussed in this article since the indications for antibiotic prophylaxis are founded on infectious risk correlated with abdominal surgery. Table 3 summarizes the main urological surgical procedures divided into diagnostic or therapeutic categories. A. Diagnostic procedures: needle biopsy of the prostate9–18 is the only procedure for which there is undoubted evidence of the necessity of using antibiotic prophylaxis. In all the other diagnostic procedures, routine use of prophylaxis is not recommended. Prophylaxis should be used only for patients with bacteriuria, recent UTI, and/or those bearing a urinary catheter19–31 (Table 4).
Table 2 The Cruse and Foord classification of urological procedures Classification
Characteristics
Prophylaxis
Clean (1–4% risk)
Intact urinary tract Complete asepsis maintenance No interruption of surgical procedure Operation on uninflamed tissue
No
Clean-contaminated (4–10% risk)
Surgical intervention on urinary tract or intestinal segment with little or no diffusion of their contents in surgical field No or minimal interruption of surgical procedure
Yes
Contaminated (10–15% risk)
Contamination of operative field by modest quantity of faecal/urinary material Surgery on inflamed tissue Presence of recent and open wound at surgical site Major interruption of surgical procedure Perforation of abdominal viscera Presence of previous post-traumatic wound Surgery on infected tissue
Therapy
Dirty (15–40% risk)
Therapy
Endourological procedure Cystoscopy Urodynamic tests Extracorporeal shockwave lithotripsy (ESWL) Transurethral resection of bladder tumour (TURB) of small dimension TURB of large or necrotic tumours Transurethral resection of the prostate (TURP) Ureterorenoscopy Ureteral endoscopic lithotripsy Uncomplicated percutaneous lithotripsy ESWL Prostatic needle biopsy during recent UTI TURP during recent UTI Complicated percutaneous lithotripsy Proximal calculus lithotripsy
Procedures on infected calculi
Table 3 Urological surgical procedures subdivided into diagnostic or therapeutic categories A Diagnostic procedures Prostatic biopsy Cystoscopy Urodynamic tests Radiological examinations of urinary tract Ureteroscopy
B Endourological procedures TURP TURB Mini-invasive prostatic surgery Uroscopic treatment of calculi, tumours Percutaneous surgery of calculi, tumours
ESWL
Note: ESWL: extracorporeal shockwave lithotripsy; TURP: transurethral resection of the prostate; TURB: transurethral resection of the bladder.
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Table 4 Indications for antibiotic prophylaxis in endoscopic urological procedures Procedure
Most frequently isolated pathogens
Diagnostic procedures Prostatic needle biopsy Cystoscopy
Ureteroscopy
Endoscopic surgery ESWL Ureteroscopic lithotripsy/ Extracorporeal shockwave lithotripsy TURP TURB
Enterobacteriaceae Enterobacteriaceae Enterococci Staphylococci Enterobacteriaceae Enterococci Staphylococci
Yes No, unless patient bears a urinary catheter, has bacteriuria or history of continuing UTI
Enterobacteriaceae Enterococci Enterobacteriaceae Enterococci Staphylococci Enterobacteriaceae Enterococci Enterobacteriacea Enterococci
No, unless patient bears internal stent or calculi are presumed to be infected No, unless calculi are of large dimension and/or are in proximal site and/or cause obstruction of urinary tract, or if patient has history of continuing UTI Yes
B. Endoscopic and/or ESWL therapeutic procedures: also in this category, the evidence for the utility of antibiotic prophylaxis varies from procedure to procedure. Even though many studies recommend antibiotic prophylaxis for TURP,32–34 this should be reserved only for patients with specific risk factors as with the other procedures (Table 4):
N N
N
TURB:20,35,36 antibiotic prophylaxis should be reserved to patients with one or more risk factors listed in Table 1 or with large dimension tumours, especially if necrotic core is present. Ureteroscopy/percutaneous removal of calculi: antibiotic prophylaxis should be reserved for those patients with large stones (due to increased risk of bleeding), especially if located at the intrarenal level or in the most proximal part of the excretory canals.37–43 ESWL: antibiotic prophylaxis must be reserved for patients bearing intrarenal stents (such as the double J) and/or those with presumed infected stones.44–48
Table 4 summarizes the indications for antibiotic prophylaxis in diagnostic procedures and endoscopic surgery. C. Laparoscopic/laparotomic procedures: as already mentioned, these procedures are being listed for thoroughness, but will not be further discussed since indications for their antibiotic prophylaxis are strictly correlated with the surgical site and relative infectious risk. The reference classification proposed by Cruse and Foord for clean, clean-contaminated, contaminated, and dirty surgical interventions is useful (Table 2). Clean operations include all those where the urinary tract is not opened, and therefore, the infectious risk is minimal and routine use of antibiotic prophylaxis is unnecessary.49–51 Clean-contaminated operations include those in which the urinary tract and/or part of the intestine are involved, carried out after adequate preparation of the patient and with negligible amount of spillage of faecal/urinary content in the operative field. For surgery in this field, a single dose of antibiotic prophylaxis administered preoperatively, is indicated.52–54 Contaminated operations involving the intestine with partial spillage of
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No, unless patient bears a urinary catheter, has bacteriuria or history of continuing UTI
No, unless tumours are large and/or necrotic
its contents in the operative field, and dirty operations, that is, all those conducted in the absence of preoperative preparation (in other words, urgent operations) or following visceral perforation and spillage in the abdomen or surgery of clearly infected tissue, all necessitate antibiotic therapy (rather than prophylxis) which should be started before surgery and be continued afterwards, according to the duration and specific type of infection.
Table 2 summarizes the various characteristics of urological procedures according to the Cruse and Foord classification in order to determine the risk of infection from the surgery.
Epidemiology of Antibiotic-Resistant Bacteria From what has been discussed previously, it is apparent that the majority of bacteria responsible for postoperative urological infections are Enterobacteriaceae, Pseudomonas aeruginosa, eneterococci, and less frequently, staphylococci. In recent years, unfortunately, there has been the tendency for almost all the abovementioned bacteria to become resistant to numerous classes of antibiotics, making not only therapy difficult but also prophylaxis. Starting from the Gram-positive bacteria, the last report from the European Center for Disease Prevention and Control (ECDC) in 2011 documents that about 80% of Enterococcus faecium strains in Italy are resistant or intermediately resistant to aminopenicillins, and about 50% are highly resistant to gentamicin. On the other hand, they remain highly sensitive to vancomycin, with less than 5% of strains resistant. Enterococcus faecalis, on the contrary, remain highly sensitive to the aminopenicillins with only 10% resistant and 3% resistant to vancomycin, whereas more than 40% are highly resistant to gentamicin. Tables 5 and 6 describe the sensitivity of E. faecium and E. faecalis to the aminopenicillins and vancomycin between 2009 and 2011.
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Table 5 E. faecium and E. faecalis susceptibility to the aminopenicillins in Italy, 2009–2011
E. faecium Sensitive (%) Intermediate (%) Resistant (%) E. faecalis Sensitive (%) Intermediate (%) Resistant (%)
2009
2010
2011
40.1 0 59.9
30.4 0 69.6
17.3 0.8 81.9
80.1 0 19.9
86.8 0 13.2
89.4 0.2 10.4
Approximately 40% of Staphylococcus aureus were found to be methicillin-resistant and this frequency was substantially constant between 2009 and 2011 (Table 7). Resistance of P. aeruginosa in 2011 to piperacillintazobactam and the anti-Pseudomonas carbapenems was about 20%, tending to improve between 2009 and 2011. The number of strains resistant to ceftazidime remained stable at about 15%, whereas there was a decided improvement in sensitivity to the fluoroquinolones, with 26% of strains resistant in 2011 compared to 42% in 2009. Only 5% of strains were resistant to amikacin. Table 8 describes the situation of P. aerugionosa susceptibility to these various classes of antibiotics in Italy between 2009 and 2011. Taking into consideration the Enterobacteriaceae, the 2011 report documents that 40% of Escherichia coli is resistant to fluoroquinolones, with a tendency to worsen from previous years; about 20% is stably resistant to the III generation cephalosporins; 18% is resistant to aminoglycosides and tending to worsen, and 0.2% is resistant to the carbapenems (Table 9). On the other hand, the situation of susceptibility of Klebsiella pneumoniae to antibiotics documented in the same period indicates a clear worsening for all the tested molecules, especially resistance to fluoroquinolones, III generation cephalosporins (around 45%), whereas 35% were found resistant to the aminoglycosides Table 6 E. faecium and E. faecalis vancomycin in Italy, 2009–2011
E. faecium Sensitive (%) Intermediate (%) Resistant (%) E. faecalis Sensitive (%) Intermediate (%) Resistant (%)
susceptibility
2009
2010
2011
95.2 0.5 4.3
95.6 0.5 3.9
95.8 0 4.2
96.3 1.1 2.6
97.2 0.6 2.2
96.9 0.2 2.9
S. aureus Sensitive (%) Intermediate (%) Resistant (%)
2010
2011
62.6 0 37.4
63.5 0 36.5
61.8 0 38.2
Table 8 P. aeruginosa susceptibility antibiotics in Italy, 2009–2011
to
P. aeruginosa Fluoroquinolones Sensitive (%) Intermediate (%) Resistant (%) Ceftazidime Sensitive (%) Intermediate (%) Resistant (%) Piperacillin-tazobactam Sensitive (%) Intermediate (%) Resistant (%) Carbapenems Sensitive (%) Intermediate (%) Resistant (%) Amikacin Sensitive (%) Intermediate (%) Resistant (%)
2009
2010
2011
54.9 3.1 42
63.2 5.8 31
70.1 3.8 26.1
72 11.6 16.5
76.2 6.1 17.7
80.2 3.6 16.2
75.1 0.5 24.3
78.6 0.2 21.2
76.4 1.7 21.9
65.4 3.7 30.9
73.7 4.3 22
74.1 5.4 20.6
91.7 2.1 6.2
87.9 2.8 9.3
89.7 4.7 5.6
various
and 25% to the carbapenems. About 33% of multidrugresistant strains (MDR) were concomitantly resistant to the III generation cephalosporins, fluoroquinolones, and aminoglycosides (Table 10). The principal problem connected with the exponential increase in K. pneumoniae resistance in the last 10 years in various countries, including Italy (Fig. 1 and Table 11),55,56 involves strains which produce carbapenemases. These can be of various types (VIM, OXA, KPC) and have slightly different substrates (Table 12). The most problematic are strains producing KPC, which are phenotypically resistant not only to carbapenems but also to the III and IV generation cephalosporins, aztreonam, and the fluoroquinolones. Generally, the only molecules to which K. pneumoniae is still sensitive or intermediately sensitive are tigecycline, colistin, the aminoglycosides (especially gentamicin), and fosfomycin, making not only therapy very difficult, but also prophylaxis in the genitourinary tract.
to
Table 7 S. aureus susceptibility to methicillin in Italy, 2009–2011 2009
Aetiology and antibiotic resistance issues
Table 9 E. coli susceptibility to various antibiotics in Italy, 2009–2011 E. coli
2009
Fluoroquinolones Sensitive (%) 63.7 Intermediate (%) 0.1 Resistant (%) 36.2 III generation cephalosporins Sensitive (%) 82 Intermediate (%) 1 Resistant (%) 17 Carbapenems Sensitive (%) 100 Intermediate (%) 0 Resistant (%) 0 Aminoglycosides Sensitive (%) 86.6 Intermediate (%) 0.9 Resistant (%) 12.5
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2011
60.6 0.2 39.2
58.8 0.6 40.5
78.4 0.5 21
79.2 1 19.8
99.8 0 0.1
99.8 0 0.2
83.5 1 15.5
79.4 2.3 18.3
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Figure 1 Epidemiological distribution of K. pneumoniae strains producing carbapenemases.55
Antimicrobial Agents To correctly select an antimicrobial agent for use in prophylaxis, it is necessary to consider its spectrum of activity necessary to combat the bacteria most frequently responsible for infection following urological surgery. Although the great majority of postoperative infections are caused by bacteria of the Enterobacteriaceae family and the enterococci, infections due to the staphylococci may occur in those procedures involving artificial sphincters or prosthetic implants. The most frequently used antibiotics for prophylaxis and their relative dosages are summarized in Table 13. Given the previously reported epidemiological data on antimicrobial resistance, it is obvious that it is Table 10 K. pneumoniae susceptibility antibiotics in Italy, 2009–2011
to
K. pneumoniae
2011
2009
2010
Fluoroquinolones Sensitive (%) 78.9 60.3 Intermediate (%) 0.7 1.1 Resistant (%) 2.4 38.5 III generation cephalosporins Sensitive (%) 62.1 52.8 Intermediate (%) 0.7 0.7 Resistant (%) 37.1 46.5 Carbapenems Sensitive (%) 98.7 84.1 Intermediate (%) 0 0.7 Resistant (%) 1.3 15.2 Aminoglycosides Sensitive (%) 79 65.7 Intermediate (%) 1.6 5.2 Resistant (%) 19.4 29.1 MDR (fluoroquinoloneszIII generation cephalosporinszaminoglycosides) Total (%) 12.6 26.3
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52.3 2 45.7 52.3 1.8 45.9 70.4 2.9 26.7 59.8 5.6 34.6
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necessary to limit the use, especially for prophylaxis, of wide-spectrum agents. On the contrary, it is suggested to utilize efficacious antibiotics which are active locally on the urinary tract as ‘antiseptics’, thus reducing the risk of selecting strains which are antibiotic-resistant. As mentioned above, urinary and prostatic infections caused by multidrug-resistant Enterobacteriaceae (MDR-GNB) represent a growing problem. Especially the resistance to the fluoroquinolones is worrying, considering their important role as perioperative prophylaxis for ultrasound-guided transrectal prostatic biopsy and for treatment of prostatitis.57 Several studies have documented the persistence of the susceptibility of many of the Enterobacteriaceae to fosfomycin. Fosfomycin is actually bactericidal against numerous Gram-negative and Gram-positive bacterial strains, due to precocious inhibition of peptidoglycan synthesis by blocking muramic acid synthesis.58–61 Among the Gram-positive bacteria, fosfomycin is particularly active against methicillin-resistant and sensitive S. aureus, penicillin- and cephalosporin-resistant Streptococcus pneumoniae, and Enterococcus spp. including those strains resistant to vancomycin. It is also active against Gram-negative bacteria, including E. coli, Proteus mirabilis, K. pnemoniae, Enterobacter spp., Serratia spp., Shigella spp., Salmonella typhi, and N. meningitidis. It has only moderate activity against P. aeruginosa and is inactive against A. baumannii.60 It is hypothesized that the low level of crossresistance to fosfomycin by the extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae is tied to a different mechanism of transmission. Resistance to the beta-lactam antibiotics, commonly used for treatment of infections caused by this family
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Table 11 Resistance mechanisms in Enterobacteriaceae strains resistant to carbapenems isolated in Italy (15 May–30 June 2011)56 Carbapenemases Species E. coli K. pneumoniae K. oxytoca E. cloacae Other Total
Isolates
Total (%)
5 234 1 15 15 270
2 (40%) 223 (95.3%) 1 (100) 3 (20%) 0 229 (84.8%)
KPC
Non-carbapenemases
VIM-1
1 204 0 0 0 205
OXA-48
1 16 1 3 0 21
of pathogens, is mediated by plasmids, whereas fosfomycin resistance is transmitted through chromosomes.62 Furthermore, fosfomycin remains efficacious against strains contemporarily resistant to the III/IV generation cephalosporins and the fluoroquinolones, thanks to its particular chemical structure and specific mechanism of action. Proof of this emerges from the ECDC 2011 report, indicating that about 59 000 strains of ESBL-producing E. coli, contemporarily resistant to quinolones and aminoglycosides, retained their susceptibility to fosfomycin. Another characteristic of fosfomycin is its capacity to intervene on bacterial adhesion to uroepithelial cells. This adhesion is due to interaction between bacterial wall fimbria and specific receptor structures of the epithelial cell membrane, and represents a fundamental pathogenetic moment, necessary until the bacteria is able to resist urinary flow and successively to invade the bladder wall. Many studies63,64 have demonstrated
Total (%)
0 3 0 0 0 3
3 11 0 12 15 41
(60%) (4.7%) (80%) (100%) (15.2%)
the efficacy of fosfomycin trometamol in reducing this bacterial adhesion to the urothelium, indicating often a concentration-dependent correlation between level of drug dose and inhibition of bacterial adhesion. Urinary concentrations of fosfomycin trometamol equal to those seen after administration of 3 g of the drug, have been demonstrated to be able to efficaciously decrease urothelial adhesion of both E. coli and P. mirabilis strains. In the last 20 years, due to its spectrum of action, low-resistance profile, and simplicity of administration due to excellent oral bioavailability, many studies have hypothesized that fosfomycin would be efficacious also for urological procedure prophylaxis.65 These studies have fully justified the indication for use as prophylaxis against the risk of postoperative UTI or urological diagnostic procedures, as reported in the technical information sheet of fosfomycin trometamol in some of the European countries where it is commercially
Table 12 Possible carbapenemases produced by Gram-negative bacteria Carbapenemases IMP family, VIM, GIM-1, SPM-1 (metallo-beta-lactamases) family
KPC-1, KPC-2, KPC-3 OXA-23, OXA-24, OXA-25, OXA-26, OXA-27, OXA-40, OXA-48
Substrates
Inhibited by clavulanate
Penicillin Wide-spectrum cephalosporins Monobactams Cephamycin Carbapenems Same as above Same as above
Molecular class
0
B
zzzz z
A D
Table 13 The most frequently used antibiotics for urological procedure prophylaxis with relative dosages Procedure/Surgery Nephrectomy, suprarenalectomy, varicocelectomy, orchiectomy, scrotal surgery TURP, TURB*, cystoscopy with bladder biopsy or endoscopic diathermocoagulation, cystolithectomy, bladder/ureteral diverticulectomy, ureteropyeloplasty, ureteroplasty, urethrectomy, ureterocystanastomosis Percutaneous or ureteroscopic lithotripsy
Prostatic adenomectomy, radical prostatectomy with lymph node extraction, radical cystectomy with lymph node extraction Artificial sphincter or prosthetic implant
Antibiotic
Preoperative dose
Cefazolin
2 g i.v.
Ampicillin/sulbactam Ciprofloxacin Gentamicin
3 g i.v. 500 mg oral/400 mg i.v. 1.5 mg/kg i.v.
Ampicillin/sulbactam Ciprofloxacin Gentamicin Ampicillin/sulbactam Gentamicinzmetronidazole
3 g i.v. 500 mg oral/400 mg i.v. 1.5 mg/kg i.v. 3 g i.v. 1.5 mg/kg i.v. z 1 g oral
Cefazolin Vancomycin
2 g i.v. 15 mg/kg (max. 1 g) i.v.
Note: *With indications reported in Table 3.
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Table 14 The in vitro susceptibility of multidrug-resistant bacteria to fosfomycin (modified from Neuner et al.67) MIC (mg/ml) Microorganism (n)
50%
90%
% susceptible
32 8 64 1 1
64 256 64 16 128
92 75 86 100 80 75
K. pneumoniae carbapenem-resistant (13) P. aeruginosa (8) E. faecium vancomycin-resistant (7) E. coli and K. pneumoniae ESBL-positive (7) E. coli (5) Other (4)
available,. Up to now, given the lack of data regarding this antimicrobial agent’s ability to penetrate prostatic tissue, none of the guidelines recommend its use for this indication. In fact, fosfomycin’s high and rapid capacity of tissue distribution in the prostate has only been described and published by Italian scientists in the 1980s.66 Recently, Gardiner et al.57 have confirmed fosfomycin’s capability to reach adequate intraprostatic concentrations, thus stimulating a re-evaluation of this ‘forgotten drug’ and favouring its insertion among the antibiotics recommended in the guidelines for shortterm prophylaxis in urology. Fosfomycin is available in two oral formulations (fosfomycin calcite and fosfomycin trometamol salt) and in a parenteral formulation (fosfomycin sodium) available only in some countries. It is quickly absorbed in the form of trometamol salt, and thus has very high bioavailability (40% versus 12% for the calcite salt).58 About 30–60% of the administered dose of fosfomycin trometamol is excreted in active form and 95% is eliminated through the kidneys without being secreted at a tubular level, with the consequent possibility of reaching high urinary concentrations, even 3000 mg/l, and therefore, well over the minimum inhibitory concentrations (MICs) for most of the uropathogenic species. In strictly microbiological terms, the usual method of defining in vitro susceptibility to fosfomycin is through diffusion on agar or Mueller-Hinton broth supplemented with glucose-6-fosfate. Notwithstanding this standardization, the EUCAST, in its last revision (February 2013), furnished only the sensitivity
breakpoints for oral fosfomycin against Enterobacteriaceae (sensitive if MIC #32 mg/l), without specifying those for staphylococci, enterococci, and P. aeruginosa. Several epidemiological investigations have documented the antibacterial activity and clinical efficacy of fosfomycin used for infections sustained by MDR enterobacteria. Falagas et al.62 systematically reviewed 17 articles, for a total of 5057 enterobacterial clinical isolates (88% of which were ESBL producers), to determine fosfomycin’s antibacterial activity and clinical efficacy for infections caused by MDR bacteria such as ESBL-producing enterobacteria. In 11 of the 17 articles selected, at least 90% of the isolated strains remained sensitive to fosfomycin,62 especially E. coli (96.8%) and K. pneumoniae (81.3%). In one study of 290 clinical isolates of ESBL-producing E. coli, 99.7% of strains were susceptible to fosfomycin,59 while 92.7% of the 138 K. pneumoniae isolates were also susceptible to this drug.59 Neuner et al.,67 in a study about the use of fosfomycin for treatment of 41 patients with UTIs due to MDR bacteria, found that 86% of the isolated strains were susceptible to this antibiotic (Table 14) and its use was associated with microbiological eradication in 59% of patients. Microbiological eradication was also reached in 46% of patients with infections caused by K. pneumoniae resistant to carbapenems, in 38% of those due to P. aeruginosa, in 71% of those due to vancomycin-resistant enterococci, and in 57% of those due to ESBL-producing bacteria.67 Analogous results were obtained by Pullukcu et al.,68 Prakash et al.,69 and Fournier et al.70
Table 15 Studies published in the literature relative to endourological procedures and surgery
the use of
trometamol
for
prophylaxis in
Reference
Year
Indication
Study design
Comparator drug
Patients (n)
Periti et al.74 Periti et al.74 Di Silverio et al.75 Baert et al.72 Di Silverio et al.76 Selvaggi et al.77 Nicoletti et al.73 Szopinski et al.78 Jimenez-Pacheco et al.71
1988 1988 1988 1990 1990 1992 1994 2002 2012
TURP TURB/Cystoscopy ESWL, URSL* TURP TURP, TURB TURP Cystoscopy TURP, PCNL*, URSL Cystoscopy
Randomized Open Open Randomized Open Open Randomized Open Randomized
Amoxicillin Cotrimoxazole … … Placebo … … Placebo … Placebo
900 283 30 61 712 70 174 80 60
Note: *URSL: ureteroscopy lithotripsy; PCNL, percutaneous nephrolithotomy.
20
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Table 16 Outcome of perioperative antibiotic prophylaxis
TURP (n) Fever .38uC I postoperative day Fever .38uC VI–VIII postoperative days Bacteriuria .105 CFU/ml within 2 weeks Symptomatic infection within 1 week Adverse events
Amoxicillin
Cotrimoxazole
Fosfomycin trometamol
283 6% 3.5% 24.7% 8.1% 6.4%
288 4.9% 3.8% 27.4% 8.3% 8.3%
329 3% 0.3% 16.4%* 3.3%* 3.6%
Note: CFU: colony forming units. *P,0.01: significantly lower compared to results with amoxicillin and cotrimoxazole.
Furthermore, Wagenlehner et al.65 reviewed the use of fosfomycin trometamol as prophylaxis for endourological procedures, analysing a total of 1614 patients from nine clinical studies (four randomized and five open), published between 1988 and 2012 (Table 15). The drug was usually prescribed in most cases at a dosage of 3 g administered 3 hours before the procedure and another 3 g given 24 hours following. The only exceptions were 88 patients undergoing cystoscopy, who were given a single 3 g dose of fosfomycin trometamol 3 hours before the procedure. In all the studies analysed, except that of JimenezPacheco et al.,71 fosfomycin trometamol proved to be at least as efficacious as the other prophylactic regimens employed, and certainly more effective than placebo.72,73 Table 16 reports the results of the study by Periti et al.74 which compared amoxicillin, cotrimoxazole, and fosfomycin trometamol for perioperative urological prophylaxis. Fosfomycin was significantly more efficacious in reducing bacteriuria and symptomatic infections within a week after the procedures than the other two drugs. What emerges from above is that fosfomycin, although being in clinical use for several years, presents numerous interesting attributes in the field of urology — not only for strictly therapeutic but also for prophylactic uses, especially in this period of growing resistance of Gram-negative bacteria to the other antibiotics habitually used in this field.
Disclaimer Statements Contributors The contributors to the article are all the authors. Funding None. Conflicts of interest Professor Concia and Dr Azzini have no conflicts of interest. Ethics approval Since it is a review article, it was not necessary to have any ethics approval.
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Concia and Azzini
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Journal of Chemotherapy
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