Proteus species

Authors: Chelsie E. Armbruster, Harry L. T. Mobley

Authors (Second Edition 2002): Dora Szabo, David L. Paterson

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MICROBIOLOGY

Proteus is a member of the Enterobacteriaceae family. The genus of Proteus consists of motile, aerobic and facultatively anaerobic, Gram-negative rods. Proteus is a member of the tribe Proteeae, which also includes Morganella and Providencia. The genus Proteus currently consists of five named species: P. mirabilis, P. vulgaris, P. penneri, P. myxofaciens and P. hauseri and three unnamed genomospecies: Proteus genomospecies 4, 5, 6 (104). However, a recent study indicated that P. myxofaciens may represent a separate genus with low similarity to tribe Proteeae, and it has been suggested that this organism be renamed Cosenzaea myxofaciens (47).

A striking microbiologic characteristic of Proteus species is their swarming activity. Swarming appears macroscopically as concentric rings of growth emanating from a single colony or inoculum. On a cellular level, swarming results from bacterial transformation from "swimmer cells" in broth to "swarmer cells" on a surface such as agar, in a process involving cellular elongation and increased flagellin synthesis (62). The genus name Proteus originates from the mythological Greek sea god Proteus, who was an attendant to Poseidon (62). Proteus could change his shape at will. This attribute reminded early microbiologists of the morphologic variability of the Protei on subculture, including their ability to swarm.

EPIDEMIOLOGY

Members of the genus Proteus are widespread in the environment and are found in the human gastrointestinal tract (9). The most common infections caused by Proteus spp. are urinary tract infections (UTIs). Proteus spp. can be found to colonize the vaginal introitus prior to onset of bacteruria. Therefore, like Escherichia coli, Proteus spp. causes urinary tract infections by ascending from the rectum to the periurethra and bladder.

P. mirabilis is by far the most common species identified in clinical specimens. P. mirabilis is a common cause of both community-acquired and catheter-associated UTI, cystitis, pyelonephritis, prostatitis, wound infections, and burn infections, and occasionally causes respiratory tract infections, chronic suppurative otitis media, eye infections (endophthalmitis), meningitis, and meningoencephalitis (3, 4, 51, 81, 137). It is a common cause of bacteremia following catheter-associated UTI (90), and in rare cases has been reported to cause cellulitis, endocarditits, mastoiditis, empyema, and osteomyelitis (24, 61, 86, 137). It has also been suggested that P. mirabilis could have a role in the etiology of rheumatoid arthritis (145).

P. vulgaris, previously considered biogroup 2, has been reported to cause UTIs, wound infections, burn infections, bloodstream infections, and respiratory tract infections (71, 137). There has also been one case study of P. vulgaris causing bacteremia and brain abscesses, with the suspected point of entry being the digestive tract(16).>

P. penneri, previously biogroup 1, generally causes UTIs, wound infections, burn infections, bloodstream infections, and respiratory tract infections (71, 137).There has been one case study ofP. penneri Fournier's gangrene in a child with congenital genitourinary anomalies (33). There has also been one recent report of P. penneri causing "red body disease" of the Pacific white shrimp Penaeus vannamei (25). Notably, P. penneri may be incorrectly identified as P. mirabilis due to being indole-negative (72), and it cannot be clearly resolved from P. vulgaris by 16S sequencing unless using the 16S-23S internal transcribed spacer (26). Thus, the burden of human infections caused by this organism may be underestimated.>

P. myxofaciens was originally isolated from a gypsy moth and has been isolated from UTIs in India (129).

P. hauseri, previously considered biogroup 3, has not been associated with infections in humans.

CLINICAL MANIFESTATIONS

The clinical manifestations of infections with Proteus spp. are, in the main, non-specific. However, urinary tract infections involving struvite stones are characteristic. By producing urease, Proteus spp. can hydrolyze urea into ammonia and carbon dioxide, and therefore raise urinary pH. Alkalinization of urine promotes precipitation of magnesium-ammonium phosphate salts leading to the formation of struvite stones, which may serve as a nidus for the persistence of infection or may directly obstruct the urinary tract, thereby promoting infection.

LABORATORY DIAGNOSIS

The members of the genus Proteus are Gram negative, motile facultative anaerobic rods. On culture plates, Proteus species are distinguished by their ability to swarm. Proteus spp. have 2-3mm colorless, flat, colonies on MacConkey agar, whereas they swarm in waves to cover blood agar plates and LB agar plates.

Proteus spp. are identified by the following biochemical characteristics: positive methyl-red reaction, negative Voges-Proskauer reaction, phenylalanine deaminase production, growth on KCN and urease production. P. mirabilis and P. penneri are indole-negative, while other Proteus species are indole-positive. The Proteus genomospecies (4, 5, and 6) can be distinguished from other Proteus species based on five biochemical characteristics: esculin hydrolysis, salicin fermentation, L-rhamnose fermentation, and elaboration of DNase and lipase.

PATHOGENESIS

Proteus spp. possess several virulence factors that explain their uropathogenic potential, many of which have been investigated in a murine model of UTI (>9). They have pili or fimbriae for adherence to uroepithelium. Additionally, they elaborate cytotoxic hemolysins that lyse red cells and release iron, a bacterial growth factor. Proteus isolates possess flagella for motility. As noted above they produce urease, leading to the formation of struvite stones.

SUSCEPTIBILITY IN VITRO AND IN VIVO

Proteus spp. can be naturally resistant to antibiotics, such as benzylepenicillin, oxacillin, tetracycline, and macrolides (137). Proteus spp. can acquire resistance to ampicillin through plasmid mediated beta-lactamases, and chromosomal beta-lactamase expression has now been reported (136). In the last decade there have also been numerous reports of production of extended-spectrum beta-lactamases (ESBLs) by Proteus spp.. The ESBLs can confer resistance to third generation cephalosporins such as cefotaxime, ceftriaxone and ceftazidime, as well as the monobactam, aztreonam (115). The cephamycins (cefoxitin, cefotetan and cefmetazole) and the carbapenems (imipenem and meropenem) are generally not hydrolyzed by ESBLs (115). However, resistance to carbapenems is starting to be observed inProteus spp. (63, 109, 128).

It should be noted that the MICs for third generation cephalosporins or aztreonam may not reach widely used breakpoints for resistance with some ESBL producing Proteus isolates. In 2010, there was a change in the CLSI recommendations for susceptibility breakpoints, resulting in many ESBL-producing isolates previously considered to be resistant to these antibiotics now being regarded as susceptible (39, 93, 142).For instance, 78-97% of ESBL-producing strains tested were considered susceptible to ceftazidime, cefepime, and aztreonam using the new breakpoints (93, 142). Another change in CLSI recommendations occurred in 2012, and SENTRY data from North America indicates that this change decreased the level of imipenem susceptibility compared to the 2010 criteria (64.5% of 1244 isolates were susceptible by 2012 criteria vs 99.8% by 2010 criteria) (117). Due to these changes in breakpoints for susceptibility, data concerning resistance to celphalosporins, aztreonam, and carbapenems may be underestimated.

Single Drug

Proteus mirabilis: Overall, the majority of P. mirabilis isolates from the past two decade have been susceptible to commonly used antibiotics (58). SENTRY data from the US and EU of isolates collected in 2009-2011 reported <10% of isolates resistant to amikacin, aztreonam, cefepime, ceftazidime, ceftriaxone, meropenem, and piperacillin/taxobactam (120), and a study of P. mirabilis catheter-associated UTI isolates from Poland similarly reported only 14% of isolates being resistant to amikacin. However, vancomycin, teicoplanin, linezolid, quinupristin/ dalfopristin, daptomycin, clindamycin, metronidazole, macrolides and ketolides do not have clinically useful activity against >P. mirabilis, and a high level of resistance (>60% of isolates) has been observed for cefuroxime, tetracycline, polymyxin B, colistin sulfate, and nitrofurantoin (2). The new glycylcycline, tigecycline, also has surprisingly poor in vitro activity, compared to its activity against other Gram negative bacilli (45). High levels of ciprofloxacin resistance have been reported in Poland (94), though norfloxacin remained effective against these isolates (94), and qnr quinolone resistance genes have been identified in P. mirabilis isolates (52, 92).A compendium of antibiotic resistance of P. mirabilis is given in Table 1.

A wide variety of ESBLs have been detected in P. mirabilis, and recent reports indicate a rise in ESBL-producing P. mirabilis, for instance in Japan (29). CTX-M-type ESBLs have been detected in > P. mirabilis isolates from Korea and Taiwan (136, 141). CTX-M2 is the most common ESBL in Japan (64, 65, 97), as well as Israel (5) and it appears to be spreading rapidly (64, 98).CTX-M type β-lactamases also appear to be evolving in P. mirabilis via recombination (44). CTX-M has been found on the P. mirabilis chromosome as part of an integrative and conjugative element (ICE) in addition to being plasmid-encoded (87). TEM is another common ESBL in P. mirabilis (69), and the most common type of ESBL in P. mirabilis isolates from Croatia and Italy (5, 125, 138).A new TEM (TEM-187) has been reported in P. mirabilis, which has broad activity against penicillins but lower activity than TEM-1 (31, 32).It has been suggested that TEM-187 may represent an evolution of TEM enzymes from penicillinases to ESBLs, leading to underestimation of ESBLs in P. mirabilis (31). Other ESBL types include: VEB-1, an integron borne ESBL that was detected in a P. mirabilis isolate from a Vietnamese patient hospitalized in France (95), a multidrug-resistant isolate from Greece (109), and in Taiwan (59); PER-1, which was detected in a P. mirabilis isolate from Italy (106); VIM-1, detected in three ESBL P. mirabilis isolates from Bulgaria (128); and SHV-type β-lactamases, detected in P. mirabilis isolates from Bulgaria (128) and Taiwan (59).>

Metallo-beta-lactamases (MBLs) are also being reported in recent P. mirabilis isolates. For instance, one study from France identified a P. mirabilis isolate with a metallo-beta-lactamases (11), and a New Dehli metallo-beta-lactamase (NDM-1) has been identified in P. mirabilis isolates from New Zealand and India (15, 49, 144). Interestingly, NDM-1 was present in a genomic island in one isolate of P. mirabilis and co-occurred with a VEB-6 ESBL and SGI-1 (described below) (49), and it has been proposed that the presence of NDM-1 in a genomic island structure may enhance the spread of carbapenemases.

Multidrug resistance in P. mirabilis is also becoming more common (92). SGI-1 (>Salmonella genomic island 1), an integrative mobilizable element of multidrug-resistant Salmonella Typhimurim, has recently been detected in a surprisingly high percentage of P. mirabilis clinical isolates from France and indicates that P. mirabilis is a bacterial species of concern involved in dissemination of this multidrug-resistant element (41, 132, 133). SGI-1 confers resistance to a wide variety of older drugs that are no longer commonly used to treat human infection, but the multidrug-resistant regions of SGI-1 from P. mirabilis isolates had complex mosaic structures and rearrangements capable of facilitating acquisition and/or movement of antibiotic resistance genes that jeopardizes use of third-generation cephalosporins and quinolones (>132, 133).An ESBL-producing P. mirabilis isolate has also been identified with both TEM and CTX-M (110). Interestingly, ESBL production was found to be a risk factor for ciprofloxacin-resistant bacteremia due to P. mirabilis (135), and recent treatment with quinolone antibiotics was a risk factor for carriage of ESBL-producing P. mirabilis (5). A recent study from Tunisia also identified a high prevalence of plasmid-mediated quinolone resistance determinants among ESBL-producing P. mirabilis isolates (83).

Importantly, ESBL and non-ESBL producing isolates of P. mirabilis are frequently susceptible to beta-lactam/beta-lactamase inhibitor combinations. However, there have been some reports of inhibitor resistant TEM mutants (IRT) occurring in P. mirabilis (18, 84, 102). These beta-lactamases are not inhibited by clavulanic acid, sulbactam and tazobactam. It should be noted that these beta-lactamases do not have extended-spectrum activity (that is, they do not hydrolyze third generation cephalosporins).

Another mechanism of beta-lactamase inhibitor resistance in P. mirabilis isolates is presence of plasmid-mediated AmpC beta-lactamases. AmpC type beta-lactamases (also termed group 1 or class C beta-lactamases) can either be chromosomally encoded or plasmid encoded in P. mirabilis (99, 116). AmpC has also been found on the chromosome as part of integrative and conjugative elements (ICE) (87). Strains with plasmid-mediated AmpC beta-lactamases are consistently resistant to aminopenicillins (ampicillin or amoxicillin), carboxypenicillins (carbenicillin or ticarcillin) and ureidopenicillins (piperacillin). These enzymes are also resistant to third generation cephalosporins and the 7-α-methoxy group (cefoxitin, cefotetan, cefmetazole, moxalactam). MICs for aztreonam are usually in the resistant range but may occasionally be in the susceptible range. AmpC beta-lactamases generally do not effectively hydrolyze cefepime or the carbapenems.>One type of AmpC beta-lactamase is CMY, and clonal spread of CMY-producing P. mirabilis has been reported in Europe (36). CMY is also the predominant AmpC in Taiwan (141), and AmpC has been reported in P. mirabilis isolates from Korea (136) and Spain (87).

Carbapenems are generally active against P. mirabilis. However, imipenem MICs are frequently higher for P. mirabilis compared to other members of the Enterobacteriaceae, and a recent study from Taiwan found that only 11.4% of P. mirabilis isolates were susceptible to imipenem (139). Meropenem is more potent than imipenem against P. mirabilis (46, 139). Carbapenemases have been found in >P. mirabilis (130), albeit rarely. A recent report has documented the presence of the class D carbapenemase, OXA-23, in P. mirabilis (19).

Proteus vulgaris: Proteus vulgaris produces a chromosomally encoded beta-lactamase (23), referred to as the cefuroxime-hydrolyzing beta-lactamase (cefuroximase or CumA) (34), which hydrolyzes cephalosporins. The enzyme can be induced by ampicillin, amoxicillin and first generation cephalosporins, weakly induced by carboxypenicillins, ureidopenicillins, cefotaxime and ceftriaxone, and inhibited by clavulanate. Strains of P. vulgaris that have a mutation in the regulatory genes of this beta-lactamase produce high levels of the enzyme and are resistant to penicillins, cefuroxime, ceftriaxone and cefotaxime. However, these isolates will generally be susceptible to ceftazidime, aztreonam, cephamycins, carbapenems and beta-lactam/beta-lactamase inhibitor combinations. Ertapenem and meropenem are substantially more active than imipenem (80). A compendium of antibiotic resistance of P. vulgaris is included in Table 1.

Recent reports have indicated the presence of ESBLs in P. vulgaris isolates (69, 78, 130), similar to P. mirabilis, including TEM and PER (60, 69). It has been noted that the MICs of several oxyimino type expanded-spectrum cephalosporins, such as cefotaxime and cefpodoxime, are much higher when broth microdilution methods are used than when agar dilution methods are used in vitro susceptibility testing of P. vulgaris. Proposed mechanisms for this MIC gap phenomenon are unclear (105).

Quinolones and aminoglycosides are usually active against P. vulgaris strains (45), though qnr genes for quinolone resistance have been detected in recent isolates (52, 92). Tigecycline has lesser activity against >P. vulgaris than against other Enterobacteriaceae (for example, MIC₅₀ 4 µg/mL against P. vulgaris but 0.25 µg/mL against E. coli) (45).

P. penneri: Like P. vulgaris, P. penneri is naturally resistant to ampicillin, narrow-spectrum cephalosporins and cefuroxime, by virtue of production of a similar beta-lactamase (77).P. penneri is considered to be a nosocomial pathogen with an underestimated potential to cause disease, and a recent case report identified a multidrug-resistant ESBL-producing P. penneri isolate (107).

P. myxofaciens: One report of P. myxofaciens from UTIs in India discussed antibiotic susceptibility, and found this species to be susceptible to imipenem, ciprofloxacin, amikacin, gentamicin, trimethoprim-sulfamethoxazole, aztreonam, ofloxacin and piperacillin and resistant to methicillin and nalidixic acid (129).

In Vivo Experiments

Very few in vivo (animal) models of Proteus infections have been established in which antimicrobial activities were assessed. Treatment of Proteus sepsis in rats with ceftazidime or carbapenems was associated with an increase in the plasma endotoxin concentration (57). However, the antibiotic concentrations in those animals treated with carbapenems were significantly lower than for animals treated with ceftazidime. The significance of this finding is uncertain.

ANTIMICROBIAL THERAPY

General

Urinary tract infection is the most common clinical manifestation of Proteus infections. Empiric treatment for community-acquired urinary tract infection will depend more on susceptibilities of E. coli than of P. mirabilis, since E. coli is by far the more common pathogen. For hospitalized patients or those with urinary catheters, the first decision is whether the isolate is clinically significant. Isolates which are not accompanied by pyuria or symptoms do not warrant treatment. Based on the compiled antibiotic resistance data provided in Table 1, trimethoprim or cotrimoxazole may no longer be viable treatment options for P. mirabilis infections. Quinolone resistance is also increasing, and P. mirabilis is almost uniformly resistant to nitrofurantoin, tetracycline, and polymyxins. The most appropriate treatment for P. mirabilis may be aminoglycosides, carbapenems (except imipenem), and 3^rd generation cephalosporins. Recent P. mirabilis isolates were also mostly susceptible to augmentin, ampicillin-sulbactam, and piperacillin/tazobactam. In general, treatment should be with intravenous agents (or oral therapy for quinolones) until fever has resolved. Correction of the underlying anatomical abnormality or removal of a urinary catheter is also frequently necessary.

The treatment of choice of P. mirabilis bacteremia depends on whether or not the organism is an ESBL producer. Carbapenems are the treatment of choice for ESBL producing isolates causing bacteremia (112). The basis for this statement is not just the almost uniform in vitro susceptibility but also increasingly extensive clinical experience. However it must be pointed out that this experience is in organisms such as K. pneumoniae rather than P. mirabilis. Meropenem is preferred over imipenem for ESBL producing P. mirabilis in view of the superior in vitro susceptibility of meropenem against P. mirabilis (46). Piperacillin/tazobactam has been successfully used to treat ESBL producing P. mirabilis infections in Italy (82). Quinolones are probably a reasonable option if the isolate is susceptible. Cephalosporins are not recommended for the treatment of ESBL producing P. mirabilis isolates; failures have been observed (82).

In view of the presence of an inducible beta-lactamase in P. vulgaris, we would not recommend penicillins, cefuroxime, ceftriaxone or cefotaxime as first line therapy for serious infections due to this organism. However, the MICs of ceftazidime and aztreonam are almost always less than 1 µg/mL, these antibiotics do not induce production of the beta-lactamase of P. vulgaris and the enzyme does not hydrolyze these antibiotics. Therefore, aztreonam, beta-lactam/ beta-lactamase inhibitor combinations, or carbapenems would be reasonable, since these drugs are resistant to the hydrolytic activity of class A beta-lactamase.

The development of resistance to ceftriaxone, occurring during treatment, has been seen with P. penneri (82). Treatment recommendations are the same for this organism as for P. vulgaris.

Special Infections

Meningitis:

Proteus meningitis usually follows neurosurgical procedures (28). Third generation cephalosporins are indicated in the treatment of P. mirabilis meningitis only if the organism is proven not to be an ESBL producer. Aztreonam has also been successfully used in the treatment of Proteus meningitis, and may be an option in penicillin allergic patients (70). Meropenem (2 grams every 8 hours intravenously, in adult patients with normal renal function) should be regarded as the therapy of choice for meningitis due to >P. vulgaris, P. penneri and ESBL producing P. mirabilis. Although only a single case report of failure exists, ceftriaxone or > cefotaxime should probably be avoided for >P. vulgaris or P. penneri meningitis (77). Removal of neurosurgical hardware should be considered wherever possible.

Endocarditis:

Infective endocarditis due to P. mirabilis has been rarely reported. The few cases that have been reported appear to have been related to prosthetic valves (8, 50). Therefore early surgical intervention is likely the key to successful outcome. Therapeutic options would appear to be an appropriate beta-lactam (see section on therapy of bacteremia above) plus an aminoglycoside.

Underlying Diseases

The therapeutic recommendations are not different for those patients with immunosuppression.

Alternate Therapy

Serious infections in patients with life-threatening allergies to beta-lactam antibiotics could comprise aminoglycosides or possibly either quinolones or cotrimoxazole. Nitrofurantoin is not an option nor is tetracycline or the glycylcycline class.

ADJUNCTIVE THERAPY

As noted above, early surgical consultation is necessary in patients with Proteus endocarditis or post-neurosurgical meningitis. Urologic consultation should be sought in patients with recurrent Proteus urinary tract infection, especially in the presence of struvite stones (123).

ENDPOINTS FOR MONITORING THERAPY

Generally, standard clinical endpoints are used for determining the adequacy of therapy for Proteus infections. After initiation of therapy, a favorable response is signified by resolution of systemic and local symptoms and signs of infection. In patients with primary or secondary bacteremia, blood cultures should become negative. For urinary tract infections, urine cultures should become negative. In patients with Proteus meningitis, a repeat spinal tap after 48 to 72 hours may be helpful to document microbiologic clearance. The duration of therapy after an initial favorable clinical response is generally empiric. Pneumonia, bacteremia and urinary tract infections require at least 10 days of therapy. Meningitis should be treated for 21 days, and endocarditis for at least 42 days.

If fever recurs during therapy, then a superinfection or a drug allergy should be considered. Many of the patients infected with P. vulgaris will have serious underlying illnesses which predispose them to superinfections.

VACCINES

No vaccines are commercially available at the present time. However, P. mirabilis vaccine candidates are being identified and efficacy tested in a murine model of ascending UTI (6, 53, 74, 75, 76, 103, 126, 127).

INFECTION CONTROL MEASURES

Typing methods for P. mirabilis have been studied for greater than 30 years (3, 4). The ability of P. mirabilis to swarm over the surface of agar media has been utilized in a typing method known as the Dienes mutual inhibition test (114). The Dienes test is based on the mutual inhibition of two different strains as they swarm towards one another on an agar surface. If the two strains are genetically distinct, a clear line of demarcation will form as the swarming edge of one strain meets the other. In contrast, if the two strains are related or identical, there is no mutual inhibition and the swarming edges merge with no visible line of demarcation (114). Genetic determinants of Dienes line formation have been identified and are an active area of research (7, 22, 48, 143). Discriminatory power of the Dienes test is virtually identical to pulsed field gel electrophoresis or ribotyping (114). Polymerase chain reaction based methods have also been used to characterize the molecular epidemiology of P. mirabilis (42).

Outbreaks of ESBL and non-ESBL producing Proteus mirabilis infections have occurred. The gastrointestinal tract is the likely reservoir of infection (30). We believe that contact isolation precaution measures should be used as a mode of control of spread of ESBL producing P. mirabilis. Such an approach requires the identification of asymptomatic carriers of the organism and then accommodation of such individuals in single rooms or cohorting with other colonized patients. Those who enter the room of a patient colonized with an ESBL producing organism should wear gloves and gowns and practice appropriate hand hygiene on leaving the patient's room and removal of the protective apparel. Restriction of use of third generation cephalosporins should also be considered to reduce selective pressure leading to mutations contributing to ESBL production.

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Tables

Table 1. Resistance of Proteus Species to Selected Antibiotics (3708 P. mirabilis isolates and P. vulgaris isolates were included from references 1, 2, 14, 21, 54, 55, 63, 68, 91, 92, 94, 111, 120, 121, 122, 135, 139, 141; )

Antibiotic	Resistant Isolates/Total Number Tested (%)
Antibiotic	P. mirabilis	P. vulgaris
Aminoglycosides:
Amikacin	64/1500 (4.3)	23/65 (35.4)
Gentamicin	195/1532 (12.7)	17/49 (34.7)
Netilmicin	34/201 (16.9)	19/47 (40.4)
Tobramycin	143/1073 (13.3)	NR
Carbapenems:
Ertapenem	10/319 (3.1)	0/2 (0)
Imipenem	754/2142 (35.2)	0/20 (0)
Merepenem	11/1390 (0.8)	0/2 (0)
Oripenem	0/44 (0)	NR
1^st Generation Cephalosporins:
Cefalothin	13/106 (12.3)	NR
Cefazolin (Cephazolin)	3/25 (12.0)	2/2 (100)
2^nd Generation Cephalosporins:
Cefaclor	6/22 (27.3)	NR
Cefoxitin	24/176 (13.6)	10/18 (55.6)
Cefuroxime	94/408 (23.0)	39/67 (58.2)
3^rd Generation Cephalosporins:
Cefditoren	4/106 (3.8)	NR
Cefoperozone+Sulbactam	0/18 (0)	0/18 (0)
Cefotaxime (Cefatam)	251/1398 (17.9)	NR
Ceftazidime	153/2700 (5.7)	19/47 (40.4)
Ceftriaxone (Rocephin/Epicephin)	88/1357 (6.5)	15/20 (75.0)
4^th Generation Cephalosporins:
Cefepime	81/1455 (5.6)	22/65 (33.8)
Monobactams:
Aztreonam	58/1262 (4.6)	0/2 (0)
Nitrofurans:
Nitrofurantoin	150/204 (73.5)	13/47 (27.7)
Penicillins:
Amoxicillin	73/161 (45.3)	NR
Amoxicillin-Clavulanic Acid (Augmentin)	65/393 (16.5)	19/47 (40.4)
Ampicillin	95/282 (33.7)	21/49 (42.9)
Ampicillin-Sulbatam	218/1310 (16.6)	6/18 (33.3)
Carbenicillin	32/142 (22.5)	NR
Mecillinam	25/106 (23.6)	NR
Piperacillin	49/95 (51.6)	16/47 (34.0)
Piperacillin/Tazobactam	55/1491 (3.7)	18/47 (39.3)
Ticarcillin	25/33 (75.8)	NR
Phosphonics:
Fosfomycin	11/156 (7.0)	NR
Quinolones:
Ciprofloxacin	1063/3337 (31.8)	0/2 (0)
Gatifloxacin	20/62 (32.2)	18/47 (38.3)
Levofloxacin	368/1839 (20.0)	13/65 (20.0)
Nalidixic Acid	8/106 (7.5)	NR
Norfloxacin	78/259 (30.0)	20/47 (42.5)
Ofloxacin	45/204 (22.0)	19/47 (40.4)
Sulfonamides:
Trimethoprim-sulfamethoxazole (Co-trimoxazole)	178/587 (30.3)	16/49 (32.6)
Polymyxins:
Colistin (Polymyxin E)	238/242 (98.3)	NR
Polymyxin B	133/142 (93.7)	NR
Tetracyclines:
Tetracycline	158/164 (96.3)	NR
Tigecycline	357/1040 (34.3)	NR