AMR

An R package to simplify the analysis and prediction of Antimicrobial Resistance (AMR) and work with antibiotic properties by using evidence-based methods.

This R package was created for academic research by PhD students of the Faculty of Medical Sciences of the University of Groningen and the Medical Microbiology & Infection Prevention (MMBI) department of the University Medical Center Groningen (UMCG).

▶️ Download it with install.packages("AMR") or see below for other possibilities.

Authors

Matthijs S. Berends^1,2,a, Christian F. Luz^1,a, Erwin E.A. Hassing², Corinna Glasner^1,b, Alex W. Friedrich^1,b, Bhanu Sinha^1,b

¹ Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands - rug.nl umcg.nl
² Certe Medical Diagnostics & Advice, Groningen, the Netherlands - certe.nl
^a R package author and thesis dissertant
^b Thesis advisor

Contents

• Why this package?
• How to get it?
  • Install from CRAN
  • Install from GitHub
• How to use it?
  • New classes
  • Overwrite/force resistance based on EUCAST rules
  • Other (microbial) epidemiological functions
  • Frequency tables
  • Data sets included in package
• Copyright

Why this package?

This R package was intended to make microbial epidemiology easier. Most functions contain extensive help pages to get started.

With AMR you can:

• Calculate the resistance (and even co-resistance) of microbial isolates with the portion_R, portion_IR, portion_I, portion_SI and portion_S functions, that can also be used with the dplyr package (e.g. in conjunction with summarise)
• Plot AMR results with geom_rsi, a function made for the ggplot package
• Predict antimicrobial resistance for the nextcoming years with the resistance_predict function
• Apply EUCAST rules to isolates with the EUCAST_rules function
• Identify first isolates of every patient using guidelines from the CLSI (Clinical and Laboratory Standards Institute) with the first_isolate function
  • You can also identify first weighted isolates of every patient, an adjusted version of the CLSI guideline. This takes into account key antibiotics of every strain and compares them. The following 12 antibiotics will be used as key antibiotics at default:
    • Universal: amoxicillin, amoxicillin/clavlanic acid, cefuroxime, piperacillin/tazobactam, ciprofloxacin, trimethoprim/sulfamethoxazole
    • Specific for Gram-positives: vancomycin, teicoplanin, tetracycline, erythromycin, oxacillin, rifampicin
    • Specific for Gram-negatives: gentamicin, tobramycin, colistin, cefotaxime, ceftazidime, meropenem
• Categorise Staphylococci into Coagulase Negative Staphylococci (CoNS) and Coagulase Positve Staphylococci (CoPS) according to Karsten Becker et al.
• Categorise Streptococci into Lancefield groups
• Get antimicrobial ATC properties from the WHO Collaborating Centre for Drug Statistics Methodology (WHOCC), to be able to:
  • Translate antibiotic codes (like AMOX), official names (like amoxicillin) and even trade names (like Amoxil or Trimox) to an ATC code (like J01CA04) and vice versa with the abname function
  • Get the latest antibiotic properties like hierarchic groups and defined daily dose (DDD) with units and administration form from the WHOCC website with the atc_property function
• Conduct descriptive statistics: calculate kurtosis, skewness and create frequency tables

And it contains:

• A recent data set with ~2500 human pathogenic microorganisms, including family, genus, species, gram stain and aerobic/anaerobic
• A recent data set with all antibiotics as defined by the WHOCC, including ATC code, official name and DDD's
• An example data set septic_patients, consisting of 2000 blood culture isolates from anonymised septic patients between 2001 and 2017.

With the MDRO function (abbreviation of Multi Drug Resistant Organisms), you can check your isolates for exceptional resistance with country-specific guidelines or EUCAST rules. Currently guidelines for Germany and the Netherlands are supported. Please suggest addition of your own country here: https://github.com/msberends/AMR/issues/new.

Read all changes and new functions in NEWS.md.

How to get it?

This package is published on CRAN, the official R network.

Install from CRAN

(Note: Downloads measured only by cran.rstudio.com, this excludes e.g. the official cran.r-project.org)

• Install using RStudio (recommended):

  • Click on Tools and then Install Packages...
  • Type in AMR and press Install

• Install in R directly:

  • install.packages("AMR")

Install from GitHub

devtools::install_github("msberends/AMR") ```

## How to use it?
```r
# Call it with:
library(AMR)

# For a list of functions:
help(package = "AMR")

New classes

This package contains two new S3 classes: mic for MIC values (e.g. from Vitek or Phoenix) and rsi for antimicrobial drug interpretations (i.e. S, I and R). Both are actually ordered factors under the hood (an MIC of 2 being higher than <=1 but lower than >=32, and for class rsi factors are ordered as S < I < R). Both classes have extensions for existing generic functions like print, summary and plot.

These functions also try to coerce valid values.

RSI

The septic_patients data set comes with antimicrobial results of more than 40 different drugs. For example, columns amox and cipr contain results of amoxicillin and ciprofloxacin, respectively.

summary(septic_patients[, c("amox", "cipr")])
#      amox          cipr     
#  Mode  :rsi    Mode  :rsi   
#  <NA>  :1002   <NA>  :596   
#  Sum S :336    Sum S :1108  
#  Sum IR:662    Sum IR:296   
#  -Sum R:659    -Sum R:227   
#  -Sum I:3      -Sum I:69  

You can use the plot function from base R:

plot(septic_patients$cipr)

Or use the ggplot2 and dplyr packages to create more appealing plots:

library(dplyr)
library(ggplot2)

septic_patients %>%
  select(amox, cipr) %>%
  ggplot_rsi()

septic_patients %>%
    select(amox, cipr) %>%
    ggplot_rsi(x = "Interpretation", facet = "Antibiotic")

It also supports grouping variables. Let's say we want to compare resistance of these antibiotics between hospitals A to D (variable hospital_id):

septic_patients %>%
  select(hospital_id, amox, cipr) %>%
  group_by(hospital_id) %>%
  ggplot_rsi() +               # start adding ggplot elements here with `+`
  facet_grid("hospital_id") +  # splitting the plots on our grouping variable
  labs(title = "AMR of Amoxicillin And Ciprofloxacine Per Hospital")

You could use this to group on anything in your plots: Gram stain, age (group), genus, geographic location, et cetera.

MIC

# Transform values to new class
mic_data <- as.mic(c(">=32", "1.0", "8", "<=0.128", "8", "16", "16"))

summary(mic_data)
#  Mode:mic      
#  <NA>:0        
#  Min.:<=0.128  
#  Max.:>=32 

plot(mic_data)

Overwrite/force resistance based on EUCAST rules

This is also called interpretive reading.

before <- data.frame(bactid = c("STAAUR",  # Staphylococcus aureus
                                "ENCFAE",  # Enterococcus faecalis
                                "ESCCOL",  # Escherichia coli
                                "KLEPNE",  # Klebsiella pneumoniae
                                "PSEAER"), # Pseudomonas aeruginosa
                     vanc = "-",           # Vancomycin
                     amox = "-",           # Amoxicillin
                     coli = "-",           # Colistin
                     cfta = "-",           # Ceftazidime
                     cfur = "-",           # Cefuroxime
                     stringsAsFactors = FALSE)
before
#   bactid vanc amox coli cfta cfur
# 1 STAAUR    -    -    -    -    -
# 2 ENCFAE    -    -    -    -    -
# 3 ESCCOL    -    -    -    -    -
# 4 KLEPNE    -    -    -    -    -
# 5 PSEAER    -    -    -    -    -

# Now apply those rules; just need a column with bacteria ID's and antibiotic results:
after <- EUCAST_rules(before)
after
#   bactid vanc amox coli cfta cfur
# 1 STAAUR    -    -    R    R    -
# 2 ENCFAE    -    -    R    R    R
# 3 ESCCOL    R    -    -    -    -
# 4 KLEPNE    R    R    -    -    -
# 5 PSEAER    R    R    -    -    R

Bacteria ID's can be retrieved with the guess_bactid function. It uses any type of info about a microorganism as input. For example, all these will return value STAAUR, the ID of S. aureus:

guess_bactid("stau")
guess_bactid("STAU")
guess_bactid("staaur")
guess_bactid("S. aureus")
guess_bactid("S aureus")
guess_bactid("Staphylococcus aureus")
guess_bactid("MRSA") # Methicillin Resistant S. aureus
guess_bactid("VISA") # Vancomycin Intermediate S. aureus
guess_bactid("VRSA") # Vancomycin Resistant S. aureus

Other (microbial) epidemiological functions

# G-test to replace Chi squared test
g.test(...)

# Determine key antibiotic based on bacteria ID
key_antibiotics(...)

# Selection of first isolates of any patient
first_isolate(...)

# Calculate resistance levels of antibiotics, can be used with `summarise` (dplyr)
rsi(...)
# Predict resistance levels of antibiotics
rsi_predict(...)

# Get name of antibiotic by ATC code
abname(...)
abname("J01CR02", from = "atc", to = "umcg") # "AMCL"

Frequency tables

Base R lacks a simple function to create frequency tables. We created such a function that works with almost all data types: freq (or frequency_tbl). It can be used in two ways:

# Like base R:
freq(mydata$myvariable)

# And like tidyverse:
mydata %>% freq(myvariable)

Factors sort on item by default:

septic_patients %>% freq(hospital_id)
# Frequency table of `hospital_id` 
# Class:     factor
# Length:    2000 (of which NA: 0 = 0.0%)
# Unique:    4
# 
#      Item    Count   Percent   Cum. Count   Cum. Percent   (Factor Level)
# ---  -----  ------  --------  -----------  -------------  ---------------
# 1    A         319     16.0%          319          16.0%                1
# 2    B         661     33.1%          980          49.0%                2
# 3    C         256     12.8%         1236          61.8%                3
# 4    D         764     38.2%         2000         100.0%                4

This can be changed with the sort.count parameter:

septic_patients %>% freq(hospital_id, sort.count = TRUE)
# Frequency table of `hospital_id` 
# Class:     factor
# Length:    2000 (of which NA: 0 = 0.0%)
# Unique:    4
# 
#      Item    Count   Percent   Cum. Count   Cum. Percent   (Factor Level)
# ---  -----  ------  --------  -----------  -------------  ---------------
# 1    D         764     38.2%          764          38.2%                4
# 2    B         661     33.1%         1425          71.2%                2
# 3    A         319     16.0%         1744          87.2%                1
# 4    C         256     12.8%         2000         100.0%                3

All other types, like numbers, characters and dates, sort on count by default:

septic_patients %>% freq(date)
# Frequency table of `date` 
# Class:     Date
# Length:    2000 (of which NA: 0 = 0.0%)
# Unique:    1151
# 
# Oldest:    2 January 2002
# Newest:    28 December 2017 (+5839)
# Median:    7 Augustus 2009 (~48%)
# 
#      Item          Count   Percent   Cum. Count   Cum. Percent
# ---  -----------  ------  --------  -----------  -------------
# 1    2016-05-21       10      0.5%           10           0.5%
# 2    2004-11-15        8      0.4%           18           0.9%
# 3    2013-07-29        8      0.4%           26           1.3%
# 4    2017-06-12        8      0.4%           34           1.7%
# 5    2015-11-19        7      0.4%           41           2.1%
# 6    2005-12-22        6      0.3%           47           2.4%
# 7    2015-10-12        6      0.3%           53           2.6%
# 8    2002-05-16        5      0.2%           58           2.9%
# 9    2004-02-02        5      0.2%           63           3.1%
# 10   2004-02-18        5      0.2%           68           3.4%
# 11   2005-08-16        5      0.2%           73           3.6%
# 12   2005-09-01        5      0.2%           78           3.9%
# 13   2006-06-29        5      0.2%           83           4.2%
# 14   2007-08-10        5      0.2%           88           4.4%
# 15   2008-08-29        5      0.2%           93           4.7%
# [ reached getOption("max.print.freq") -- omitted 1136 entries, n = 1907 (95.3%) ]

For numeric values, some extra descriptive statistics will be calculated:

freq(runif(n = 10, min = 1, max = 5))
# Frequency table  
# Class:     numeric
# Length:    10 (of which NA: 0 = 0.0%)
# Unique:    10
# 
# Mean:      3.4
# Std. dev.: 1.3 (CV: 0.38, MAD: 1.3)
# Five-Num:  1.6 | 2.0 | 3.9 | 4.7 | 4.8 (IQR: 2.7, CQV: 0.4)
# Outliers:  0
# 
#           Item   Count   Percent   Cum. Count   Cum. Percent
# ---  ---------  ------  --------  -----------  -------------
# 1     1.568997       1     10.0%            1          10.0%
# 2     1.993575       1     10.0%            2          20.0%
# 3     2.022348       1     10.0%            3          30.0%
# 4     2.236038       1     10.0%            4          40.0%
# 5     3.579828       1     10.0%            5          50.0%
# 6     4.178081       1     10.0%            6          60.0%
# 7     4.394818       1     10.0%            7          70.0%
# 8     4.689871       1     10.0%            8          80.0%
# 9     4.698626       1     10.0%            9          90.0%
# 10    4.751488       1     10.0%           10         100.0%
# 
# Warning message:
# All observations are unique. 

Learn more about this function with:

?freq

Data sets included in package

Datasets to work with antibiotics and bacteria properties.

# Dataset with 2000 random blood culture isolates from anonymised
# septic patients between 2001 and 2017 in 5 Dutch hospitals
septic_patients   # A tibble: 2,000 x 49

# Dataset with ATC antibiotics codes, official names, trade names 
# and DDD's (oral and parenteral)
antibiotics       # A tibble: 420 x 18

# Dataset with bacteria codes and properties like gram stain and 
# aerobic/anaerobic
microorganisms    # A tibble: 2,453 x 12

Copyright

This R package is licensed under the GNU General Public License (GPL) v2.0. In a nutshell, this means that this package:

• May be used for commercial purposes

• May be used for private purposes

• May not be used for patent purposes

• May be modified, although:

  • Modifications must be released under the same license when distributing the package
  • Changes made to the code must be documented

• May be distributed, although:

  • Source code must be made available when the package is distributed
  • A copy of the license and copyright notice must be included with the package.

• Comes with a LIMITATION of liability

• Comes with NO warranty