Rat guide azithromycin for uti


MICROBIOLOGY

The genus Klebsiella consists of non-motile, aerobic and facultatively anaerobic, Gram negative rods. At the time of writing, the genus Klebsiella comprises K. pneumoniae subsp. pneumoniae, K. pneumoniae subsp.ozaenae, K. pneumoniae subsp. rhinoscleromatisK. oxytoca, K. ornithinolytica, K. planticola, and K. terrigena (1). However, comparison of the sequences of each species shows that the genus is heterogeneous, and may be more reasonably arranged in three clusters (76). Cluster 1 contains the three subspecies of K. pneumoniae, cluster 3 contains K. oxytoca and cluster 2 contains the other species (which are notable for growth at 10° C and utilization of L-sorbose as a carbon source). It has been proposed that the genus Klebsiella be divided into two genera and one genogroup, with the name Raoultella being the genus name for those organisms in cluster 2 (76).

For the purpose of conforming to current clinical usage, the clinically important species and subspecies will be referred to as K. pneumoniae, K. ozaenae, K. rhinoscleromatis and K. oxytoca in this chapter.

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EPIDEMIOLOGY

Klebsiella spp. are amongst the most common causes of a variety of community-acquired and hospital-acquired infections. K. pneumoniae is an important emerging pathogen in community-acquired liver abscess worldwide, especially in Taiwan, Asia and the USA (36,55,66,150,190). The prevalence rate of K. pneumoniae in pyogenic liver abscess is as high as 78% in Taiwan and 41% in the USA (55, 218,267). They rank fourth as causes of intensive care unit (ICU) acquired pneumonia, fifth as causes of ICU acquired bacteremia and sixth as causes of ICU acquired urinary tract infection (225). K. pneumoniae is the leading cause of disease followed by K. oxytoca. K. ozaenae and K. rhinoscleromatis are rarely isolated, but can cause defined clinical syndromes (ozena and rhinoscleroma, respectively). K. ornithinolytica and K. planticola are rare causes of disease (178). K. terrigena (like K. pneumoniae on occasion) can be grown from soil and water; it can also be grown from human feces and from clinical specimens (1). It possesses a number of the virulence characteristics of K. pneumoniae (211) so is likely to be an occasional cause of disease.

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CLINICAL MANIFESTATIONS

Hospital-acquired Klebsiella infections are not easily distinguished clinically from other bacterial causes of infection. However, community-acquired Klebsiella infections do have some characteristic features. Traditionally,Klebsiella has been regarded as an important cause of community-acquired pneumonia. The classic clinical presentation is dramatic: toxic presentation with sudden onset of high fever and hemoptysis (currant jelly sputum). Chest radiographic abnormalities such as bulging interlobar fissure and cavitary abscesses are prominent (118, 146). Recent work suggests that community-acquired Klebsiella pneumonia is now exceedingly rare in North America, Western Europe and Australia (accounting for less than 1% of cases of pneumonia requiring hospitalization) (143). However the classic syndrome of bacteremic Klebsiella pneumonia remains common in Asia and Africa. In these regions there is an association of the syndrome with alcoholism, although previously healthy people have been affected (143).

An unusual invasive presentation of Klebsiella infection has also been described, occurring particularly in Asia (especially Taiwan). The predominant manifestation is liver abscess occurring in the absence of underlying hepatobiliary disease (36,55,59,143, 288). Seventy percent of such patients have diabetes mellitus. In some patients, other septic metastatic lesions are observed including endophthalmitis, pyogenic meningitis, brain abscess, septic pulmonary emboli, prostatic abscess, osteomyelitis, septic arthritis or psoas abscess.

K. oxytoca can produce community-acquired infections similar to those produced by K. pneumoniae but is substantially less common. K. rhinoscleromatis produces rhinoscleroma, a rare granulomatous infiltration of the mucosa of the nose and upper respiratory system (7). Cases have been reported in patients with human immunodeficiency virus (HIV) infection and in immigrants from parts of the world where the disease is endemic (202, 264). K. ozaenae may be responsible for a form of chronic atrophic rhinitis called ozena. K. ozaenae is also considered to be an opportunistic pathogen in immunocompromised hosts (65,145, 257).

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LABORATORY DIAGNOSIS

The members of the genus Klebsiella are Gram negative, nonmotile, facultative anaerobic rods ranging from 0.3 to 1.0 μm in width to 0.6-6.0 μm in length (1). Most strains grown readily on standard media, although occasionally cysteine requiring urinary isolates of K. pneumoniae are encountered. These strains will appear as pinpoint colonies on routine media, and require supplementation of media with cysteine for more adequate growth (1). The vast majority of Klebsiella spp. are encapsulated - contrary to popular belief it is probably not capsule which primarily contributes to the mucoid appearance that some Klebsiella strains exhibit.  The Klebsiella which has been linked to the invasive syndrome presenting as liver abscess have a mucoid appearance.

In practice, K. pneumoniae and K. oxytoca are distinguished by indole production by K. oxytoca but not K. pneumoniae. It should be noted however that K. ornitholytica is also an indole producer. The five clinically important species can be distinguished by tests for indole production, ornithine decarboxylase production, he Voges-Proskauer reaction, malonate utilization and o-nitrophenyl-β-D-galactopyranoside (ONPG) production (1).

Production of plasmid-mediated extended-spectrum beta-lactamases (ESBLs) by Klebsiella spp. has become a major problem (197). The nature and characteristics of ESBLs are described in greater detail below. Detection of ESBLs in clinical isolates of Klebsiella spp. is problematic since a significant proportion of ESBL producing isolates appear susceptible to third generation cephalosporins or aztreonam. Yet, poor clinical outcomes have been observed when these same antibiotics have been used to treat serious infections due to apparently susceptible ESBL producers (198). A single surrogate marker for ESBL production, such as ceftazidime resistance, is insufficient for the detection of ESBLs. Virtually all reliable laboratory tests used for detection of ESBLs rely on the change in in vitro activity of oxyimino containing beta-lactams in the presence of a beta-lactamase inhibitor such as clavulanic acid. Examples of ESBL detection methods include the double disk diffusion test, Etest strips containing ceftazidime or cefotaxime with and without clavulanic acid, the Vitek ESBL detection card and the Microscan ESBL plus detection system (34). Clinical and Laboratory Standards Institute (CLSI) has also developed screening and confirmatory tests for detection of ESBLs (67). It should be noted that these are standardized for K. pneumoniae and K. oxytoca only.

In some circumstances there is a need to detect ESBL producing Klebsiella spp. from stool or rectal swabs. Examples of such media include Drigalski agar supplemented with cefotaxime 0.5 mg/L (246), MacConkey agar supplemented with ceftazimide 4 mg/L (205) and nutrient agar supplemented with ceftazimide 2 mg/L, vancomycin 5 mg/L and amphotericin B 1667 mg/L (106).

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PATHOGENESIS

Members of the genus Klebsiella usually have prominent capsules composed of complex acidic polysaccharides. Capsules appear essential to the virulence of Klebsiella, protecting the bacterium from phagocytosis by neutrophils and preventing killing of the bacteria by bactericidal serum factors (212). Strains expressing capsular types K1 or K2 may be particularly virulent. We have demonstrated the high prevalence (63.4%) of serotype K1 in K. pneumoniae liver abscess and 85.7% in complicated endophthalmitis in which those K1 isolates are highly resistant to neutrophil phagocytosis (94, 158). Although Fang et al have identified a virulence gene magA that caused K. pneumoniae liver abscess and septic metastatic complications (84), they have not correlated the virulence between the gene and serotype specificity. Struve et al have further investigated the above correlation (251) and found that 495Klebsiella isolates from a worldwide collection isolated from unknown different sites, all 39 magA-positive isolates were of the serotype K1 and none of the 456 non-K1 serotypes contained magA. They concluded that magA is only restricted to the capsular gene cluster of serotype K1. We have sequenced the whole K1 capsular gene clusters and we have investigated on the prevalence of magA among serotypes K1, K2 and other serotypes from liver abscess patients. Our results with the results from Struve et al show that magA is only present in serotype K1 in liver and non-liver abscess isolates (285). In conclusion, the magA is a component of K1 capsule formation but is not an independent virulence gene in K. pneumoniae liver abscess. In contrast, K1 capsule is an important virulence factor for K. pneumoniae liver abscess. However some strains belonging to the K2 capsular serotype, for example, may be less virulent than others. This suggests that other pathogenicity factors may be present; possibilities include pili (fimbriae), siderophores and extracapsular polysaccharides.

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SUSCEPTIBILITY IN VITRO AND IN VIVO

Klebsiella pneumoniae

Single Drug In Vitro Studies

An overview of the susceptibility of K. pneumoniae to antimicrobial agents is given in Table 1. K. pneumoniaeis intrinsically resistant to penicillin, ampicillin, amoxicillin, oxacillin, carbenicillinand ticarcillin, with mean minimum inhibitory levels ranging from 200 to > 1000 mg/L (51). The vast majority of K. pneumoniae strains produce a chromosomally encoded SHV-1 beta-lactamase, which accounts for this resistance (14, 56). Some strains possess plasmid-mediated SHV-1, TEM-1 or TEM-2 beta-lactamases as well (14, 56). Strains that hyperexpress these beta-lactamases or produce both SHV-1 and TEM-1 may be resistant to piperacillin or first generation cephalosporins. Beta-lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam are active against the SHV-1 and TEM-1 beta-lactamases of K. pneumoniae. However, clinical isolates have been described that are resistant to beta-lactam/beta-lactamase inhibitor combinations (27, 52, 100,152,186). One potential mechanism is production of inhibitor-resistant TEM (IRT) beta-lactamases (52). The IRT beta-lactamases differ from their parental TEM-1 or TEM-2 beta-lactamases by one, two or three amino acid substitutions at different locations. These substitutions are listed in detail at http://www.lahey.org/studies/temtable.htm.  Studies of IRT beta-lactamases produced by E. coli have shown that IRT-producers have high-level resistance to amoxicillin and ticarcillin (MIC90 > 4096 mg/L); addition of clavulanic acid reduces the MIC by only two dilutions. A lower degree of resistance was observed to piperacillin, and tazobactam substantially reduced the piperacillin MIC (52). An inhibitor-resistant beta-lactamase derived from a parent SHV enzyme has also been described (214). Of note is that IRT producers are usually susceptible to the third generation cephalosporins.

Although almost all isolates of K. pneumoniae were initially considered to be susceptible to cephalosporins, studies over the last two decades have shown variable susceptibility to this antibiotic class. This reduced susceptibility has been predominantly mediated by plasmid-mediated extended-spectrum beta-lactamases (ESBLs) and to a lesser extent, plasmid-mediated AmpC type beta-lactamases.

Extended spectrum beta-lactamases (ESBLs) were first described in Germany in 1983 (142). They were subsequently described in France (41, 243) and by the late 1980s numerous outbreaks had occurred in the United States (174,185,216), Australia (79,181) and many other parts of the world (69,123,208,230). These enzymes are now found in every inhabited continent. The ESBLs can confer resistance to third generation cephalosporins such ascefotaxime, ceftriaxone and ceftazidime, as well as the monobactam, aztreonam (208). The cephamycins (cefoxitin, cefotetan and cefmetazole) and the carbapenems (imipenem and meropenem) are not hydrolyzed by the ESBLs (208). It should be pointed out that the MICs for third generation cephalosporins or aztreonam may not reach widely used breakpoints for resistance with some ESBL producing isolates. The clinical significance of this is discussed below.

The molecular basis of extended spectrum beta-lactamases is most often mutation in the genes encoding the common plasmid-mediated SHV-1, TEM-1 and TEM-2 beta-lactamases (124). The resulting amino acid changes lead to alteration in the active site of these enzymes, thus expanding their spectrum of activity (204,245). A change in only one amino acid in the structure of a TEM beta-lactamase may dramatically alter the susceptibility to cephalosporins. At least one hundred such modifications of the TEM and SHV beta-lactamases have been described. An up to date listing of TEM and SHV beta-lactamases is maintained on the Internet by George Jacoby and Karen Bush at www.lahey.org/studies/webt.htm. 

A number of other ESBL types have been detected in K. pneumoniae which are not related to parent TEM or SHV beta-lactamases. The most prevalent of these is the CTX-M-type ESBLs. The name "CTX" is an abbreviation for cefotaximase. This reflects the potent hydrolytic activity of these beta-lactamases against cefotaxime. Organisms producing CTX-M type beta-lactamases typically have cefotaxime MICs in the resistant range (>64 μg/mL), whilst ceftazidime MICs are usually in the apparently susceptible range (2-8 μg/mL). Aztreonam MICs are variable. CTX-M-type beta-lactamases hydrolyze cefepime with high efficiency (269). Cephamycins and carbapenems are not appreciably affected. Tazobactam exhibits an almost 10-fold greater inhibitory activity than clavulanic acid against CTX-M-type beta-lactamases (42). It should be noted that the same organism may harbor both CTX-M-type and SHV-type ESBLs or CTX-M-type ESBLs and AmpC type beta-lactamases, which may alter the antibiotic resistance phenotype (282,283). Other non-TEM, non-SHV type ESBLs which have been described in K. pneumoniae include PER-2 (23) and GES-1 (213).

AmpC type beta-lactamases (also termed group 1 or class C beta-lactamases) are chromosomally encoded in organisms such as Enterobacter cloacae, Citrobacter freundii, Serratia marcescens and Pseudomonas aeruginosa. However in 1989, Bauernfeind et al described a K. pneumoniae isolate possessing a plasmid-mediated beta-lactamase, termed CMY-1, which had many characteristics of a class C beta-lactamase (24). In 1990, Papanicolaou et al described a novel plasmid-mediated beta-lactamase, termed MIR-1, produced by K. pneumoniae (193). The gene encoding MIR-1 was 90% identical to the ampC gene of E. cloacae. Subsequently numerous plasmid-encoded ampC beta-lactamases have been discovered in K. pneumoniae (207). These include FOX-1, 2 and 3, CMY-2, 4 and 8, MOX-1 and 2, DHA-1 and 2, LAT-1 and 2 and ACC-1 (207).

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. Although AmpC beta-lactamases do not effectively hydrolyze cefepime or the carbapenems, strains possessing plasmid-mediated AmpC beta-lactamases and additionally having loss of outer membrane protein channels can have elevated cefepime or carbapenem MICs (35).

The presence of one or multiple ESBLs, or plasmid-mediated AmpC enzymes, is not the only potential mechanism of resistance to third generation cephalosporins in K. pneumoniae. Isolates lacking ESBLs or AmpC enzymes, but hyperproducing SHV-1 may have ceftazidime MICs as high as 32 μg/mL (177,220). Rice and colleagues (220) characterized one such organism -- a single base pair change in the promoter sequence resulted in increased production of chromosomally encoded SHV-1. Additionally, outer membrane protein analysis revealed a decrease in the quantity of a minor 45 kD outer membrane protein. Cephamycin resistance can occur, in the absence of AmpC beta-lactamases, due to the loss of outer membrane porins mediating permeability to cefoxitin (191).

By definition, ESBLs are inhibited to beta-lactamase inhibitors such as clavulanate. AmpC producing strains are not inhibited by beta-lactamase inhibitors. However, in practice a significant proportion of ESBL producing strains are resistant to ticarcillin/clavulanate or piperacillin/tazobactam, and some isolates possessing AmpC beta-lactamases are susceptible to beta-lactam/beta-lactamase inhibitors, especially piperacillin/tazobactam. In a recent survey of ESBL producing Klebsiella isolates from European Intensive Care Units, 63% of isolates were resistant to piperacillin/tazobactam (13). An ESBL produced by K. pneumoniae has been described that is resistant to the actions of the beta-lactamase inhibitor tazobactam (221). Hyperproduction of SHV-5 beta-lactamase, leading to resistance to beta-lactam-beta-lactamase inhibitor combinations (amoxicillin-clavulanic acid, ampicillin-sulbactam, piperacillin-tazobactam, ceftazidime-clavulanic acid) has also been reported (91). Production of large amounts of SHV-1 or TEM-1 beta-lactamase, or the presence of an outer membrane protein deficiency, in addition to production of an ESBL, may also lead to resistance to beta-lactam/beta-lactamase inhibitor combinations.

Susceptibilities of ESBL producing K. pneumoniae to antimicrobial agents are given in Table 2. It should be noted that the carbapenems are the most active agents in vitro. However, carbapenem resistant strains have now been reported. As noted above, neither ESBLs nor plasmid-mediated AmpC beta-lactamases are capable of hydrolyzing carbapenems to any great degree. However, in an experimental investigation of the roles of beta-lactamases and porins in the activities of carbapenems against K. pneumoniae, Martinez-Martinez et al (169) found that carbapenem resistance could be achieved by the combination of porin loss and the presence of the plasmid-mediated beta-lactamases. Clinically relevant examples include porin loss plus ESBLs (SHV-2) (164) or newly characterized AmpC type enzymes (ACT-1, CMY-4) (35, 44). A second documented mechanism for carbapenem resistance is the presence of a beta-lactamase capable of hydrolysis of carbapenems. Worryingly, such carbapenemases have been found to be plasmid-mediated. This is a great concern given the propensity for Klebsiellae to host plasmids. Two types of carbapenemases have thus far been detected. The first are Bush-Jacoby-Medeiros group 3 enzymes. These metalloenzymes were originally found in K. pneumoniae isolates in Japan in 1994. This IMP-1 enzyme has now been found in a K. pneumoniae isolate in Singapore, where a combination with porin loss contributed to high-level carbapenem resistance. A recent report from Taiwan has described a K. pneumoniae isolate with a novel IMP-type carbapenemase (IMP-7), which was encoded on a plasmid also harboring genes encoding TEM-1 and the ESBL, SHV-12 (284). The second carbapenemase detected in K. pneumoniae was the novel Bush-Jacoby-Medeiros group 2f beta-lactamase, coined KPC-1 (287). The amino acid sequence of this beta-lactamase showed 45% homology to the Sme-1 carbapenemase of Serratia marcescens. Although the strain also harbored an ESBL, SHV-29, the carbapenemase was also responsible for resistance to extended-spectrum cephalosporins and aztreonam. A third potential mechanism for carbapenem resistance is a change in the affinity of penicillin binding proteins for carbapenems. Thus far, such a mechanism has not been described in carbapenem resistant, ESBL producing strains.

Ertapenem is active against K. pneumoniae, including ESBL producing strains. For most strains it is approximately two dilutions more active than imipenem, but slightly less active than meropenem (127, 144, 151). However, occasional imipenem susceptible isolates are ertapenem resistant, but these appear to be extremely rare (127). It would be prudent to perform ertapenem susceptibility testing on isolates from patients with serious infections with ESBL producing organisms, rather than rely on imipenem susceptibility as a surrogate marker for ertapenem susceptibility.

The plasmids containing ESBLs frequently carry aminoglycoside modifying enzymes (87). One study of 120 extended spectrum beta-lactamase producing K. pneumoniae showed that percentages of strains resistant to various aminoglycosides were as follows: 100% dibekacin, 89% sisomicin, 84% gentamicin, 84% tobramycin, 78% netilmicin, 65% streptomycin, 65% kanamycin, 57% spectinomycin, 48% neomycin, 19% amikacin (87). The aminoglycoside modifying enzymes most frequently associated with TEM and SHV type extended spectrum beta-lactamases were AAC(3)V, APH (3") and APH (3')I (87).

At least 20% of K. pneumoniae harboring ESBLs may also be resistant to quinolones (199), even though traditionally quinolone resistance has not been thought to be plasmid-mediated. However, a multiresistance plasmid has been detected in a K. pneumoniae strain from Alabama, which conferred reduced quinolone susceptibility and which possessed an AmpC gene (170). Non-ESBL  K. pneumoniae may also be quinolone resistant. Globally, between 5% and 10% of strains are quinolone resistant, although there is considerable geographical variation (199). The predominant mechanism of resistance is mutation in the chromosomal genes gyrA and parC, which encode the targets of quinolone activity. Other potential explanations include active efflux and outer membrane protein alterations.

Ciprofloxacin appears to be consistently more active than other quinolones against K. pneumoniae, although the superiority is only one to two dilutions (21, 95, 96, 175, 255, 279). Levofloxacin, gatifloxacin and gemifloxacin appear to have equivalent coverage to each other, while moxifloxacin may be one to two dilutions less active. In general, organisms resistant to one quinolone will also be resistant to other quinolones.

Vancomycin, teicoplanin, linezolid, quinupristin/dalfopristin, daptomycin, clindamycin, metronidazole, macrolides and ketolides do not have clinically useful activity against K. pneumoniae. However the new glycylcycline, tigecycline, has good in vitro activity (30).

The mechanisms of resistance of K. pneumoniae to commonly used antibiotics are summarized in Table 3.

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Klebsiella oxytoca

K. oxytoca has similar antibiotic resistance profiles to K. pneumoniae. Most strains of K. oxytoca produce a chromosomally mediated beta-lactamase (K1) that is in the same group, 2be, as plasmid-mediated ESBLs. Like the plasmid-mediated ESBLs, K1 hydrolyzes extended-spectrum cephalosporins and aztreonam and is inhibited by clavulanic acid (8). Mutational hyperproduction of the chromosomal K1 enzyme produces a characteristic antibiogram with frank susceptibility to ceftazidime, but resistance to piperacillin, cefuroxime and aztreonam. Cefotaxime and ceftriaxone MICs are usually in the range of 4-32 μg/mL. Although the majority of K. oxytoca isolates produce only low levels of the K1 beta-lactamase, hyperproduction of the enzyme is seen in 10-20% of clinical isolates (161). K. oxytoca isolates producing TEM or SHV type ESBLs can usually be distinguished from isolates hyperproducing K1 since the former beta-lactamases usually have ceftazidime MICs >2 μg/mL (or equivalent zone diameters), while K1 hyperproducers do not. The majority of isolates have the OXY-2 form of the K1 enzyme, with a minority producing the OXY-1 form (90, 99). In one study isolates with the OXY-2 enzyme were more resistant than those with the OXY-1 form, but this difference may have reflected enzyme quantity rather than enzyme subtype (99).

Like K. pneumoniae, K. oxytoca can contain IRT beta-lactamases (28, 105), plasmid-mediated extended spectrum beta-lactamases (123) and plasmid-mediated ampC type beta-lactamases (207).

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Klebsiella rhinoscleromatis

In vitro studies have been performed on 23 clinical isolates of K. rhinoscleromatis submitted to the Centers for Disease Control and Prevention between 1956 and 1987 (206). All isolates were inhibited by and killed by amoxicillin-clavulanate, ciprofloxacin, cefuroxime and cefpodoxime using clinically achievable concentrations (206). Ciprofloxacin had the greatest in vitro activity of any of the above. Forty-five percent of isolates were susceptible to ampicillin. Beta-lactamase production is suggested by the disparity between the ampicillin and amoxicillin-clavulanate results. All 23 isolates were susceptible to trimethoprim-sulfamethoxazole but the combination was bactericidal for only 65% of isolates. Tetracycline at less than or equal to 4 mg/L inhibited 87% isolates and was bactericidal at this concentration for 52%. Streptomycin at less than or equal to 1 mg/L inhibited and killed 21 of 23 isolates; two isolates were resistant to streptomycin at 32 mg/L. Only 27% of isolates were inhibited and killed by rifampin at concentrations of less than or equal to 1 mg/L, although all isolates were killed by less than or equal to 4 mg/L. Cephalexin at less than or equal to 4 mg/L inhibited all isolates and killed all but one. Chloramphenicol inhibited all isolates but was not bactericidal.

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Klebsiella ozaenae

Limited in vitro data on antibiotic susceptibility of K. ozaenae exist. Goldstein (102) performed antibiotic susceptibility testing by the agar dilution method on 21 isolates. Ninety five percent of the 21 isolates were susceptible to cephalothin, 90% of 20 isolates susceptible to gentamicin, 90% of 9 isolates susceptible to amikacin and 88% of 8 isolates susceptible to kanamycin. Only 26% of 19 isolates were susceptible to ampicillin and 21% of 14 isolates susceptible to tetracycline. All of three isolates were susceptible to chloramphenicol and one of two isolates susceptible to tobramycin. Murray (182) examined 16 strains of K. ozaenae. All were susceptible to cephalothin, chloramphenicol, tetracycline, gentamicin, streptomycin, kanamycin and amikacin. Less than 20% were susceptible to ampicillin and carbenicillin. K. ozaenae was susceptible to cefotaxime in the one isolate tested by Strampfer (250) and to ciprofloxacin in the isolate tested by Chowdhury (65).

Interestingly, the first report of plasmid mediated resistance to broad-spectrum cephalosporins was of an isolate of K. ozaenae in Germany analyzed in 1983 (139, 210). There have been no subsequent reported isolates of ESBL producing K. ozaenae.

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Combination Drugs In Vitro for Klebsiella pneumoniae

The addition of beta-lactamase inhibitors to beta-lactams is well known to result in enhanced activity of the beta-lactams against beta-lactamase producing strains of K. pneumoniae. Several groups have found that the combination of piperacillin with tazobactam results in greater activity than ticarcillin and clavulanate against piperacillin resistant K. pneumoniae (148,262,273).

Synergy has been frequently found in vitro between beta-lactams and aminoglycosides against K. pneumoniae (10,75,88,93,135,136,137,172,289), although in a small number of studies no synergy was demonstrated between these drug classes (120,149,274). A recent publication has noted synergy between ertapenem and gentamicin against K. pneumoniae isolates (127).

Synergy has been less frequently observed in vitro between combinations of beta-lactams. It has rarely, if ever, been observed between combinations of the commonly used third generation cephalosporins, extended spectrum penicillins or the


Source: http://antimicrobe.org/new/b107.asp


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