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Published Ahead of Print 19 March 2012.10.1128/AAC.06364-11.

2012, 56(6):3395. DOI:Antimicrob. Agents Chemother.Cornelius J. Clancy and Ryan K. ShieldsMeredith G. Jernigan, Ellen G. Press, M. Hong Nguyen,pneumoniaeCarbapenemase-Producing KlebsiellaColistin-Resistant,Is Bactericidal and Synergistic againstThe Combination of Doripenem and Colistin

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The Combination of Doripenem and Colistin Is Bactericidal andSynergistic against Colistin-Resistant, Carbapenemase-ProducingKlebsiella pneumoniae

Meredith G. Jernigan,a Ellen G. Press,b M. Hong Nguyen,b Cornelius J. Clancy,b,c and Ryan K. Shieldsb

Department of Pharmacy and Therapeutics, University of Pittsburgh,a Department of Medicine, University of Pittsburgh,b and VA Pittsburgh Healthcare System,c

Pittsburgh, Pennsylvania, USA

We tested two-drug combinations of doripenem, colistin, gentamicin, and doxycycline against 12 carbapenemase-producing

Klebsiella pneumoniae(KPC) isolates by time-kill. The combination of doripenem and colistin reduced the starting inocula by 2

logs for each isolate (range, 2.02 to 6.01 log10

) and was bactericidal and synergistic against 75 and 50%, respectively. Among

colistin- and pan-drug-resistant isolates, synergy was identified in 60 and 67%, respectively. All other combinations were infe-

rior. We are currently evaluating the combination of doripenem and colistin as a frontline therapy for KPC infection.

Infections with carbapenemase-producing Klebsiella pneu-moniae (KPC) are emerging causes of morbidity and mortalityat institutions worldwide (2, 11, 1416). KPC isolates are definedby resistance to carbapenems and are generally resistant to mostother antimicrobial classes. Salvage agents that may retain activityagainst KPC isolates include colistin, gentamicin, doxycycline,and tigecycline (8, 9, 18). Resistance to these agents is increasing(1, 6), however, and treatment failures are well recognized witheach (8). Given the dearth of effective antimicrobial agents andpoor clinical outcomes among patients with KPC infections, com-bination therapy has been utilized. Unfortunately, in vitro synergystudies have yielded conflicting results and left clinicians with noclear direction in selecting combination regimens. At our center,we have utilized the combination of doripenem and colistin to

treat patients with KPC infections, a decision that was extrapo-lated from our encouraging preliminary experience in treatingextensively drug-resistant (XDR) Acinetobacter baumannii infec-tions (17). The primary objective of this study was to determine ifthis combination is activeagainst KPC isolates recoveredfrom ourpatients. In particular, we focused on colistin-resistant isolatesdetermined in vitro by broth dilution. We also sought to test other

two-drug combinations that include commonly employed salvageagents.Toward these ends, we determined the in vitro activity of

doripenem, colistin, gentamicin, and doxycycline, alone and incombination, against 12 KPC isolates collected over a 3-year pe-riod from unique patients at our center. We included doxycyclinerather than tigecycline because it is more commonly used at ourcenter, particularly as part of the treatment of KPC urinary tractinfections.

We confirmed the presence of KPC for each isolate by a mod-ified Hodge test, and we determined MICs by standard broth mi-crodilution methods (4). One hundred percent (12/12), 83% (10/

Received 13 December 2011 Returned for modification 18 January 2012

Accepted 9 March 2012

Published ahead of print 19 March 2012

Address correspondence to Cornelius J. Clancy, [email protected].

Copyright 2012, American Society for Microbiology. All Rights Reserved.

doi:10.1128/AAC.06364-11

TABLE 1 MICs for KPC isolatesa

Strain

MIC (g/ml) Log from the starting inoculum (log10

CFU/ml)b

Doripenem Colistin Gentamicin Doxycycline Doripenem Colistin Gentamicin Doxycycline

1c 64 8 16 8 3.67 3.76 3.78 1.40

18 16 64 32 4 4.96 2.86 3.75 2.7382 16 8 8 4 3.64 3.64 3.22 3.95

124c 16 16 64 16 2.99 1.89 2.35 2.87

133c 128 16 64 16 3.83 3.60 3.62 3.70

136 128 4 64 4 3.53 2.05 2.78 3.24

141 128 0.5 1 4 4.44 3.19 2.74 3.90

145c 128 16 64 16 2.66 1.11 0.03 2.12

167 32 1 16 8 3.75 4.74 4.43 3.49

180c 32 8 32 16 4.06 0.47 3.53 3.69

182c 32 8 64 16 2.66 0.47 3.93 3.98

183 64 16 1 2 4.39 0.79 3.70 3.52a The following susceptibility breakpoints were used: doripenem and colistin,2 g/ml, and gentamicin and doxycycline,4 g/ml.b Log Final inoculum starting inoculum (log10 CFU/ml). Negative numbers represent a decrease from the starting inoculum, and positive numbers represent an increase.

Fixed concentrations of doripenem (8 g/ml), colistin (1 g/ml), gentamicin (2 g/ml), and doxycycline (2 g/ml) were used for all isolates.c Indicates isolates resistant to all agents tested.

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12), 83% (10/12), and 58% (7/12) of isolates were resistant to

doripenem, colistin, gentamicin, and doxycycline, respectively;50% (6/12) were resistant to allagents. The corresponding MIC

90s

were 128, 16, 64, and 16 g/ml, respectively. Using time-killassays (12), we found that colistin was bactericidal (3 log

10de-

crease from the starting inoculum) against 33% (4/12), includingboth colistin-susceptible strains. Doripenem and gentamicin werebactericidal against one isolate each, whereas doxycycline was notbactericidal against any isolate (Table 1).

We next assessed the activity of two-drug combinations bytime-kills using 50-ml flasks containing 9.9 ml of cation-adjustedMueller-Hinton broth, 0.1 ml of organism (starting inoculums of1 106 CFU/ml), and fixed drug concentrations alone and incombination (doripenem, 8g/ml; colistin, 1g/ml; gentamicin,

2 g/ml; and doxycycline, 2 g/ml). Flasks were incubated withagitationat 37C, andviable bacterialcolonieswere enumerated at0, 4, 8, 12, and 24 h as previously reported (17). Antimicrobialconcentrations were representative of achievable serum levels.Synergy and antagonism were defined as 2-log

10greater and

lesser kills, respectively, in combination treatments versus themost active single agent (21). The combination of doripenem andcolistin was bactericidal against 75% (9/12) of isolates (Table 2)and synergistic against 50% (6/12) (Table 3). Log kills rangedfrom 2.02 to 6.01 log

10CFU/ml (median, 3.95 log

10CFU/ml) (Ta-

ble2), and this was the only combination that reduced the startinginocula of all strains. Moreover, doripenem plus colistin was syn-ergistic against 60% (6/10) or 67% (4/6) of isolates that were re-sistant to colistin (MICs, 4 to 64 g/ml) or resistant to all agents,respectively.

Other combinations were less active (Table 3). Colistin plus

gentamicin was bactericidal and synergistic against 50% (6/12)and 25% (3/12) of isolates, respectively. The next most activecombination, gentamicin plus doxycycline, was bactericidal andsynergistic against 25% (3/12) and 42% (5/12) of isolates, respec-tively. Synergy was achieved against isolates that were doxycyclinesusceptible; bactericidal activity or synergy was not identifiedamong doxycycline-resistant strains. Doripenem plus gentamicinwas also bactericidal against 25% (3/12), but synergy was evidentagainst only 8% (1/12). The least active combinations were colis-tin plus doxycycline and doripenem plus doxycycline, which werebactericidal against 17% (2/12) and 8% (1/12) of isolates, respec-tively. Doripenem plus doxycycline was synergistic against 25%(3/12)of isolates, whereas colistin plusdoxycycline was synergistic

against 8% (1/12). Antagonism was identified with all combina-tions except doripenem plus colistin (Table 3). The combinationof colistin and doxycycline was antagonistic in 25% (3/12).

Doripenem plus colistin and doripenem plus gentamicin wereassociated with the lowest and highest median areas under the curve(AUCs), respectively (Table 4). Indeed, the median AUC for colistinplus doripenem was lower than those for the other combinations(P 0.004), including the individual combinations of gentamicinplus doxycycline (P 0.04) and doripenem plus doxycycline (P0.0001) (Fig. 1) (GraphPad Prism Software, La Jolla, CA).

Taken together, our data demonstrate that doripenem pluscolistin was the most active two-drug combination against KPCisolates.Doripenem plus colistin attained thehighest levelsof bac-

tericidalactivityand synergy, andit was theonly combination thatdid not show any antagonism. Moreover, the combination waseffective at clinically achievable concentrations of both drugs (3,7) and it was particularly active against colistin- and pan-drug-resistant isolates. In this regard, our findings are similar to thosewe reported against XDRAcinetobacter baumannii isolates fromour center (17). Furthermore, our results extend our understand-ing ofin vitro synergy against KPC isolates, which have been stud-ied in colistin-susceptible strains (10, 20, 22) or by checkerboardbroth microdilution (5) previously.

At present, the treatment options for patients with KPC infec-tions are limited, as evident by crude mortality rates that are re-portedto range from 42 to69% (13, 14, 19, 24). Mortalityrates are

TABLE 2 Log change (log10

CFU/ml) from the starting inoculum and most active single agent after 24 h of incubation

Combination

Log (log10

CFU/ml)a for isolate:

1 18 82 124 133 136 141 145 167 180 182 183

Colistin doripenem 6.01 4.12 2.09 5.99 3.57 3.95 3.94 4.65 5.76 2.02 2.73 3.90

2.25 0.84 5.73 4.10 0.03 1.90 0.75 3.54 1.02 1.55 2.26 3.11

Colistin gentamicin 4.56 3.07 3.20 5.87 2.07 2.22 5.60 1.70 2.05 0.60 0.56 5.00

0.80 0.21 6.84 3.52 1.53 0.17 2.41 1.73 2.69 0.13 0.09 1.30Colistin doxycycline 1.21 0.38 0.29 0.57 1.06 0.85 3.37 0.24 5.48 0.02 0.60 1.15

2.55 2.48 3.35 1.35 2.54 1.20 0.18 0.87 0.74 0.49 0.13 0.36

Doripenem gentamicin 3.69 5.95 2.40 3.85 4.11 0.99 4.43 2.63 3.88 3.94 3.40 5.04

0.02 0.99 5.62 6.20 0.49 1.79 1.69 2.66 0.13 0.41 0.74 1.34

Doripenem doxycycline 4.47 0.88 3.90 3.03 4.13 3.21 3.95 2.70 4.49 0.43 4.06 1.99

5.87 4.08 0.26 5.90 0.89 0.03 0.05 0.58 1.00 4.12 1.40 5.51

Gentamicindoxycycline 1.61 0.54 5.98 4.01 2.93 1.38 5.65 2.74 4.51 3.42 3.73 5.73

0.21 3.27 9.20 6.36 0.69 4.16 2.91 2.77 1.02 0.11 0.20 2.03a Log is defined as follows. Nonshaded rows: final inoculum starting inoculum (log10 CFU/ml). Negative numbers represent a decrease from the starting inoculum, and

positive numbers represent an increase. Shaded rows: final inoculum of the most active single drug final inoculum of the two-drug combination (log10 CFU/ml). Negative

numbers represent greater killing with two-drug combinations versus a single drug. Fixed concentrations of doripenem (8 g/ml), colistin (1 g/ml), gentamicin (2 g/ml), and

doxycycline (2 g/ml) were used for all isolates. Bold numbers indicate synergy.

TABLE 3 Interactions between two drugs tested in combination

Backbone

agent

Agent tested

in combination

Synergy,

n (%)

Indifference,

n (%)

Antagonism,

n (%)

Colistin Doripenem 6 (50) 6 (50) 0

Gentamicin 3 (25) 8 (67) 1 (8)

Doxycycline 1 (8) 8 (67) 3 (25)

Doripenem Gentamicin 1 (8) 9 (75) 2 (17)

Doxycycline 3 (25) 7 (58) 2 (17)

Gentamicin Doxycycline 5 (42) 5 (42) 2 (17)

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higher among patients infected with colistin-resistant isolates

(24). Investigators have reported that combination therapy mayimprove outcomes of KPC infections compared to those achievedwith monotherapy (8, 23), but optimal regimens are not definedandnone have been shown to be effectiveagainst colistin-resistantisolates. Of note, we reported promising preliminary data in apilot clinical study using doripenem plus colistin to treat XDR A.baumannii infections (17). Based on these data and the in vitrofindings of the current study, we are currently using the combina-tion as the recommended front-line regimen against KPC infec-tions.

The other combinations tested in this study demonstrated in-ferior bactericidal activity and less synergy. Furthermore, the sec-ond most potent combination in vitro (colistin plus gentamicin) is

limited in clinical settings by the potential for additive toxicity.Our data suggest that doxycycline plus gentamicin may be useful

against isolates that retainsusceptibilityto theformer agent,but at

our center such isolates are in the minority. In the end, this com-bination was synergistic against only 25% (3/12) of isolates andmay be unsuitable for the treatment of severe or life-threateningKPC infections. At present, we reserve doxycycline-containingregimens forthe treatment of uncomplicated cystitis at ourcenter.The remaining combinations were even less effective in vitro, andwe do not employ them in the clinic. Finally, it is important tonote that the number of strains evaluated here is limited and fu-ture studies are needed. Toward this, the exact mechanisms un-derlying the synergistic effects between doripenem and colistinhave not been identified and merit further investigation. It is pos-sible that colistin permeabilizes the outer cell membrane of KPCisolates, allowing high concentrations of doripenem to access pen-

icillin-binding proteins in the cytoplasmic membrane where thedrug acts.

TABLE 4 AUCs for two-drug combinations after 24 h of incubation

Isolate

AUCa

Colistin Doripenem

Gentamicin plus doxycyclinePlus doripenem Plus gentamicin Plus doxycycline Plus gentamicin Plus doxycycline

1 62.34 88.02 NA 209.5 NA 106.6

18 69.6 103.9 NA 81.7 NA 134.2

82 74.8 57.4 141.0 62.8 150.6 52.9124 47.8 37.46 132.5 NA 128.2 NA

133 87.9 110.2 NA 176.5 168.5 206.0

136 84.8 121.4 138.5 202.9 213.6 143.4

141 59.4 29.1 99.9 22.4 156.7 50.8

145 81.5 139.0 157.4 NA 195.3 NA

167 33.9 NA 51.0 207.6 207.4 220.1

180 118.3 132.4 146.7 155.4 138.7 203.7

182 112.3 137.0 135.5 183.8 164.8 168.2

183 82.1 10.0 132.1 15.9 107.5 26.4

Median (range) 78.2 (33.9118.3) 103.9 (10.0139.0) 135.5 (51.0157.4) 165.9 (15.9209.5) 160.8 (107.5213.6) 138.8 (26.4220.1)a NA, not applicable; area under the curve was not calculated for antagonistic combinations.

FIG 1 Representative area under the curve (AUC) for isolates alone and in combination for the following drug combinations: (a) colistin (dark gray) plusdoripenem (light gray); (b) gentamicin (light gray) plus doxycycline (dark gray); and (c) doripenem (light gray) plus doxycycline (dark gray). Black shadingrepresents the AUC for two-drug combinations.

Doripenem and Colistin Are Synergistic against KPCs

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In conclusion, it is important to stress that these results wereobtained against KPC isolates from a single center. As such, theresults may not be applicable to isolates from other centers orgeographic locations. It is advisable for centers to test isolates re-covered from patients at their institution. Having introduceddoripenem plus colistin as the recommended therapy for KPCinfections at our center, we are in the process of accumulating our

clinical experience and assessing the impact of the regimen onpreventing the emergence of colistin resistance.

ACKNOWLEDGMENTS

The project described was supported by award number KL2 RR024154from the National Center for Research Resources to R.K.S.

The content is solely the responsibility of the authors and does notnecessarily represent the official views of the National Center for ResearchResources or the National Institutes of Health.

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