AMR/R/mdro.R

# ==================================================================== #
# TITLE                                                                #
# Antimicrobial Resistance (AMR) Analysis                              #
#                                                                      #
# SOURCE                                                               #
# https://gitlab.com/msberends/AMR                                     #
#                                                                      #
# LICENCE                                                              #
# (c) 2019 Berends MS (m.s.berends@umcg.nl), Luz CF (c.f.luz@umcg.nl)  #
#                                                                      #
# This R package is free software; you can freely use and distribute   #
# it for both personal and commercial purposes under the terms of the  #
# GNU General Public License version 2.0 (GNU GPL-2), as published by  #
# the Free Software Foundation.                                        #
#                                                                      #
# This R package was created for academic research and was publicly    #
# released in the hope that it will be useful, but it comes WITHOUT    #
# ANY WARRANTY OR LIABILITY.                                           #
# Visit our website for more info: https://msberends.gitlab.io/AMR.    #
# ==================================================================== #

#' Determine multidrug-resistant organisms (MDRO)
#'
#' Determine which isolates are multidrug-resistant organisms (MDRO) according to (country-specific) guidelines.
#' @param guideline a specific guideline to follow. When left empty, the publication by Magiorakos \emph{et al.} (2012, Clinical Microbiology and Infection) will be followed, see Details.
#' @param info print progress
#' @inheritParams eucast_rules
#' @param pct_required_classes minimal required percentage of antimicrobial classes that must be available per isolate, rounded down. For example, with the default guideline, 17 antimicrobial classes must be available for \emph{S. aureus}. Setting this \code{pct_required_classes} argument to \code{0.5} (default) means that for every \emph{S. aureus} isolate at least 8 different classes must be available. Any lower number of available classes will return \code{NA} for that isolate.
#' @param verbose a logical to turn Verbose mode on and off (default is off). In Verbose mode, the function does not return the MDRO results, but instead returns a data set in logbook form with extensive info about which isolates would be MDRO-positive, or why they are not.
#' @inheritSection eucast_rules Antibiotics
#' @details 
#' For the \code{pct_required_classes} argument, values above 1 will be divided by 100. This is to support both fractions (\code{0.75} or \code{3/4}) and percentages (\code{75}).
#' Currently supported guidelines are (case-insensitive):
#' \itemize{
#'   \item{\code{guideline = "CMI2012"}: Magiorakos AP, Srinivasan A \emph{et al.} "Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance." Clinical Microbiology and Infection (2012) (\href{https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)61632-3/fulltext}{link})}
#'   \item{\code{guideline = "EUCAST"}: The European international guideline - EUCAST Expert Rules Version 3.1 "Intrinsic Resistance and Exceptional Phenotypes Tables" (\href{http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Expert_Rules/Expert_rules_intrinsic_exceptional_V3.1.pdf}{link})}
#'   \item{\code{guideline = "TB"}: The international guideline for multi-drug resistant tuberculosis - World Health Organization "Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis" (\href{https://www.who.int/tb/publications/pmdt_companionhandbook/en/}{link})}
#'   \item{\code{guideline = "MRGN"}: The German national guideline - Mueller et al. (2015) Antimicrobial Resistance and Infection Control 4:7. DOI: 10.1186/s13756-015-0047-6}
#'   \item{\code{guideline = "BRMO"}: The Dutch national guideline - Rijksinstituut voor Volksgezondheid en Milieu "WIP-richtlijn BRMO (Bijzonder Resistente Micro-Organismen) [ZKH]" (\href{https://www.rivm.nl/Documenten_en_publicaties/Professioneel_Praktisch/Richtlijnen/Infectieziekten/WIP_Richtlijnen/WIP_Richtlijnen/Ziekenhuizen/WIP_richtlijn_BRMO_Bijzonder_Resistente_Micro_Organismen_ZKH}{link})}
#' }
#'
#' Please suggest your own (country-specific) guidelines by letting us know: \url{https://gitlab.com/msberends/AMR/issues/new}.
#' 
#' @return \itemize{
#'   \item{CMI 2012 paper - function \code{mdr_cmi2012()} or \code{mdro()}:\cr Ordered factor with levels \code{Negative < Multi-drug-resistant (MDR) < Extensively drug-resistant (XDR) < Pandrug-resistant (PDR)}}
#'   \item{TB guideline - function \code{mdr_tb()} or \code{mdro(..., guideline = "TB")}:\cr Ordered factor with levels \code{Negative < Mono-resistant < Poly-resistant < Multi-drug-resistant < Extensively drug-resistant}}
#'   \item{German guideline - function \code{mrgn()} or \code{mdro(..., guideline = "MRGN")}:\cr Ordered factor with levels \code{Negative < 3MRGN < 4MRGN}}
#'   \item{Everything else:\cr Ordered factor with levels \code{Negative < Positive, unconfirmed < Positive}. The value \code{"Positive, unconfirmed"} means that, according to the guideline, it is not entirely sure if the isolate is multi-drug resistant and this should be confirmed with additional (e.g. molecular) tests}
#' }
#' @rdname mdro
#' @importFrom dplyr %>% filter_at vars all_vars pull mutate_at
#' @importFrom crayon blue bold italic
#' @importFrom cleaner percentage
#' @export
#' @inheritSection AMR Read more on our website!
#' @source
#' Please see Details for the list of publications used for this function.
#' @examples
#' library(dplyr)
#' 
#' example_isolates %>%
#'   mdro() %>%
#'   freq()
#'   
#' \donttest{
#' example_isolates %>%
#'   mutate(EUCAST = eucast_exceptional_phenotypes(.),
#'          BRMO = brmo(.),
#'          MRGN = mrgn(.))
#'          
#' example_isolates %>% 
#'   rename(PIP = TZP) %>% # no piperacillin, so take piperacillin/tazobactam
#'   mrgn() %>%            # check German guideline
#'   freq()                # check frequencies
#' }
mdro <- function(x,
                 guideline = NULL,
                 col_mo = NULL,
                 info = TRUE,
                 verbose = FALSE,
                 pct_required_classes = 0.5,
                 ...) {
  
  if (verbose == TRUE & interactive()) {
    txt <- paste0("WARNING: In Verbose mode, the mdro() function does not return the MDRO results, but instead returns a data set in logbook form with extensive info about which isolates would be MDRO-positive, or why they are not.",
                  "\n\nThis may overwrite your existing data if you use e.g.:",
                  "\ndata <- mdro(data, verbose = TRUE)\n\nDo you want to continue?")
    if ("rstudioapi" %in% rownames(utils::installed.packages())) {
      q_continue <- rstudioapi::showQuestion("Using verbose = TRUE with mdro()", txt)
    } else {
      q_continue <- menu(choices = c("OK", "Cancel"), graphics = TRUE, title = txt)
    }
    if (q_continue %in% c(FALSE, 2)) {
      message("Cancelled, returning original data")
      return(x)
    }
  }
  
  if (!is.data.frame(x)) {
    stop("`x` must be a data frame.", call. = FALSE)
  }
  if (!is.numeric(pct_required_classes)) {
    stop("`pct_required_classes` must be numeric.", call. = FALSE)
  }
  if (pct_required_classes > 1) {
    # allow pct_required_classes = 75 -> pct_required_classes = 0.75
    pct_required_classes <- pct_required_classes / 100
  }
  
  if (!is.null(list(...)$country)) {
    warning("Using `country` is deprecated, use `guideline` instead. Please see ?mdro.", call. = FALSE)
    guideline <- list(...)$country
  }
  if (length(guideline) > 1) {
    stop("`guideline` must be a length one character string.", call. = FALSE)
  }
  
  if (is.null(guideline)) {
    # default to the paper by Magiorakos et al. (2012)
    guideline <- "cmi2012"
  }
  if (tolower(guideline) == "nl") {
    guideline <- "BRMO"
  }
  if (tolower(guideline) == "de") {
    guideline <- "MRGN"
  }
  if (!tolower(guideline) %in% c("brmo", "mrgn", "eucast", "tb", "cmi2012")) {
    stop("invalid guideline: ", guideline, call. = FALSE)
  }
  guideline <- list(code = tolower(guideline))
  
  # try to find columns based on type
  # -- mo
  if (is.null(col_mo)) {
    col_mo <- search_type_in_df(x = x, type = "mo")
  }
  if (is.null(col_mo) & guideline$code == "tb") {
    message(blue("NOTE: No column found as input for `col_mo`,",
                 bold("assuming all records contain", italic("Mycobacterium tuberculosis.\n"))))
    x$mo <- AMR::as.mo("Mycobacterium tuberculosis")
    col_mo <- "mo"
  }
  if (is.null(col_mo)) {
    stop("`col_mo` must be set.", call. = FALSE)
  }
  
  if (guideline$code == "cmi2012") {
    guideline$name <- "Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance."
    guideline$author <- "Magiorakos AP, Srinivasan A, Carey RB, ..., Vatopoulos A, Weber JT, Monnet DL"
    guideline$version <- "N/A"
    guideline$source <- "Magiorakos et al. (2012) Clinical Microbiology and Infection 18:3. DOI: 10.1111/j.1469-0691.2011.03570.x"
    
  } else if (guideline$code == "eucast") {
    guideline$name <- "EUCAST Expert Rules, \"Intrinsic Resistance and Exceptional Phenotypes Tables\""
    guideline$author <- "EUCAST (European Committee on Antimicrobial Susceptibility Testing)"
    guideline$version <- "3.1"
    guideline$source <- "http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Expert_Rules/Expert_rules_intrinsic_exceptional_V3.1.pdf"
    
  } else if (guideline$code == "tb") {
    guideline$name <- "Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis"
    guideline$author <- "WHO (World Health Organization)"
    guideline$version <- "WHO/HTM/TB/2014.11"
    guideline$source <- "https://www.who.int/tb/publications/pmdt_companionhandbook/en/"
    
    # support per country:
  } else if (guideline$code == "mrgn") {
    guideline$name <- "Cross-border comparison of the Dutch and German guidelines on multidrug-resistant Gram-negative microorganisms"
    guideline$author <- "M\u00fcller J, Voss A, K\u00f6ck R, ..., Kern WV, Wendt C, Friedrich AW"
    guideline$version <- "N/A"
    guideline$source <- "M\u00fcller et al. (2015) Antimicrobial Resistance and Infection Control 4:7. DOI: 10.1186/s13756-015-0047-6"
    
  } else if (guideline$code == "brmo") {
    guideline$name <- "WIP-Richtlijn Bijzonder Resistente Micro-organismen (BRMO)"
    guideline$author <- "RIVM (Rijksinstituut voor de Volksgezondheid)"
    guideline$version <- "Revision as of December 2017"
    guideline$source <- "https://www.rivm.nl/Documenten_en_publicaties/Professioneel_Praktisch/Richtlijnen/Infectieziekten/WIP_Richtlijnen/WIP_Richtlijnen/Ziekenhuizen/WIP_richtlijn_BRMO_Bijzonder_Resistente_Micro_Organismen_ZKH"
  } else {
    stop("This guideline is currently unsupported: ", guideline$code, call. = FALSE)
  }
  
  if (guideline$code == "cmi2012") {
    cols_ab <- get_column_abx(x = x,
                              soft_dependencies = c(
                                # table 1 (S aureus):
                                "GEN",
                                "RIF",
                                "CPT",
                                "OXA",
                                "CIP",
                                "MFX",
                                "SXT",
                                "FUS",
                                "VAN",
                                "TEC",
                                "TLV",
                                "TGC",
                                "CLI",
                                "DAP",
                                "ERY",
                                "LNZ",
                                "CHL",
                                "FOS",
                                "QDA",
                                "TCY",
                                "DOX",
                                "MNO",
                                # table 2 (Enterococcus)
                                "GEH",
                                "STH",
                                "IPM",
                                "MEM",
                                "DOR",
                                "CIP",
                                "LVX",
                                "MFX",
                                "VAN",
                                "TEC",
                                "TGC",
                                "DAP",
                                "LNZ",
                                "AMP",
                                "QDA",
                                "DOX",
                                "MNO",
                                # table 3 (Enterobacteriaceae)
                                "GEN",
                                "TOB",
                                "AMK",
                                "NET",
                                "CPT",
                                "TCC",
                                "TZP",
                                "ETP",
                                "IPM",
                                "MEM",
                                "DOR",
                                "CZO",
                                "CXM",
                                "CTX",
                                "CAZ",
                                "FEP",
                                "FOX",
                                "CTT",
                                "CIP",
                                "SXT",
                                "TGC",
                                "ATM",
                                "AMP",
                                "AMC",
                                "SAM",
                                "CHL",
                                "FOS",
                                "COL",
                                "TCY",
                                "DOX",
                                "MNO",
                                # table 4 (Pseudomonas)
                                "GEN",
                                "TOB",
                                "AMK",
                                "NET",
                                "IPM",
                                "MEM",
                                "DOR",
                                "CAZ",
                                "FEP",
                                "CIP",
                                "LVX",
                                "TCC",
                                "TZP",
                                "ATM",
                                "FOS",
                                "COL",
                                "PLB",
                                # table 5 (Acinetobacter)
                                "GEN",
                                "TOB",
                                "AMK",
                                "NET",
                                "IPM",
                                "MEM",
                                "DOR",
                                "CIP",
                                "LVX",
                                "TZP",
                                "TCC",
                                "CTX",
                                "CRO",
                                "CAZ",
                                "FEP",
                                "SXT",
                                "SAM",
                                "COL",
                                "PLB",
                                "TCY",
                                "DOX",
                                "MNO"
                              ),
                              verbose = verbose, ...)
  } else if (guideline$code == "tb") {
    cols_ab <- get_column_abx(x = x,
                              soft_dependencies = c("CAP",
                                                    "ETH",
                                                    "GAT",
                                                    "INH",
                                                    "PZA",
                                                    "RIF",
                                                    "RIB",
                                                    "RFP"),
                              verbose = verbose, ...)
  } else if (guideline$code == "mrgn") {
    cols_ab <- get_column_abx(x = x,
                              soft_dependencies = c("PIP",
                                                    "CTX",
                                                    "CAZ",
                                                    "IPM",
                                                    "MEM",
                                                    "CIP"),
                              verbose = verbose, ...)
  } else {
    cols_ab <- get_column_abx(x = x, verbose = verbose, ...)
  }
  
  AMC <- cols_ab["AMC"]
  AMK <- cols_ab["AMK"]
  AMP <- cols_ab["AMP"]
  AMX <- cols_ab["AMX"]
  ATM <- cols_ab["ATM"]
  AZL <- cols_ab["AZL"]
  AZM <- cols_ab["AZM"]
  CAZ <- cols_ab["CAZ"]
  CED <- cols_ab["CED"]
  CHL <- cols_ab["CHL"]
  CIP <- cols_ab["CIP"]
  CLI <- cols_ab["CLI"]
  CLR <- cols_ab["CLR"]
  COL <- cols_ab["COL"]
  CPT <- cols_ab["CPT"]
  CRO <- cols_ab["CRO"]
  CTT <- cols_ab["CTT"]
  CTX <- cols_ab["CTX"]
  CXM <- cols_ab["CXM"]
  CZO <- cols_ab["CZO"]
  DAP <- cols_ab["DAP"]
  DOR <- cols_ab["DOR"]
  DOX <- cols_ab["DOX"]
  ERY <- cols_ab["ERY"]
  ETP <- cols_ab["ETP"]
  FEP <- cols_ab["FEP"]
  FLC <- cols_ab["FLC"]
  FOS <- cols_ab["FOS"]
  FOX <- cols_ab["FOX"]
  FUS <- cols_ab["FUS"]
  GEH <- cols_ab["GEH"]
  GEN <- cols_ab["GEN"]
  IPM <- cols_ab["IPM"]
  KAN <- cols_ab["KAN"]
  LIN <- cols_ab["LIN"]
  LNZ <- cols_ab["LNZ"]
  LVX <- cols_ab["LVX"]
  MEM <- cols_ab["MEM"]
  MEZ <- cols_ab["MEZ"]
  MTR <- cols_ab["MTR"]
  MFX <- cols_ab["MFX"]
  MNO <- cols_ab["MNO"]
  NAL <- cols_ab["NAL"]
  NEO <- cols_ab["NEO"]
  NET <- cols_ab["NET"]
  NIT <- cols_ab["NIT"]
  NOR <- cols_ab["NOR"]
  NOV <- cols_ab["NOV"]
  OFX <- cols_ab["OFX"]
  OXA <- cols_ab["OXA"]
  PEN <- cols_ab["PEN"]
  PIP <- cols_ab["PIP"]
  PLB <- cols_ab["PLB"]
  PRI <- cols_ab["PRI"]
  QDA <- cols_ab["QDA"]
  RID <- cols_ab["RID"]
  RIF <- cols_ab["RIF"]
  RXT <- cols_ab["RXT"]
  SAM <- cols_ab["SAM"]
  SIS <- cols_ab["SIS"]
  STH <- cols_ab["STH"]
  SXT <- cols_ab["SXT"]
  TCC <- cols_ab["TCC"]
  TCY <- cols_ab["TCY"]
  TEC <- cols_ab["TEC"]
  TGC <- cols_ab["TGC"]
  TIC <- cols_ab["TIC"]
  TLV <- cols_ab["TLV"]
  TMP <- cols_ab["TMP"]
  TOB <- cols_ab["TOB"]
  TZP <- cols_ab["TZP"]
  VAN <- cols_ab["VAN"]
  # additional for TB
  CAP <- cols_ab["CAP"]
  ETH <- cols_ab["ETH"]
  GAT <- cols_ab["GAT"]
  INH <- cols_ab["INH"]
  PZA <- cols_ab["PZA"]
  RIF <- cols_ab["RIF"]
  RIB <- cols_ab["RIB"]
  RFP <- cols_ab["RFP"]
  abx_tb <- c(CAP, ETH, GAT, INH, PZA, RIF, RIB, RFP)
  abx_tb <- abx_tb[!is.na(abx_tb)]
  if (guideline$code == "tb" & length(abx_tb) == 0) {
    stop("No antimycobacterials found in data set.", call. = FALSE)
  }
  
  if (info == TRUE) {
    cat("\nDetermining multidrug-resistant organisms (MDRO), according to:\n",
        bold("Guideline: "), italic(guideline$name), "\n",
        bold("Version:   "), guideline$version, "\n",
        bold("Author:    "),    guideline$author, "\n",
        bold("Source:    "), guideline$source, "\n",
        "\n", sep = "")
  }
  
  ab_missing <- function(ab) {
    isTRUE(ab %in% c(NULL, NA)) | length(ab) == 0
  }
  ab_NA <- function(x) {
    x[!is.na(x)]
  }
  
  verbose_df <- NULL
  
  # antibiotic classes
  aminoglycosides <- c(TOB, GEN)
  cephalosporins <- c(FEP, CTX, FOX, CED, CAZ, CRO, CXM, CZO)
  cephalosporins_3rd <- c(CTX, CRO, CAZ)
  carbapenems <- c(ETP, IPM, MEM)
  fluoroquinolones <- c(OFX, CIP, LVX, MFX)
  
  # helper function for editing the table
  trans_tbl <- function(to, rows, cols, any_all) {
    cols <- cols[!ab_missing(cols)]
    cols <- cols[!is.na(cols)]
    if (length(rows) > 0 & length(cols) > 0) {
      #print(cols)
      x <<- x %>% mutate_at(vars(cols), as.rsi)
      x[rows, "columns_nonsusceptible"] <<- sapply(rows, 
                                                   function(row, group_vct = cols) {
                                                     cols_nonsus <- sapply(x[row, group_vct, drop = FALSE], function(y) y == "R")
                                                     paste(sort(c(unlist(strsplit(x[row, "columns_nonsusceptible", drop = TRUE], ", ")),
                                                                  names(cols_nonsus)[cols_nonsus])), 
                                                           collapse = ", ")
                                                   })
      if (any_all == "any") {
        row_filter <- which(x[, cols] == "R")
      } else if (any_all == "all") {
        row_filter <- x %>%
          mutate(index = seq_len(nrow(.))) %>%
          filter_at(vars(cols), all_vars(. == "R")) %>%
          pull((index))
      }
      rows <- rows[rows %in% row_filter]
      x[rows, "MDRO"] <<- to
      x[rows, "reason"] <<- paste0(any_all, " of the required antibiotics ", ifelse(any_all == "any", "is", "are"), " R")
    }
  }
  trans_tbl2 <- function(txt, rows, lst) {
    if (info == TRUE) {
      message(blue(txt, "..."), appendLF = FALSE)
    }
    if (length(rows) > 0) {
      # function specific for the CMI paper of 2012 (Magiorakos et al.)
      lst_vector <- unlist(lst)[!is.na(unlist(lst))]
      x <<- x %>% mutate_at(vars(lst_vector), as.rsi)
      x[rows, "classes_in_guideline"] <<- length(lst)
      x[rows, "classes_available"] <<- sapply(rows, 
                                              function(row, group_tbl = lst) {
                                                sum(sapply(group_tbl, function(group) any(unlist(x[row, group[!is.na(group)], drop = TRUE]) %in% c("S", "I", "R"))))
                                              })
      
      if (verbose == TRUE) {
        x[rows, "columns_nonsusceptible"] <<- sapply(rows, 
                                                      function(row, group_vct = lst_vector) {
                                                        cols_nonsus <- sapply(x[row, group_vct, drop = FALSE], function(y) y %in% c("I", "R"))
                                                        paste(sort(names(cols_nonsus)[cols_nonsus]), collapse = ", ")
                                                      })
      }
      x[rows, "classes_affected"] <<- sapply(rows, 
                                            function(row, group_tbl = lst) {
                                              sum(sapply(group_tbl, 
                                                         function(group) {
                                                           any(x[row, group[!is.na(group)]] == "R", na.rm = TRUE) | 
                                                             any(x[row, group[!is.na(group)]] == "I", na.rm = TRUE) 
                                                         }),
                                                  na.rm = TRUE) 
                                            })
      x[filter_at(x[rows, ],
                  vars(lst_vector),
                  all_vars(. %in% c("R", "I")))$row_number, "classes_affected"] <<- 999
    }
    
    if (info == TRUE) {
      message(blue(" OK"))
    }
  }
  
  x <- x %>%
    mutate_at(vars(col_mo), as.mo) %>%
    # join to microorganisms data set
    left_join_microorganisms(by = col_mo) %>%
    # add unavailable to where genus is available
    mutate(MDRO = ifelse(!is.na(genus), 1, NA_integer_),
           row_number = seq_len(nrow(.)),
           reason = paste0("not covered by ", toupper(guideline$code), " guideline"),
           columns_nonsusceptible = "") %>% 
    # transform to data.frame so subsetting is possible with x[y, z] (might not be the case with tibble/data.table/...)
    as.data.frame(stringsAsFactors = FALSE)
  
  if (guideline$code == "cmi2012") {
    # CMI, 2012 ---------------------------------------------------------------
    # Non-susceptible = R and I
    # (see header 'Approaches to Creating Definitions for MDR, XDR and PDR' in paper)
    
    # take amoxicillin if ampicillin is unavailable
    if (is.na(AMP) & !is.na(AMX)) {
      if (verbose == TRUE) {
        message(blue("NOTE: Filling ampicillin (AMP) results with amoxicillin (AMX) results"))
      }
      AMP <- AMX
    }
    # take ceftriaxone if cefotaxime is unavailable and vice versa
    if (is.na(CRO) & !is.na(CTX)) {
      if (verbose == TRUE) {
        message(blue("NOTE: Filling ceftriaxone (CRO) results with cefotaxime (CTX) results"))
      }
      CRO <- CTX
    }
    if (is.na(CTX) & !is.na(CRO)) {
      if (verbose == TRUE) {
        message(blue("NOTE: Filling cefotaxime (CTX) results with ceftriaxone (CRO) results"))
      }
      CTX <- CRO
    }
    
    # intrinsic resistant must not be considered for the determination of MDR,
    # so let's just remove them, meticulously following the paper
    x[which(x$genus == "Enterococcus" & x$species == "faecium"), ab_NA(IPM)] <- NA
    x[which(x$genus == "Enterococcus" & x$species == "faecalis"), ab_NA(QDA)] <- NA
    x[which((x$genus == "Providencia" & x$species == "rettgeri")
            | (x$genus == "Providencia" & x$species == "stuartii")), ab_NA(c(GEN, TOB, NET))] <- NA
    x[which(x$genus == "Escherichia" & x$species == "hermannii"), ab_NA(c(TCC, TZP))] <- NA
    x[which((x$genus == "Citrobacter" & x$species == "freundii")
            | (x$genus == "Enterobacter" & x$species == "aerogenes")
            | (x$genus == "Enterobacter" & x$species == "cloacae")
            | (x$genus == "Hafnia" & x$species == "alvei")
            | (x$genus == "Morganella" & x$species == "morganii")
            | (x$genus == "Proteus" & x$species == "penneri")
            | (x$genus == "Proteus" & x$species == "vulgaris")
            | (x$genus == "Serratia" & x$species == "marcescens")), ab_NA(CZO)] <- NA
    x[which((x$genus == "Morganella" & x$species == "morganii")
            | (x$genus == "Proteus" & x$species == "penneri")
            | (x$genus == "Proteus" & x$species == "vulgaris")
            | (x$genus == "Serratia" & x$species == "marcescens")), ab_NA(CXM)] <- NA
    x[which((x$genus == "Morganella" & x$species == "morganii")
            | (x$genus == "Proteus" & x$species == "mirabilis")
            | (x$genus == "Proteus" & x$species == "penneri")
            | (x$genus == "Proteus" & x$species == "vulgaris")
            | (x$genus == "Providencia" & x$species == "rettgeri")
            | (x$genus == "Providencia" & x$species == "stuartii")), ab_NA(TGC)] <- NA
    x[which((x$genus == "Citrobacter" & x$species == "koseri")
            | (x$genus == "Citrobacter" & x$species == "freundii")
            | (x$genus == "Enterobacter" & x$species == "aerogenes")
            | (x$genus == "Enterobacter" & x$species == "cloacae")
            | (x$genus == "Escherichia" & x$species == "hermannii")
            | (x$genus == "Hafnia" & x$species == "alvei")
            | (x$genus == "Klebsiella")
            | (x$genus == "Morganella" & x$species == "morganii")
            | (x$genus == "Proteus" & x$species == "penneri")
            | (x$genus == "Proteus" & x$species == "vulgaris")
            | (x$genus == "Providencia" & x$species == "rettgeri")
            | (x$genus == "Providencia" & x$species == "stuartii")
            | (x$genus == "Serratia" & x$species == "marcescens")), ab_NA(AMP)] <- NA
    x[which((x$genus == "Citrobacter" & x$species == "freundii")
            | (x$genus == "Enterobacter" & x$species == "aerogenes")
            | (x$genus == "Enterobacter" & x$species == "cloacae")
            | (x$genus == "Hafnia" & x$species == "alvei")
            | (x$genus == "Morganella" & x$species == "morganii")
            | (x$genus == "Providencia" & x$species == "rettgeri")
            | (x$genus == "Providencia" & x$species == "stuartii")
            | (x$genus == "Serratia" & x$species == "marcescens")), ab_NA(AMC)] <- NA
    x[which((x$genus == "Citrobacter" & x$species == "freundii")
            | (x$genus == "Citrobacter" & x$species == "koseri")
            | (x$genus == "Enterobacter" & x$species == "aerogenes")
            | (x$genus == "Enterobacter" & x$species == "cloacae")
            | (x$genus == "Hafnia" & x$species == "alvei")
            | (x$genus == "Providencia" & x$species == "rettgeri")
            | (x$genus == "Serratia" & x$species == "marcescens")), ab_NA(SAM)] <- NA
    x[which((x$genus == "Morganella" & x$species == "morganii")
            | (x$genus == "Proteus" & x$species == "mirabilis")
            | (x$genus == "Proteus" & x$species == "penneri")
            | (x$genus == "Proteus" & x$species == "vulgaris")
            | (x$genus == "Providencia" & x$species == "rettgeri")
            | (x$genus == "Providencia" & x$species == "stuartii")
            | (x$genus == "Serratia" & x$species == "marcescens")), ab_NA(COL)] <- NA
    x[which((x$genus == "Morganella" & x$species == "morganii")
            | (x$genus == "Proteus" & x$species == "mirabilis")
            | (x$genus == "Proteus" & x$species == "penneri")
            | (x$genus == "Proteus" & x$species == "vulgaris")
            | (x$genus == "Providencia" & x$species == "rettgeri")
            | (x$genus == "Providencia" & x$species == "stuartii")), ab_NA(TCY)] <- NA
    x[which((x$genus == "Morganella" & x$species == "morganii")
            | (x$genus == "Proteus" & x$species == "penneri")
            | (x$genus == "Proteus" & x$species == "vulgaris")
            | (x$genus == "Providencia" & x$species == "rettgeri")
            | (x$genus == "Providencia" & x$species == "stuartii")), ab_NA(c(DOX, MNO))] <- NA
    
    x$classes_in_guideline <- NA_integer_
    x$classes_available <- NA_integer_
    x$classes_affected <- NA_integer_
    
    # now add the MDR levels to the data
    trans_tbl(2,
              which(x$genus == "Staphylococcus" & x$species == "aureus"),
              c(OXA, FOX),
              "any")
    trans_tbl2(paste("Table 1 -", italic("S. aureus")),
               which(x$genus == "Staphylococcus" & x$species == "aureus"),
               list(GEN,
                    RIF,
                    CPT,
                    c(OXA, FOX),
                    c(CIP, MFX),
                    SXT,
                    FUS,
                    c(VAN, TEC, TLV),
                    TGC,
                    CLI,
                    DAP,
                    ERY,
                    LNZ,
                    CHL,
                    FOS,
                    QDA,
                    c(TCY, DOX, MNO)))
    trans_tbl2(paste("Table 2 -", italic("Enterococcus"), "spp."),
               which(x$genus == "Enterococcus"),
               list(GEH,
                    STH,
                    c(IPM, MEM, DOR),
                    c(CIP, LVX, MFX),
                    c(VAN, TEC),
                    TGC,
                    DAP,
                    LNZ,
                    AMP,
                    QDA,
                    c(DOX, MNO)))
    trans_tbl2(paste0("Table 3 - ", italic("Enterobacteriaceae"), 
                      " (before the taxonomic reclassification by Adeolu ", italic("et al."), ", 2016)"),
               # this new order was previously 'Enterobacteriales' and contained only the family 'Enterobacteriaceae':
               which(x$order == "Enterobacterales"),
               list(c(GEN, TOB, AMK, NET),
                    CPT,
                    c(TCC, TZP),
                    c(ETP, IPM, MEM, DOR),
                    CZO,
                    CXM,
                    c(CTX, CAZ, FEP),
                    c(FOX, CTT),
                    CIP,
                    SXT,
                    TGC,
                    ATM,
                    AMP,
                    c(AMC, SAM),
                    CHL,
                    FOS,
                    COL,
                    c(TCY, DOX, MNO)))
    trans_tbl2(paste("Table 4 -", italic("Pseudomonas aeruginosa")),
               which(x$genus == "Pseudomonas" & x$species == "aeruginosa"),
               list(c(GEN, TOB, AMK, NET),
                    c(IPM, MEM, DOR),
                    c(CAZ, FEP),
                    c(CIP, LVX),
                    c(TCC, TZP),
                    ATM,
                    FOS,
                    c(COL, PLB)))
    trans_tbl2(paste("Table 5 -", italic("Acinetobacter"), "spp."),
               which(x$genus == "Acinetobacter"),
               list(c(GEN, TOB, AMK, NET),
                    c(IPM, MEM, DOR),
                    c(CIP, LVX),
                    c(TZP, TCC),
                    c(CTX, CRO, CAZ, FEP),
                    SXT,
                    SAM,
                    c(COL, PLB),
                    c(TCY, DOX, MNO)))
    
    # now set MDROs: 
    # MDR (=2): >=3 classes affected
    x[which(x$classes_affected >= 3), "MDRO"] <- 2
    if (verbose == TRUE) {
      x[which(x$classes_affected >= 3), "reason"] <- paste0("at least 3 classes contain R or I: ", x$classes_affected[which(x$classes_affected >= 3)],
                                                            " out of ", x$classes_available[which(x$classes_affected >= 3)], " available classes")
    }
    
    # XDR (=3): all but <=2 classes affected
    x[which((x$classes_in_guideline - x$classes_affected) <= 2), "MDRO"] <- 3
    if (verbose == TRUE) {
      x[which(x$MDRO == 3), "reason"] <- paste0("less than 3 classes remain susceptible (", x$classes_in_guideline[which((x$classes_in_guideline - x$classes_affected) <= 2)] - x$classes_affected[which(x$MDRO == 3)],
                                                                                       " out of ", x$classes_in_guideline[which(x$MDRO == 3)], " classes)")
    }
    
    # PDR (=4): all agents are R 
    x[which(x$classes_affected == 999 & x$classes_in_guideline == x$classes_available), "MDRO"] <- 4
    if (verbose == TRUE) {
      x[which(x$MDRO == 4), "reason"] <- paste("all antibiotics in all", x$classes_in_guideline[which(x$MDRO == 4)], "classes were tested R or I")
    }
    
    # not enough classes available
    x[which(x$MDRO %in% c(1, 3) & x$classes_available < base::floor(x$classes_in_guideline * pct_required_classes)), "MDRO"] <- -1
    if (verbose == TRUE) {
      x[which(x$MDRO == -1), "reason"] <- paste0("not enough classes available: ", x$classes_available[which(x$MDRO == -1)], 
                                                 " of required ", (base::floor(x$classes_in_guideline * pct_required_classes))[which(x$MDRO == -1)], 
                                                 " (~", percentage(pct_required_classes), " of ", x$classes_in_guideline[which(x$MDRO == -1)], ")")
    }
    
    # add antibiotic names of resistant ones to verbose output
    
  }
  
  if (guideline$code == "eucast") {
    # EUCAST ------------------------------------------------------------------
    # Table 5
    trans_tbl(3,
              which(x$order == "Enterobacterales"
                    | x$fullname %like% "^Pseudomonas aeruginosa"
                    | x$genus == "Acinetobacter"),
              COL,
              "all")
    trans_tbl(3,
              which(x$fullname %like% "^Salmonella Typhi"),
              c(carbapenems, fluoroquinolones),
              "any")
    trans_tbl(3,
              which(x$fullname %like% "^Haemophilus influenzae"),
              c(cephalosporins_3rd, carbapenems, fluoroquinolones),
              "any")
    trans_tbl(3,
              which(x$fullname %like% "^Moraxella catarrhalis"),
              c(cephalosporins_3rd, fluoroquinolones),
              "any")
    trans_tbl(3,
              which(x$fullname %like% "^Neisseria meningitidis"),
              c(cephalosporins_3rd, fluoroquinolones),
              "any")
    trans_tbl(3,
              which(x$fullname %like% "^Neisseria gonorrhoeae"),
              AZM,
              "any")
    # Table 6
    trans_tbl(3,
              which(x$fullname %like% "^(Coagulase-negative|Staphylococcus (aureus|epidermidis|hominis|haemolyticus|intermedius|pseudointermedius))"),
              c(VAN, TEC, DAP, LNZ, QDA, TGC),
              "any")
    trans_tbl(3,
              which(x$genus == "Corynebacterium"),
              c(VAN, TEC, DAP, LNZ, QDA, TGC),
              "any")
    trans_tbl(3,
              which(x$fullname %like% "^Streptococcus pneumoniae"),
              c(carbapenems, VAN, TEC, DAP, LNZ, QDA, TGC, RIF),
              "any")
    trans_tbl(3, # Sr. groups A/B/C/G
              which(x$fullname %like% "^Streptococcus (group (A|B|C|G)|pyogenes|agalactiae|equisimilis|equi|zooepidemicus|dysgalactiae|anginosus)"),
              c(PEN, cephalosporins, VAN, TEC, DAP, LNZ, QDA, TGC),
              "any")
    trans_tbl(3,
              which(x$genus == "Enterococcus"),
              c(DAP, LNZ, TGC, TEC),
              "any")
    trans_tbl(3,
              which(x$fullname %like% "^Enterococcus faecalis"),
              c(AMP, AMX),
              "any")
    # Table 7
    trans_tbl(3,
              which(x$genus == "Bacteroides"),
              MTR,
              "any")
    trans_tbl(3,
              which(x$fullname %like% "^Clostridium difficile"),
              c(MTR, VAN),
              "any")
  }
  
  if (guideline$code == "mrgn") {
    # Germany -----------------------------------------------------------------
    CTX_or_CAZ <- CTX %or% CAZ
    IPM_or_MEM <- IPM %or% MEM
    x$missing <- NA_character_
    if (is.na(PIP)) PIP <- "missing"
    if (is.na(CTX_or_CAZ)) CTX_or_CAZ <- "missing"
    if (is.na(IPM_or_MEM)) IPM_or_MEM <- "missing"
    if (is.na(IPM)) IPM <- "missing"
    if (is.na(MEM)) MEM <- "missing"
    if (is.na(CIP)) CIP <- "missing"
    
    # Table 1
    x[which((x$order == "Enterobacterales" |  # following in fact the old Enterobacteriaceae classification
               x$fullname %like% "^Acinetobacter baumannii") &
              x[, PIP] == "R" &
              x[, CTX_or_CAZ] == "R" &
              x[, IPM_or_MEM] == "S" &
              x[, CIP] == "R"),
      "MDRO"] <- 2 # 2 = 3MRGN
    
    x[which((x$order == "Enterobacterales" |  # following in fact the old Enterobacteriaceae classification
               x$fullname %like% "^Acinetobacter baumannii") &
              x[, PIP] == "R" &
              x[, CTX_or_CAZ] == "R" &
              x[, IPM_or_MEM] == "R" &
              x[, CIP] == "R"),
      "MDRO"] <- 3 # 3 = 4MRGN, overwrites 3MRGN if applicable
    
    x[which((x$order == "Enterobacterales" |  # following in fact the old Enterobacteriaceae classification
               x$fullname %like% "^Acinetobacter baumannii") &
              x[, IPM] == "R" | x[, MEM] == "R"),
      "MDRO"] <- 3 # 3 = 4MRGN, always when imipenem or meropenem is R
    
    x[which(x$fullname %like% "^Pseudomonas aeruginosa" &
              (x[, PIP] == "S") +
              (x[, CTX_or_CAZ] == "S") +
              (x[, IPM_or_MEM] == "S") +
              (x[, CIP] == "S") == 1),
      "MDRO"] <- 2 # 2 = 3MRGN, if only 1 group is S
    
    x[which((x$fullname %like% "^Pseudomonas aeruginosa") &
              x[, PIP] == "R" &
              x[, CTX_or_CAZ] == "R" &
              x[, IPM_or_MEM] == "R" &
              x[, CIP] == "R"),
      "MDRO"] <- 3 # 3 = 4MRGN
  }
  
  if (guideline$code == "brmo") {
    # Netherlands -------------------------------------------------------------
    aminoglycosides <- aminoglycosides[!is.na(aminoglycosides)]
    fluoroquinolones <- fluoroquinolones[!is.na(fluoroquinolones)]
    carbapenems <- carbapenems[!is.na(carbapenems)]
    amino <- AMX %or% AMP
    third <- CAZ %or% CTX
    ESBLs <- c(amino, third)
    ESBLs <- ESBLs[!is.na(ESBLs)]
    if (length(ESBLs) != 2) {
      ESBLs <- character(0)
    }
    
    # Table 1
    trans_tbl(3,
              which(x$order == "Enterobacterales"), # following in fact the old Enterobacteriaceae classification
              c(aminoglycosides, fluoroquinolones),
              "all")
    
    trans_tbl(2,
              which(x$order == "Enterobacterales"), # following in fact the old Enterobacteriaceae classification
              carbapenems,
              "any")
    
    trans_tbl(2,
              which(x$order == "Enterobacterales"), # following in fact the old Enterobacteriaceae classification
              ESBLs,
              "all")
    
    # Table 2
    trans_tbl(2,
              which(x$genus == "Acinetobacter"),
              c(carbapenems),
              "any")
    trans_tbl(3,
              which(x$genus == "Acinetobacter"),
              c(aminoglycosides, fluoroquinolones),
              "all")
    
    trans_tbl(3,
              which(x$fullname %like% "^Stenotrophomonas maltophilia"),
              SXT,
              "all")
    
    if (!ab_missing(MEM) & !ab_missing(IPM)
        & !ab_missing(GEN) & !ab_missing(TOB)
        & !ab_missing(CIP)
        & !ab_missing(CAZ)
        & !ab_missing(TZP)) {
      x$psae <- 0
      x[which(x[, MEM] == "R" | x[, IPM] == "R"), "psae"] <- 1 + x[which(x[, MEM] == "R" | x[, IPM] == "R"), "psae"]
      x[which(x[, GEN] == "R" & x[, TOB] == "R"), "psae"] <- 1 + x[which(x[, GEN] == "R" & x[, TOB] == "R"), "psae"]
      x[which(x[, CIP] == "R"), "psae"] <- 1 + x[which(x[, CIP] == "R"), "psae"]
      x[which(x[, CAZ] == "R"), "psae"] <- 1 + x[which(x[, CAZ] == "R"), "psae"]
      x[which(x[, TZP] == "R"), "psae"] <- 1 + x[which(x[, TZP] == "R"), "psae"]
    } else {
      x$psae <- 0
    }
    x[which(
      x$fullname %like% "Pseudomonas aeruginosa"
      & x$psae >= 3
    ), "MDRO"] <- 3
    
    # Table 3
    trans_tbl(3,
              which(x$fullname %like% "Streptococcus pneumoniae"),
              PEN,
              "all")
    trans_tbl(3,
              which(x$fullname %like% "Streptococcus pneumoniae"),
              VAN,
              "all")
    trans_tbl(3,
              which(x$fullname %like% "Enterococcus faecium"),
              c(PEN, VAN),
              "all")
  }
  
  prepare_drug <- function(ab) {
    # returns vector values of drug
    # if `ab` is a column name, looks up the values in `x`
    if (length(ab) == 1 & is.character(ab)) {
      if (ab %in% colnames(x)) {
        ab <- as.data.frame(x)[, ab]
      }
    }
    ab <- as.character(as.rsi(ab))
    ab[is.na(ab)] <- ""
    ab
  }
  drug_is_R <- function(ab) {
    # returns logical vector
    ab <- prepare_drug(ab)
    if (length(ab) == 1) {
      rep(ab, NROW(x)) == "R"
    } else {
      ab == "R"
    }
  }
  drug_is_not_R <- function(ab) {
    # returns logical vector
    ab <- prepare_drug(ab)
    if (length(ab) == 1) {
      rep(ab, NROW(x)) != "R"
    } else {
      ab != "R"
    }
  }
  
  if (guideline$code == "tb") {
    # Tuberculosis ------------------------------------------------------------
    x <- x %>%
      mutate(mono_count = 0,
             mono_count = ifelse(drug_is_R(INH), mono_count + 1, mono_count),
             mono_count = ifelse(drug_is_R(RIF), mono_count + 1, mono_count),
             mono_count = ifelse(drug_is_R(ETH), mono_count + 1, mono_count),
             mono_count = ifelse(drug_is_R(PZA), mono_count + 1, mono_count),
             mono_count = ifelse(drug_is_R(RIB), mono_count + 1, mono_count),
             mono_count = ifelse(drug_is_R(RFP), mono_count + 1, mono_count),
             # from here on logicals
             mono = mono_count > 0,
             poly = ifelse(mono_count > 1 & drug_is_not_R(RIF) & drug_is_not_R(INH),
                           TRUE, FALSE),
             mdr = ifelse(drug_is_R(RIF) & drug_is_R(INH),
                          TRUE, FALSE),
             xdr = ifelse(drug_is_R(LVX) | drug_is_R(MFX) | drug_is_R(GAT),
                          TRUE, FALSE),
             second = ifelse(drug_is_R(CAP) | drug_is_R(KAN) | drug_is_R(AMK),
                             TRUE, FALSE),
             xdr = ifelse(mdr & xdr & second, TRUE, FALSE)) %>%
      mutate(MDRO = case_when(xdr ~ 5,
                              mdr ~ 4,
                              poly ~ 3,
                              mono ~ 2,
                              TRUE ~ 1),
             # keep all real TB, make other species NA
             MDRO = ifelse(x$fullname == "Mycobacterium tuberculosis", MDRO, NA_real_))
  }
  
  if (info == TRUE) {
    cat(bold(paste0("=> Found ", sum(x$MDRO %in% c(2:5), na.rm = TRUE), " MDROs out of ", sum(!is.na(x$MDRO)), 
                    " tested isolates (", percentage(sum(x$MDRO %in% c(2:5), na.rm = TRUE) / sum(!is.na(x$MDRO))), ")\n")))
  }
  
  # some more info on negative results
  if (verbose == TRUE ) {
    if (guideline$code == "cmi2012") {
        x[which(x$MDRO == 1 & !is.na(x$classes_affected)), "reason"] <- paste0(x$classes_affected[which(x$MDRO == 1 & !is.na(x$classes_affected))], " of ", x$classes_available[which(x$MDRO == 1 & !is.na(x$classes_affected))], " available classes contain R or I (3 required for MDR)")
    } else {
      x[which(x$MDRO == 1), "reason"] <- "too few antibiotics are R"
    }
  }
  
  # Results ----
  if (guideline$code == "cmi2012") {
    if (any(x$MDRO == -1, na.rm = TRUE)) {
      warning("NA introduced for isolates where the available percentage of antimicrobial classes was below ",
              percentage(pct_required_classes), " (set with `pct_required_classes`)")
      # set these -1s to NA
      x[which(x$MDRO == -1), "MDRO"] <- NA_integer_
    }
    x$MDRO <- factor(x = x$MDRO,
                     levels = 1:4,
                     labels = c("Negative", "Multi-drug-resistant (MDR)", 
                                "Extensively drug-resistant (XDR)", "Pandrug-resistant (PDR)"),
                     ordered = TRUE)
  } else if (guideline$code == "tb") {
    x$MDRO <- factor(x = x$MDRO,
                     levels = 1:5,
                     labels = c("Negative", "Mono-resistant", "Poly-resistant", 
                                "Multi-drug-resistant", "Extensively drug-resistant"),
                     ordered = TRUE)
  } else if (guideline$code == "mrgn") {
    x$MDRO <- factor(x = x$MDRO,
                     levels = 1:3,
                     labels = c("Negative", "3MRGN", "4MRGN"),
                     ordered = TRUE)
  } else {
    x$MDRO <- factor(x = x$MDRO,
                     levels = 1:3,
                     labels = c("Negative", "Positive, unconfirmed", "Positive"),
                     ordered = TRUE)
  }
  
  if (verbose == TRUE) {
    x[, c("row_number",
          col_mo,
          "MDRO",
          "reason",
          "columns_nonsusceptible")]
    #x
  } else {
    x$MDRO
  }
  
}

#' @rdname mdro
#' @export
brmo <- function(x, guideline = "BRMO", ...) {
  mdro(x, guideline = "BRMO", ...)
}

#' @rdname mdro
#' @export
mrgn <- function(x, guideline = "MRGN", ...) {
  mdro(x = x, guideline = "MRGN", ...)
}

#' @rdname mdro
#' @export
mdr_tb <- function(x, guideline = "TB", ...) {
  mdro(x = x, guideline = "TB", ...)
}

#' @rdname mdro
#' @export
mdr_cmi2012 <- function(x, guideline = "CMI2012", ...) {
  mdro(x = x, guideline = "CMI2012", ...)
}


#' @rdname mdro
#' @export
eucast_exceptional_phenotypes <- function(x, guideline = "EUCAST", ...) {
  mdro(x = x, guideline = "EUCAST", ...)
}